Prevpac

Proton-pump inhibitor (PPI) combinations for the treatment of Helicobacter pylori

Oral Administration

Administer lansoprazole; amoxicillin; clarithromycin doses before eating, once in the morning and evening.
Instruct patients to swallow each pill whole.

Severe

GI bleeding / Delayed / 0-1.0
bezoar / Delayed / 0-1.0
esophageal ulceration / Delayed / 0-1.0
hematemesis / Delayed / 0-1.0
pulmonary embolism / Delayed / 0-1.0
atrial fibrillation / Early / 0-1.0
stroke / Early / 0-1.0
cardiac arrest / Early / 0-1.0
bradycardia / Rapid / 0-1.0
myocardial infarction / Delayed / 0-1.0
seizures / Delayed / 0-1.0
hearing loss / Delayed / 0-1.0
visual impairment / Early / 0-1.0
pancreatitis / Delayed / 0-1.0
anaphylactic shock / Rapid / 1.0
anaphylactoid reactions / Rapid / 1.0
pancytopenia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
hyperkalemia / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
serum sickness / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
renal failure / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
C. difficile-associated diarrhea / Delayed / Incidence not known
torsade de pointes / Rapid / Incidence not known
ventricular tachycardia / Early / Incidence not known
bone fractures / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known

Moderate

stomatitis / Delayed / 0-3.0
glossitis / Early / 0-3.0
candidiasis / Delayed / 0-3.0
vaginitis / Delayed / 0-3.0
confusion / Early / 0-3.0
thrombocytopenia / Delayed / 0-1.0
lymphadenopathy / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
hemolysis / Early / 0-1.0
eosinophilia / Delayed / 0-1.0
anemia / Delayed / 0-1.0
neutropenia / Delayed / 0-1.0
dysphagia / Delayed / 0-1.0
cholelithiasis / Delayed / 0-1.0
gastritis / Delayed / 0-1.0
esophagitis / Delayed / 0-1.0
melena / Delayed / 0-1.0
oral ulceration / Delayed / 0-1.0
constipation / Delayed / 1.0-1.0
edema / Delayed / 0-1.0
chest pain (unspecified) / Early / 0-1.0
contact dermatitis / Delayed / 0-1.0
bullous rash / Early / 0-1.0
peripheral edema / Delayed / 0-1.0
hypoglycemia / Early / 0-1.0
hyperglycemia / Delayed / 0-1.0
dehydration / Delayed / 0-1.0
gout / Delayed / 0-1.0
migraine / Early / 0-1.0
sinus tachycardia / Rapid / 0-1.0
palpitations / Early / 0-1.0
hypertension / Early / 0-1.0
peripheral vasodilation / Rapid / 0-1.0
hypotension / Rapid / 0-1.0
angina / Early / 0-1.0
myopathy / Delayed / 0-1.0
synovitis / Delayed / 0-1.0
dyskinesia / Delayed / 0-1.0
hypertonia / Delayed / 0-1.0
hyperesthesia / Delayed / 0-1.0
depression / Delayed / 0-1.0
amnesia / Delayed / 0-1.0
hallucinations / Early / 0-1.0
hostility / Early / 0-1.0
goiter / Delayed / 0-1.0
diabetes mellitus / Delayed / 0-1.0
hypothyroidism / Delayed / 0-1.0
cataracts / Delayed / 0-1.0
blurred vision / Early / 0-1.0
amblyopia / Delayed / 0-1.0
photophobia / Early / 0-1.0
blepharitis / Early / 0-1.0
conjunctivitis / Delayed / 0-1.0
hyperbilirubinemia / Delayed / 0-1.0
hepatitis / Delayed / 0-1.0
cholestasis / Delayed / 0-1.0
bleeding / Early / Incidence not known
colitis / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
crystalluria / Delayed / Incidence not known
dysuria / Early / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
urethral pain / Early / Incidence not known
urinary retention / Early / Incidence not known
glycosuria / Early / Incidence not known
hematuria / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known
pyuria / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
dyspnea / Early / Incidence not known
superinfection / Delayed / Incidence not known
pseudomembranous colitis / Delayed / Incidence not known
pernicious anemia / Delayed / Incidence not known
vitamin B12 deficiency / Delayed / Incidence not known
hypomagnesemia / Delayed / Incidence not known
QT prolongation / Rapid / Incidence not known
myasthenia / Delayed / Incidence not known
mania / Early / Incidence not known
psychosis / Early / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
jaundice / Delayed / Incidence not known

Mild

diarrhea / Early / 7.0-7.0
headache / Early / 6.0-6.0
dysgeusia / Early / 5.0-5.0
abdominal pain / Early / 0-3.0
tongue discoloration / Delayed / 0-3.0
xerostomia / Early / 0-3.0
vomiting / Early / 0-3.0
nausea / Early / 0-3.0
myalgia / Early / 0-3.0
dizziness / Early / 0-3.0
tenesmus / Delayed / 0-1.0
hypersalivation / Early / 0-1.0
anorexia / Delayed / 0-1.0
eructation / Early / 0-1.0
appetite stimulation / Delayed / 0-1.0
flatulence / Early / 0-1.0
gastroesophageal reflux / Delayed / 0-1.0
fever / Early / 0-1.0
malaise / Early / 0-1.0
chills / Rapid / 0-1.0
back pain / Delayed / 0-1.0
asthenia / Delayed / 0-1.0
halitosis / Early / 0-1.0
pelvic pain / Delayed / 0-1.0
fatigue / Early / 0-1.0
alopecia / Delayed / 0-1.0
xerosis / Delayed / 0-1.0
pruritus / Rapid / 0-1.0
hyperhidrosis / Delayed / 0-1.0
maculopapular rash / Early / 0-1.0
acne vulgaris / Delayed / 0-1.0
weight loss / Delayed / 0-1.0
weight gain / Delayed / 0-1.0
syncope / Early / 0-1.0
tooth discoloration / Delayed / 0-1.0
ptosis / Delayed / 0-1.0
muscle cramps / Delayed / 0-1.0
arthralgia / Delayed / 0-1.0
musculoskeletal pain / Early / 0-1.0
paresthesias / Delayed / 0-1.0
diplopia / Early / 0-1.0
parosmia / Delayed / 0-1.0
vertigo / Early / 0-1.0
libido decrease / Delayed / 0-1.0
anxiety / Delayed / 0-1.0
tremor / Early / 0-1.0
libido increase / Delayed / 0-1.0
drowsiness / Early / 0-1.0
agitation / Early / 0-1.0
emotional lability / Early / 0-1.0
hyperkinesis / Delayed / 0-1.0
xerophthalmia / Early / 0-1.0
ocular pain / Early / 0-1.0
tinnitus / Delayed / 0-1.0
dyspepsia / Early / 1.0
rash / Early / 1.0
insomnia / Early / 1.0
gastric polyps / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
purpura / Delayed / Incidence not known
dysmenorrhea / Delayed / Incidence not known
increased urinary frequency / Early / Incidence not known
leukorrhea / Delayed / Incidence not known
menorrhagia / Delayed / Incidence not known
polyuria / Early / Incidence not known
urinary urgency / Early / Incidence not known
testicular pain / Early / Incidence not known
sinusitis / Delayed / Incidence not known
infection / Delayed / Incidence not known
rhinitis / Early / Incidence not known
cough / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
hiccups / Early / Incidence not known
epistaxis / Delayed / Incidence not known
hyperactivity / Early / Incidence not known
anosmia / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known

Prevpac

Rx

A triple-drug regimen pack containing an aminopenicillin (amoxicillin), a macrolide (clarithromycin), and a PPI (lansoprazole)
Used for the eradication of H. pylori in adults
Triple-drug regimens are usually recommended by the American College of Gastroenterology (ACG) guidelines for managing H. pylori infection

For Helicobacter pylori (H. pylori) eradication. Oral dosage Adults

30 mg lansoprazole PO, 1,000 mg amoxicillin PO, and 500 mg clarithromycin PO twice daily for 10 days. Guidelines recommend 14 days of treatment and this triple therapy regimen in patients without previous macrolide exposure in regions where clarithromycin resistance is less than 15%.

Hepatic Impairment

Dosage or interval adjustments of the clarithromycin component may be necessary in patients with hepatic impairment who also have concomitant significant renal impairment. However, no dosage adjustment is necessary in patients with normal renal function.

Renal Impairment

CrCl 30 mL/minute or greater: no dosage adjustment needed.
CrCl less than 30 mL/minute: Prevpac is not recommended due to the fixed dosages within the packaging; both amoxicillin and clarithromycin require dose and/or interval adjustments for significant renal impairment.

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation, such as clarithromycin.
Abemaciclib: (Major) If coadministration with clarithromycin is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If clarithromycin is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of clarithromycin. Abemaciclib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with clarithromycin increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and clarithromycin; significantly increased acalabrutinib exposure may occur. If short-term clarithromycin use is unavoidable, interrupt acalabrutinib therapy. Wait at least 24 hours after clarithromycin has been discontinued before resuming acalabrutinib at the previous dosage. Acalabrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib capsules and proton pump inhibitors (PPI), such as lansoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider onsider using the acalabrutinib tablet formlation or use an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib capsules and antacids by at least 2 hours; give acalabrutinib capsules 2 hours before a H2-blocker. Acalabrutinib capsule solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib capsules were coadministered with another PPI for 5 days.
Acarbose: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid coadministration of clarithromycin with adagrasib due to the potential for increased exposure to adagrasib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation) and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure. Adagrasib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of clarithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until clarithromycin has cleared from the circulation (approximately 3 half-lives of clarithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; clarithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of clarithromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of clarithromycin. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Alendronate: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Alendronate; Cholecalciferol: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Alfentanil: (Moderate) Use together with caution. Alfentanil is metabolized by the CYP3A4 isoenzyme. Clarithromycin is an inhibitor of CYP3A4 may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Postmarketing reports of interactions with concomitant use have been noted.
Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with clarithromycin due to the potential for serious/life-threatening reactions, including hypotension. Additive effects on the QT interval may also occur. Alfuzosin is a CYP3A4 substrate that may prolong the QT interval in a dose-dependent manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with clarithromycin is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and clarithromycin should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Alogliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Alogliptin; Pioglitazone: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Alosetron: (Moderate) Concomitant use of alosetron with clarithromycin may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; clarithromycin is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alpha-glucosidase Inhibitors: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Alprazolam: (Contraindicated) Coadministration of clarithromycin and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with clarithromycin, as these benzodiazepines are not oxidatively metabolized. There have been postmarketing reports of central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin. Alprazolam is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Amiodarone: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration of amiodarone and clarithromycin. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with clarithromycin. Amisulpride causes dose- and concentration- dependent QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Atorvastatin: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Amlodipine; Benazepril: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Celecoxib: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Olmesartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Valsartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Amobarbital: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Amphetamine: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Amphetamine; Dextroamphetamine Salts: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Amphetamine; Dextroamphetamine: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Ampicillin: (Major) Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
Ampicillin; Sulbactam: (Major) Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include clarithromycin.
Apalutamide: (Major) Avoid coadministration of lansoprazole with apalutamide due to decreased lansoprazole exposure. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. (Major) Consider alternatives to clarithromycin if treatment with apalutamide is necessary. Clarithromycin is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Exposure to apalutamide may also be increased. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
Apixaban: (Moderate) Pharmacokinetic data suggest that no dose adjustment is necessary if apixaban is coadministered with clarithromycin. However, because clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, there is a potential for increased apixaban exposure and increased risk of bleeding with concurrent use of clarithromycin. Monitor patients closely if coadministration is necessary. When combined with other P-gp and strong CYP3A4 inhibitors, the manufacturer recommends reducing the apixaban dose by 50% and avoiding concomitant administration if patients are already receiving 2.5 mg twice daily.
Apomorphine: (Major) Avoid coadministration of clarithromycin with apomorphine when possible. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of clarithromycin with aprepitant due to substantially increased exposure of aprepitant; increased clarithromycin exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in clarithromycin- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Clarithromycin is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Clarithromycin is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Minor) Use caution if lansoprazole and aprepitant, fosaprepitant are used concurrently and monitor for an increase in lansoprazole-related adverse effects for several days after administration of a multi-day aprepitant regimen. Lansoprazole is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of lansoprazole. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Concomitant use of aripiprazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Major) Concomitant use of aripiprazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation.
Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as clarithromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with QT prolongation and TdP. QT prolongation, TdP, and complete atrioventricular block have also been reported with the administration of arsenic trioxide.
Artemether; Lumefantrine: (Major) Concurrent use of artemether; lumefantrine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if clarithromycin must be used with or after artemether; lumefantrine treatment. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Artemether; lumefantrine is also associated with a possible risk for QT prolongation and TdP. In addition, clarithromycin is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with clarithromycin is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with clarithromycin increased asciminib exposure by 36%.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Aspirin, ASA: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Carisoprodol: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Dipyridamole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Atazanavir: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC).
Atazanavir; Cobicistat: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC). (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Atenolol; Chlorthalidone: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Atogepant: (Major) Avoid use of atogepant and clarithromycin when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with clarithromycin. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3; clarithromycin is a strong CYP3A inhibitor and an OATP1B1/3 inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of atomoxetine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of clarithromycin is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects.
Avapritinib: (Major) Avoid coadministration of avapritinib with clarithromycin due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4/5 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Azilsartan; Chlorthalidone: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of clarithromycin could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
Barbiturates: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with a proton pump inhibitor (PPI). Concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with other PPIs has decreased belumosudil exposure by 47% to 80% in healthy subjects.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with clarithromycin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of clarithromycin in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking clarithromycin. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Clarithromycin is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving clarithromycin. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving clarithromycin. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; clarithromycin inhibits P-gp.
Bexarotene: (Major) Coadministration of bexarotene and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Bisacodyl: (Minor) The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Bortezomib: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
Bosentan: (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored.
Bosutinib: (Major) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered a

fter 5 days of a strong CYP3A4 inhibitor. (Major) Concomitant use of bosutinib and lansoprazole resulted in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours. Bosutinib displays pH-dependent aqueous solubility. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 46% and 26%, respectively, following a single oral dose of bosutinib 400 mg administered after multiple oral doses of lansoprazole 60 mg.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level. Similar precautions apply to combination products containing clarithromycin such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
Brigatinib: (Major) Avoid coadministration of brigatinib with clarithromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of clarithromycin, resume the brigatinib dose that was tolerated prior to initiation of clarithromycin. Brigatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Brincidofovir: (Moderate) Postpone the administration of clarithromycin for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and clarithromycin is necessary. Brincidofovir is an OATP1B1/3 substrate and clarithromycin is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with clarithromycin ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; clarithromycin is a strong inhibitor of CYP3A4.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Minor) Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Bumetanide: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and loop diuretic use due to risk for hypomagnesemia.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Buspirone: (Moderate) Concomitant administration of clarithromycin with buspirone may result in increases in buspirone AUC; the mechanism is probably reduced buspirone metabolism via CYP3A4. A low dose of buspirone is recommended if administered with significant CYP3A4 inhibitors. Subsequent dose adjustments should be based on clinical assessment.
Butabarbital: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Butalbital; Acetaminophen: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and clarithromycin due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with clarithromycin 2 to 3 days after discontinuation of clarithromycin. Cabozantinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Caffeine; Sodium Benzoate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Canagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Capecitabine: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with clarithromycin is necessary. Capmatinib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Carbamazepine: (Major) Coadministration of carbamazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Drugs known to inhibit CYP3A4, such as clarithromycin, may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations. Serum carbamazepine concentrations should be monitored closely during coadministration; reduce carbamazepine doses may be necessary. Clarithromycin also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10, 11- epoxide, which may be more hepatotoxic than the parent drug. Several case reports have documented that clarithromycin can significantly decrease carbamazepine clearance, producing increases in the serum concentration of carbamazepine. Carbamazepine concentrations increased from 12 mcg/ml to 19.1 mcg/ml in a 17-year-old boy after 2 days of clarithromycin 250 mg PO bid. Patients should be monitored for carbamazepine toxicity if clarithromycin is added. Carbamazepine toxicity may be avoided if clarithromycin therapy is begun first and stabilized prior to beginning carbamazepine therapy, however, carbamazepine dosages may need to be increased if clarithromycin is subsequently discontinued. (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Carbamazepine induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If carbamazepine and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Cardiac glycosides: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as clarithromycin, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
Cefpodoxime: (Moderate) Cefpodoxime proxetil requires a low gastric pH for dissolution; therefore, concurrent administration with medications that increase gastric pH, such as proton pump inhibitors (PPIs) may decrease the bioavailability of cefpodoxime. When cefpodoxime was administered with high doses of antacids and H2-blockers, peak plasma concentrations were reduced by 24% and 42% and the extent of absorption was reduced by 27% and 32%, respectively. The rate of absorption is not affected.
Cefuroxime: (Major) Avoid the concomitant use of proton pump inhibitors (PPIs) and cefuroxime. Drugs that reduce gastric acidity, such as PPIs, can interfere with the oral absorption of cefuroxime axetil and may result in reduced antibiotic efficacy.
Cenobamate: (Major) Consider alternatives to clarithromycin if treatment with cenobamate is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of clarithromycin with ceritinib due to the additive risk of QT prolongation and increased ceritinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, further dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After clarithromycin is discontinued, resume the dose of ceritinib taken prior to initiating clarithromycin. Ceritinib is a CYP3A substrate associated with concentration-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Amitriptyline: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chloroquine: (Major) Avoid coadministration of chloroquine with clarithromycin due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Chlorothiazide: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Concurrent use of chlorpromazine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both clarithromycin and chlorpromazine are specifically associated with an established risk of QT prolongation and TdP.
Chlorpropamide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Chlorthalidone: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Chlorthalidone; Clonidine: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with clarithromycin. Monitor for an increase in cilostazol-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of clarithromycin and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Major) Concomitant use of clarithromycin and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Postmarketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Because of the potential severity of these drug interactions (increased plasma cisapride concentrations and QT prolongation), cisapride use is contraindicated with clarithromycin which inhibits the CYP3A4 isoenzyme.
Citalopram: (Major) Concomitant use of citalopram and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of clarithromycin as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4.
Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of lansoprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and lansoprazole is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
Clofazimine: (Major) Concomitant use of clofazimine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Use clarithromycin cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Clarithromycin is a CYP3A4 inhibitor.
Clorazepate: (Moderate) CYP3A4 inhibitors may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Clozapine: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Codeine; Promethazine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and clarithromycin in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Clarithromycin can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken clarithromycin in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Conivaptan: (Contraindicated) Coadministration of conivaptan and clarithromycin is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and clarithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of clarithromycin and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; QT prolongation and torsade de pointes (TdP) may also occur. If concomitant use is necessary for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of clarithromycin. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclosporine: (Major) Clarithromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Clarithromycin may also reduce the intestinal metabolism of cyclosporine. It has been recommended to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolides concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
Cysteamine: (Major) Monitor white blood cell (WBC) cystine concentration closely when administering delayed-release cysteamine (Procysbi) with proton pump inhibitors (PPIs). Drugs that increase the gastric pH may cause the premature release of cysteamine from delayed-release capsules, leading to an increase in WBC cystine concentration. Concomitant administration of omeprazole 20 mg did not alter the pharmacokinetics of delayed-release cysteamine when administered with orange juice; however, the effect of omeprazole on the pharmacokinetics of delayed-release cysteamine when administered with water have not been studied.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with clarithromycin, a P-gp inhibitor. Although the coadministration of dabigatran and clarithromycin has no effect on the pharmacokinetics of dabigatran or clarithromycin in healthy subjects, patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like clarithromycin in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with clarithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dabrafenib: (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and clarithromycin, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of clarithromycin efficacy.
Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as clarithromycin. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
Dacomitinib: (Major) Avoid coadministration of lansoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
Dapagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Dapagliflozin; Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended.
Daridorexant: (Major) Avoid concomitant use of daridorexant and clarithromycin. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir: (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Darunavir; Cobicistat: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Dasatinib: (Major) Avoid coadministration of dasatinib and clarithromycin due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to clarithromycin with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of clarithromycin in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue clarithromycin or stop dasatinib until clarithromycin is discontinued. Allow a washout of approximately 1 week after clarithromycin is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively. (Major) Do not administer proton pump inhibitors with dasatinib due to the potential for decreased dasatinib exposure and reduced efficacy. Consider using an antacid if acid suppression therapy is needed. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Concurrent use of an proton pump inhibitor reduced the mean Cmax and AUC of dasatinib by 42% and 43%, respectively.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with clarithromycin. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Major) Avoid coadministration of clarithromycin with degarelix. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Because proton pump inhibitors (PPIs) increase gastric pH, decreased delavirdine absorption may occur. However, since these agents affect gastric pH for an extended period, separation of doses may not eliminate the interaction. Chronic use of PPIs with delavirdine is not recommended. (Major) In a study involving 6 HIV-1-infected patients, coadministration of delavirdine 300 mg 3 times daily with clarithromycin 500 mg twice daily resulted in no significant change in delavirdine pharmacokinetics. However, for patients with renal dysfunction, dosage adjustment of clarithromycin is required during concurrent delavirdine treatment due to decreased clarithromycin elimination. The dose of clarithromycin should be reduced by 50% for patients with a creatinine clearance of 30 to 60 ml/min and for patients with a creatinine clearance of < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Desogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciproflo xacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Deutetrabenazine: (Major) Avoid coadministration of clarithromycin with deutetrabenazine. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of clarithromycin with dexamethasone is necessary, due to increased dexamethasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A inhibitors, especially for long-term use. Dexamethasone is primarily metabolized by CYP3A and clarithromycin is a strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextroamphetamine: (Moderate) Use amphetamine; dextroamphetamine and proton pump inhibitors concomitantly with caution. Gastrointestinal alkalinizing agents may increase exposure to amphetamine; dextroamphetamine and exacerbate its actions.
Dextromethorphan; Quinidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Quinidine (including dextromethorphan; quinidine) and disopyramide are also associated with QT prolongation and TdP. There have been post-marketing reports of TdP occurring with the coadministration of clarithromycin and quinidine or disopyramide. If used concomitantly, monitor ECGs for QT prolongation and consider monitoring serum concentrations of quinidine or disopyramide.
Diazepam: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam.
Dichlorphenamide: (Moderate) Use dichlorphenamide and amoxicillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including amoxicillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Digoxin: (Moderate) Lansoprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement. (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with clarithromycin is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Diltiazem: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Disopyramide: (Major) Concurrent administration of clarithromycin and disopyramide has been associated with post-marketing reports of torsades de pointes (TdP) and hypoglycemia. If these drugs are administered together, closely monitor ECGs for QT prolongation, blood glucose concentrations, and consider monitoring disopyramide serum concentrations. Both clarithromycin and disopyramide have been associated with an established risk for QT prolongation and TdP.
Docetaxel: (Major) Avoid coadministration of docetaxel with clarithromycin if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Coadministration of dofetilide and clarithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
Dolasetron: (Contraindicated) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin should be used cautiously with other agents known to cause QT prolongation. Agents with potential to prolong the QT interval include: dolasetron.
Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Doravirine: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like clarithromycin, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
Doxorubicin Liposomal: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Major) Use caution if coadministration of dronabinol with clarithromycin is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Concomitant use of dronedarone with clarithromycin is contraindicated. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Lansoprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include clarithromycin.
Drospirenone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Estetrol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Dulaglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of clarithromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as clarithromycin, should be avoided.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with clarithromycin. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as clarithromycin.
Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with clarithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of clarithromycin; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Elacestrant: (Major) Avoid concomitant use of elacestrant and clarithromycin due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as clarithromycin is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Clarithromycin significantly inhibits OATP1B1, and also inhibits CYP3A and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. Consider an alternative to clarithromycin in a patient receiving elagolix. (Minor) Coadministration of elagolix with lansoprazole may theoretically increase plasma concentrations of lansoprazole. Monitor for lansoprazole-related adverse effects during coadministration with elagolix. Elagolix is a weak CYP2C19 inhibitor and lansoprazole is a CYP2C19 sensitive substrate.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as clarithromycin is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Clarithromycin significantly inhibits OATP1B1, and also inhibits CYP3A and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. Consider an alternative to clarithromycin in a patient receiving elagolix. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Coadministration of elagolix with lansoprazole may theoretically increase plasma concentrations of lansoprazole. Monitor for lansoprazole-related adverse effects during coadministration with elagolix. Elagolix is a weak CYP2C19 inhibitor and lansoprazole is a CYP2C19 sensitive substrate. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of clarithromycin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of clarithromycin due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with clarithromycin; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; clarithromycin is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with clarithromycin; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); clarithromycin is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of clarithromycin and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both clarithromycin and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and clarithromycin can independently prolong the QT interval, and coadministration increases this risk. Clarithromycin is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors such as clarithromycin increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
Eluxadoline: (Major) Consider a reduction of the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with clarithromycin. Coadministration may increase exposure of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is an OATP1B1 substrate and clarithromycin is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Empagliflozin; Linagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Empagliflozin; Linagliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Empagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Encorafenib: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with clarithromycin is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; clarithromycin is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with clarithromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If clarithromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
Enzalutamide: (Major) Avoid coadministration of enzalutamide with lansoprazole due to decreased plasma concentrations of lansoprazole. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Enzalutamide is a moderate CYP2C19 inducer and a strong CYP3A4 inducer. (Major) Coadministration of enzalutamide and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction; consider alternatives to clarithromycin if treatment with enzalutamide is necessary. Clarithromycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible.
Eplerenone: (Contraindicated) Coadministration of clarithromycin and eplerenone is contraindicated. Clarithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and clarithromycin due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If clarithromycin is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
Ergotamine: (Contraindicated) Concomitant use of ergotamine with clarithromycin is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with clarithromycin is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with eribulin include clarithromycin.
Erlotinib: (Major) Avoid coadministration of erlotinib with clarithromycin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid coadministration of erlotinib with lansoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
Ertugliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Ertugliflozin; Sitagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as clarithromycin, should be done with caution and close monitoring. In addition, escitalopram is metabolized by CYP3A4. Theoretically, clarithromycin may inhibit this enzyme and lead to elevated plasma levels of this SSRI. However, because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
Eslicarbazepine: (Major) Coadministration of eslicarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of lansoprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
Estazolam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Estradiol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrog ens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estradiol; Progesterone: (Moderate) Use caution if coadministration of clarithromycin with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as clarithromycin. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Although other macrolide antibiotics, such as erythromycin, inhibit CYP3A4 to a lesser extent than clarithromycin, a clinically relevant interaction is possible, and dose adjustments of eszopiclone may be necessary.
Ethacrynic Acid: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and loop diuretic use due to risk for hypomagnesemia. (Minor) Ethacrynic acid may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
Etravirine: (Major) Coadministration of etravirine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Everolimus: (Major) Avoid coadministration of everolimus with clarithromycin due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Exenatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Ezetimibe; Simvastatin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Fedratinib: (Major) Avoid coadministration of fedratinib with clarithromycin as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If clarithromycin is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felbamate: (Major) Coadministration of felbamate and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Felodipine: (Major) Avoid coadministration of clarithromycin and felodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving felodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Felodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as lansoprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of lansoprazole during coadministration with fenofibric acid.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If clarithromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with clarithromycin. Avoid use of fesoterodine and clarithromycin in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Finerenone: (Contraindicated) Concomitant use of finerenone and clarithromycin is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include clarithromycin.
Flecainide: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with flecainide. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Contraindicated) Coadministration is contraindicated. Fluconazole has been associated with QT prolongation and clarithromycin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP). Additionally, fluconazole is an inhibitor of CYP3A4 and clarithromycin is a known inhibitor and substrate of CYP3A4. In healthy volunteers, the coadministration of clarithromycin (500 mg orally twice daily) with fluconazole (200 mg once daily) led to increases in clarithromycin mean steady-state Cmin (33%) and AUC (18%); however, mean steady-state concentrations of 14-OH clarithromycin were not affected. The changes appeared to be of minor consequence in healthy subjects. The potential for a more significant interaction between fluconazole and clarithromycin might exist at higher dosages of either drug; caution is advised in such circumstances but should not normally alter therapy. Fluconazole is usually considered a less potent inhibitor of CYP3A4 than other azole-family systemic antifungal agents (e.g., ketoconazole, itraconazole), especially at dosages of < 200 mg/day. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
Fluoxetine: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with fluphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while fluphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Flurazepam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluvastatin: (Moderate) Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and fluvastatin. Use together with caution and monitor for symptoms of myopathy and/or rhabdomyolysis.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and TdP while QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. (Moderate) Fluvoxamine is a major inhibitor of the cytochrome P450 enzyme 2C19. Several proton pump inhibitors, including lansoprazole, are primary substrates of the CYP2C19 enzyme. Reduced metabolism and resulting elevated plasma concentrations of these PPIs may occur if combined with fluvoxamine. Monitor patients for PPI toxicity, such as headache or GI distress if these drugs are combined.
Food: (Major) Administer on an empty stomach, 30 to 60 minutes before meals. If given once daily, administer before the first meal of the day. Antacids were used concomitantly with lansoprazole in clinical trials. (Major) Advise patients to avoid cannabis use during clarithromycin treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and clarithromycin is a strong CYP3A inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Concomitant administration of clarithromycin and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with clarithromycin long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with clarithromycin. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as clarithromycin. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Clarithromycin is also associated with an established risk for QT prolongation and TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Fosphenytoin: (Major) Avoid concomitant use of lansoprazole and fosphenytoin as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. (Major) Coadministration of fosphenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin, which may also occur with fosphenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Fostemsavir: (Major) Avoid coadministration of clarithromycin with fostemsavir. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Furosemide: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and loop diuretic use due to risk for hypomagnesemia. (Minor) Furosemide may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Futibatinib: (Major) Avoid concurrent use of futibatinib and clarithromycin. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; clarithromycin is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Gefitinib: (Major) Avoid coadministration of lansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with gemifloxacin. Clarithromycin is associated with an established risk for QT prolongation and TdP. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and clarithromycin together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Gilteritinib: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with clarithromycin due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and clarithromycin as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3; clarithromycin is an inhibitor of P-gp and OATP1B1/3. (Moderate) Caution is advised with the coadministration of pibrentasvir and clarithromycin as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); clarithromycin is an inhibitor of P-gp.
Glimepiride: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glipizide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glipizide; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glyburide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Glyburide; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Goserelin: (Major) Avoid coadministration of clarithromycin with goserelin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with granisetron. Both granisetron and clarithromycin are associated with prolongation of the QT interval, and clarithromycin has also been associated with an established risk for TdP.
Grapefruit juice: (Minor) Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via cytochrome CYP 3A4 isozyme. Grapefruit juice contains compounds that inhibit CYP3A4 in enterocytes in the GI tract. In a randomized crossover study in healthy volunteers, grapefruit juice did not have a significant affect on the bioavailability of clarithromycin nor did it affect the metabolism of clarithromycin to its active metabolite.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) Clarithromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If clarithromycin is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and clarithromycin is a strong CYP3A4 inhibitor.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Haloperidol: (Major) Concurrent use of clarithromycin and haloperidol should be avoided if possible. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. Because clarithromycin is also associated with an increased risk for QT prolongation and TdP, the need to coadminister clarithromycin with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits. Clarithromycin is an inhibitor of CYP3A4. Elevated haloperidol concentrations occurring through inhibition of CYP3A4 or CYP2D6 may increase the risk of adverse effects, including QT prolongation.
Histrelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocortisone: (Moderate) Clarithromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with clarithromycin. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with lansoprazole, a CYP3A substrate, as lansoprazole toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. (Major) Coadministration of idelalisib with clarithromycin may increase idelalisib exposure; use alternative agents if possible. If concomitant use of these drugs is required, monitor patients frequently for signs and symptoms of idelalisib-related adverse reactions (e.g., hepatotoxicity, diarrhea, neutropenia, and infection). Idelalisib and clarithromycin are both CYP3A4 substrates and strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased idelalisib exposure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with clarithromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of iloperidone and clarithromycin due to the potential for QT prolongation; iloperidone exposure may also increase. If coadministration cannot be avoided, decrease the iloperidone dose by one-half. Resume the prior iloperidone dose if clarithromycin is discontinued. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Iloperidone is a CYP3A4 substrate that has been associated with QT prolongation. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and should be used cautiously with CYP3A4 substrates, such as imatinib, due to the potential for reduced metabolism and drug accumulation.
Incretin Mimetics: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Indinavir: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may decrease the systemic clearance of indinavir, a CYP3A4 substrate. Patients with impaired renal function may require a reduced dosage of clarithromycin.
Indomethacin: (Minor) Indomethacin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
Infigratinib: (Major) Avoid coadministration of infigratinib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease infigratinib exposure resulting in decreased efficacy. If necessary, infigratinib may be administered two hours before or ten hours after an H2-receptor antagonist or two hours before or after a locally acting antacid. Coadministration with a PPI decreased infigratinib exposure by 45%. (Major) Avoid concomitant use of infigratinib and clarithromycin. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with clarithromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Insulin Degludec; Liraglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulin Glargine; Lixisenatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Insulins: (Moderate) The concomitant use of clarithromycin and insulin or other antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Irinotecan Liposomal: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of clarithromycin during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; clarithromycin is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Iron: (Moderate) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with clarithromycin may result in increased serum concentrations of both drugs. Clarithromycin is a substrate and moderate inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together. (Moderate) Concomitant use of isavuconazonium with lansoprazole may result in increased serum concentrations of lansoprazole. Lansoprazole is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of lansoprazole with rifampin due to the risk of decreased lansoprazole plasma concentrations which may decrease efficacy. Lansoprazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Major) Clarithromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. As compared with the plasma concentration obtained with clarithromycin 500 mg twice daily as monotherapy, the clarithromycin plasma concentration was reduced by 87% when rifampin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 0.7 +/- 0.6 mcg/ml when given in combination with rifampin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of lansoprazole with rifampin due to the risk of decreased lansoprazole plasma concentrations which may decrease efficacy. Lansoprazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Major) Clarithromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. As compared with the plasma concentration obtained with clarithromycin 500 mg twice daily as monotherapy, the clarithromycin plasma concentration was reduced by 87% when rifampin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 0.7 +/- 0.6 mcg/ml when given in combination with rifampin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Isradipine: (Major) Avoid coadministration of clarithromycin and isradipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving isradipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Isradipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with clarithromycin as istradefylline exposure and adverse effects may increase. Clarithromycin is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Consider use of azithromycin in place of clarithromycin. Both clarithromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. (Moderate) When administering proton pump inhibitors with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when proton pump inhibitors are administered with the 65 mg itraconazole capsule. Administer proton pump inhibitors at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if proton pump inhibitors are administered with itraconazole 65 mg capsules.
Ivabradine: (Contraindicated) Coadministration of ivabradine and clarithromycin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with clarithromycin due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If clarithromycin is discontinued, wait at least 5 half-lives of clarithromycin before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and clarithromycin due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid use of proton pump inhibitors (PPIs) with ketoconazole. Medications that increase gastric pH may impair oral ketoconazole absorption.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lapatinib: (Major) Avoid coadministration of lapatinib with clarithromycin due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If clarithromycin is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ledipasvir; Sofosbuvir: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
Lefamulin: (Major) Avoid coadministration of lefamulin with clarithromycin as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Clarithromycin is a P-gp and strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and clarithromycin as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and clarithromycin due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
Lesinurad; Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
Letermovir: (Moderate) Administering clarithromycin concurrently with letermovir may result in elevated concentrations of both drugs. The impact on the serum concentration of clarithromycin may be increased in patients receiving letermovir with cyclosporine. Closely monitor for adverse events including tachycardia, atrial fibrillation, gastrointestinal events, dizziness, or confusion. Clarithromycin is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent use with another CYP3A inhibitor increased clarithromycin exposure (AUC) by 94%, and decreased AUC of 14-OH clarithromycin by 70%. (Moderate) Plasma concentrations of lansoprazole could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, monitor for lansoprazole-related adverse events. Lansoprazole is a CYP3A4 substrate. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levamlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Levofloxacin: (Major) Concomitant use of levofloxacin and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid use of proton pump inhibitors (PPIs) with ketoconazole. Medications that increase gastric pH may impair oral ketoconazole absorption.
Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as clarithromycin. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levonorgestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
Linagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Linagliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Liraglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Lithium: (Major) Concomitant use of lithium and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lixisenatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with clarithromycin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Lomitapide: (Contraindicated) Concomitant use of clarithromycin and lomitapide is contraindicated. If treatment with clarithromycin is unavoidable, lomitapide should be stopped during the course of treatment. Markedly increased transaminases have been reported with coadministration. Clarithromycin is a strong CYP3A4 inhibitor and lomitapide is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lomitapide exposure approximately 27-fold.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and clarithromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Loop diuretics: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and loop diuretic use due to risk for hypomagnesemia.
Loperamide: (Major) Concomitant use of loperamide and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A4 and P-gp substrate and clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A4 and P-gp substrate and clarithromycin is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with clarithromycin due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with clarithromycin due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of clarithromycin may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If clarithromycin is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of clarithromycin. Lorlatinib is a CYP3A4 substrate and moderate CYP3A4 inducer. Clarithromycin is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Lovastatin: (Contraindicated) The concurrent use of lovastatin and clarithromycin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of treatment with clarithromycin therapy is available, lovastatin use must be suspended during clarithromycin treatment. Lovastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Luliconazole: (Minor) Theoretically, luliconazole may increase the side effects of lansoprazole, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of lansoprazole, such as electroylyte changes. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 amd CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration if possible; lumacaftor; ivacaftor may decrease the therapeutic efficacy of clarithromycin. If concomitant use is necessary, monitor microbiological activity and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when clarithromycin is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking clarithromycin, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking clarithromycin. Clarithromycin is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Increasing the metabolism of clarithromycin decreases plasma concentrations of clarithromycin, but increases plasma concentrations of 14-OH-clarithromycin (active metabolite); the microbiological activity of each is different for different bacteria. In addition, the inhibitory effects of clarithromycin may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of lansoprazole by substantially decreasing its systemic exposure. If used together, a lansoprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
Lumacaftor; Ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of lansoprazole by substantially decreasing its systemic exposure. If used together, a lansoprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of clarithromycin is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and clarithromycin due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as clarithromycin. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Mafenide: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
Maprotiline: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with maprotiline. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as clarithromycin.
Maraviroc: (Major) Coadministration of maraviroc (a substrate of CYP3A, P-gp, and OATP1B1) with clarithromycin (a strong CYP3A4 inhibitor and P-gp/OATP1B1 inhibitor) may result in increased maraviroc concentrations. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with clarithromycin (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with clarithromycin due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease efficacy of clarithromycin. Mavacamten is a substrate and moderate inducer of CYP3A and clarithromycin is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer.
Mefloquine: (Major) There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as clarithromycin. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp). Clarithromycin is an inhibitor of these enzymes and may decrease the clearance of mefloquine and further increasing the risk for QT prolongation. (Moderate) Proton pump inhibitors (PPIs) may increase plasma concentrations of mefloquine. Patients on chronic mefloquine therapy might be at increased risk of adverse reactions, especially patients with a neurological or psychiatric history.
Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Metformin; Repaglinide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Dosage reduction of repaglinide may be needed. Careful monitoring of glucose is recommended.
Metformin; Rosiglitazone: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Metformin; Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Metformin; Sitagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as clarithromycin, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with clarithromycin, an inhibitor of CYP3A4 and P-gp, may result in increased serum concentrations of methadone.
Methohexital: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Methotrexate: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Methyclothiazide: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Methylergonovine: (Contraindicated) Clarithromycin should not be coadministered with methylergonovine due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). Clarithromycin inhibits the metabolism of ergot alkaloids via inhibition of the CYP3A4 isoenzyme.
Methylprednisolone: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and methylprednisolone have been noted. Clarithromycin is a CYP3A4 inhibitor and may decrease the clearance of methylprednisolone if coadministered.
Metolazone: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Metronidazole: (Major) Concomitant use of metronidazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Major) Dose adjustments of oral midazolam may be necessary when coadministered with clarithromycin. Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as clarithromycin, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and clarithromycin due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Major) Avoid coadministration of mifepristone with clarithromycin due to the risk of additive QT prolongation and torsade de pointes (TdP); the exposure of both drugs may also be increased. If concomitant use of mifepristone is necessary for the treatment of Cushing's syndrome in a patient already receiving clarithromycin, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with clarithromycin is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with clarithromycin is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with clarithromycin is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with clarithromycin is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and clarithromycin are substrates and strong inhibitors of CYP3A4 that are associated with QT prolongation.
Miglitol: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Mirtazapine: (Major) Concomitant use of mirtazapine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of clarithromycin is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with clarithromycin due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Major) Coadministration of mitotane and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. (Moderate) Use caution if mitotane and lansoprazole are used concomitantly, and monitor for decreased efficacy of lansoprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and lansoprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lansoprazole.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and clarithromycin. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Major) Coadministration of modafinil and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin is a significant inhibitor of CYP3A4, which may increase serum concentrations of modafinil.
Mometasone: (Moderate) Concomitant administration of clarithromycin and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with clarithromycin long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Moxifloxacin: (Major) Concurrent use of clarithromycin and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin; therefore, the recommended dose or infusion rate should not be exceeded.
Mycophenolate: (Moderate) Concomitant administration of proton pump inhibitors (PPIs) with mycophenolate mofetil (Cellcept) appears to reduce MPA exposure AUC-12h (25.8 +/- 6.4 mg/L x h with omeprazole vs. 33.3 +/- 11.5 mg//L x h without omeprazole); however, the interaction does not appear to exist with mycophenolate sodium delayed-release tablets (Myfortic). Reduced systemic exposure of MPA after mycophenolate mofetil in the presence of a PPI appears to be due to impaired absorption of mycophenolate mofetil which may occur because of incomplete dissolution of mycophenolate mofetil in the stomach at elevated pH. The clinical significance of reduced MPA exposure is unknown; however patients should be evaluated periodically if mycophenolate mofetil is administered with a PPI. Of note, MPA concentrations appear to be reduced in the initial hours after mycophenolate mofetil receipt but increase later in the dosing interval because of enterohepatic recirculation. A second peak in the concentration-time profile of MPA is observed 612 hours after dosing due to enterohepatic recirculation. For example, the 12-hour plasma concentrations of MPA were similar among patients who received mycophenolate mofetil with or without omeprazole. The biphasic plasma concentration-time course of MPA due to extensive enterohepatic circulation hampers therapeutic drug monitoring of MPA. Drug exposure as measured by AUC-12h is the best estimator for the clinical effectiveness of mycophenolate, but measurement of full-dose interval MPA AUC-12h requires collection of multiple samples over a 12-hour period; MPA predose concentrations correlate poorly with MPA AUC-12h. The interaction does not appear to exist with Mycophenolate sodium (Myfortic). (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with clarithromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; clarithromycin is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as clarithromycin, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with clarithromycin is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor.
Nateglinide: (Moderate) The use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, inhibition of CYP3A by clarithromycin may occur, and dose adjustment of nateglinide may be needed. Careful monitoring of glucose is recommended.
Nelfinavir: (Major) Use of proton pump inhibitors with nelfinavir is not recommended. Coadministration may result in decreased nelfinavir exposure, subtherapeutic antiretroviral activity, and possibility resistant HIV mutations. In one study, concurrent use of nelfinavir with omeprazole resulted in decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%, respectively.
Neratinib: (Major) Avoid concomitant use of clarithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Clarithromycin is partially metabolized by CYP3A4, and increased concentrations may lead to an increased risk for side effects, including QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as clarithromycin can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of sin gle dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Nevirapine: (Major) Avoid coadministration of nevirapine and clarithromycin. Coadministration of nevirapine and clarithromycin significantly decreases clarithromycin serum concentrations. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Additionally, the exposure of nevirapine may also be increased, leading to increased toxicity. Nevirapine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Niacin; Simvastatin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Nicardipine: (Major) Avoid coadministration of clarithromycin and nicardipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nicardipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nicardipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Nifedipine: (Major) Avoid coadministration of clarithromycin and nifedipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nifedipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Nilotinib: (Major) Avoid the concomitant use of nilotinib and clarithromycin; significant prolongation of the QT interval and torsade de pointes (TdP) may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Clarithromycin is associated with an established risk for QT prolongation and TdP. If therapy with clarithromycin is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If clarithromycin is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and clarithromycin is a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Nimodipine: (Major) Avoid coadministration of clarithromycin and nimodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nimodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nimodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as clarithromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Clarithromycin is a moderate P-gp inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with clarithromycin, particularly in geriatric patients, due to increased plasma concentrations of nisoldipine. If the use of a macrolide antibiotic is necessary in a patient receiving nisoldipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and clarithromycin is a CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norethindrone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norgestimate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Octreotide: (Moderate) Coadministration of oral octreotide with proton pump inhibitors (PPIs) may require increased doses of octreotide. Coadministration of oral octreotide with drugs that alter the pH of the upper GI tract, including PPIs, may alter the absorption of octreotide and lead to a reduction in bioavailability. This interaction has been documented with esomeprazole and can occur with the other PPIs.
Ofloxacin: (Major) Concomitant use of ofloxacin and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Olanzapine; Fluoxetine: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Olanzapine; Samidorphan: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Olaparib: (Major) Avoid coadministration of olaparib with clarithromycin due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after clarithromycin is discontinued. Olaparib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and clarithromycin is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and clarithromycin may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If clarithromycin is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Olopatadine; Mometasone: (Moderate) Concomitant administration of clarithromycin and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with clarithromycin long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and clarithromycin. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole; Amoxicillin; Rifabutin: (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
Ondansetron: (Major) Concomitant use of ondansetron and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include clarithromycin.
Oritavancin: (Moderate) Clarithromycin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of clarithromycin may be reduced if these drugs are administered concurrently. (Moderate) Coadministration of oritavancin and lansoprazole may result in increases or decreases in lansoprazole exposure and may increase side effects or decrease efficacy of lansoprazole. Lansoprazole is metabolized by CYP3A4 and CYP2C19. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C19. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
Osilodrostat: (Major) Avoid coadministration of clarithromycin with osilodrostat due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of clarithromycin with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Ospemifene: (Moderate) Coadministration of clarithromycin and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Oxaliplatin: (Major) Avoid coadministration of clarithromycin with oxaliplatin due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
Oxcarbazepine: (Major) Coadministration of oxcarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Serum concentrations of oxybutynin may be increased when administered with inhibitors of the CYP3A4 enzyme system, including clarithromycin.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking clarithromycin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Paclitaxel: (Minor) Paclitaxel is partially metabolized by CYP3A4. The systemic clearance of paclitaxel may be decreased if coadministered with clarithromycin, an inhibitor of CYP3A4.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with clarithromycin is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with clarithromycin 500 mg twice a day for 5 days increased pacritinib exposure by 80%.
Palbociclib: (Major) Avoid coadministration of clarithromycin with palbociclib; significantly increased palbociclib exposure may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If clarithromycin is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of clarithromycin. Palbociclib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clarithromycin. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Palovarotene: (Major) Avoid concomitant use of palovarotene and clarithromycin due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) The co-administration of panobinostat with clarithromycin is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Clarithromycin is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. This interaction may be relevant to combination products containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole (Prevpac) and amoxicillin; clarithromycin; omeprazole (Omeclamox-Pak) triple therapy packs.
Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as clarithromycin. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pasireotide: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Cautious use of pasireotide and clarithromycin is needed, as coadministration may have additive effects on the prolongation of the QT interval.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and clarithromycin have been reported to prolong the QT interval. If pazopanib and clarithromycin must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a substrate for CYP3A4 and P-glycoprotein (P-gp) and weak inhibitor of CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4, an inhibitor of P-gp, and substrate of CYP3A4. Concurrent administration of clarithromycin and pazopanib may result in increased pazopanib and/or clarithromycin concentrations; avoid use of these agents together if possible. If co-administration of pazopanib and clarithromycin is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. (Major) Pazopanib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of pazopanib and proton pump inhibitors (PPIs) that elevate the gastric pH may reduce the bioavailability of pazopanib. In a study of patients with solid tumors, the AUC and Cmax of pazopanib were decreased by approximately 40% when coadministered with esomeprazole. If a drug is needed to raise the gastric pH, consider use of a short-acting antacid; separate antacid and pazopanib dosing by several hours.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and clarithromycin due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If clarithromycin is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of clarithromycin. Pemigatinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Pentamidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with clarithromycin include intravenous pentamidine.
Pentobarbital: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Perampanel: (Moderate) Concurrent use of perampanel with clarithromycin may increase exposure to perampanel and increase plasma concentrations. Clarithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
Perindopril; Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with perphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while perphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with perphenazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while perphenazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Pexidartinib: (Major) Avoid coadministration of pexidartinib with lansoprazole as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. As an alternative to a proton pump inhibitor (PPI), use locally-acting antacids or H2-receptor antagonists. Coadministration of another PPI decreased pexidartinib exposure by 50%. (Major) Avoid concomitant use of pexidartinib and clarithromycin due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease clarithromycin plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If clarithromycin is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of clarithromycin. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; clarithromycin is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Phenobarbital: (Major) There have been spontaneous and/or published reports of interactions between clarithromycin and phenobarbital. Inducers of CYP3A enzymes, such as phenobarbital will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Clinicians should observe patients closely for infection resolution if these drugs are administered concurrently. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) There have been spontaneous and/or published reports of interactions between clarithromycin and phenobarbital. Inducers of CYP3A enzymes, such as phenobarbital will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Clinicians should observe patients closely for infection resolution if these drugs are administered concurrently. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Phenytoin: (Major) Avoid concomitant use of lansoprazole and phenytoin as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A substrate and phenytoin is a strong CYP3A inducer. (Major) Coadministration of phenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Pimavanserin: (Major) Coadministration of pimavanserin and clarithromycin should be avoided if possible. Clarithromycin is associated with a risk for QT prolongation and torsade de pointes (TdP); pimavanserin may also cause QT prolongation. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5. Concurrent use of a strong inhibitor of CYP3A4, such as clarithromycin, is expected to increase pimavanserin exposure. If coadministration cannot be avoided, reduce the pimavanserin dose to 10 mg/day PO and closely monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of macrolide antibiotics with pimozide is contraindicated.
Pioglitazone: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Pioglitazone; Glimepiride: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Pioglitazone; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and clarithromycin due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of clarithromycin use. Resume the previous dose of pirtobrutinib after clarithromycin is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitolisant: (Major) Avoid coadministration of pitolisant with clarithromycin as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of clarithromycin due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Polyethylene Glycol; Electrolytes; Bisacodyl: (Minor) The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
Ponatinib: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking clarithromycin due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and clarithromycin is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Consider use of azithromycin in place of clarithromycin. Both posaconazole and clarithromycin are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of clarithromycin. Further, clarithromycin is an inhibitor of the drug efflux protein, P-glycoprotein, for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and clarithromycin and an increased risk for serious adverse events. Additionally, both drugs have been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. (Major) The concurrent use of posaconazole immediate-release oral suspension and proton pump inhibitors (PPIs) should be avoided, if possible, due to the potential for decreased posaconazole efficacy. If used in combination, closely monitor for breakthrough fungal infections. PPIs increase gastric pH, resulting in decreased posaconazole absorption and lower posaconazole plasma concentrations. When a single 400 mg dose of posaconazole oral suspension was administered with esomeprazole (40 mg PO daily), the mean reductions in Cmax were 46% and the mean reductions in AUC were 32% for posaconazole. The pharmacokinetics of posaconazole delayed-release tablets and oral suspension are not significantly affected by PPIs. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole). Coadministration may result in increased plasma concentration of the PPIs.
Pralsetinib: (Major) Avoid concomitant use of clarithromycin and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and clarithromycin is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Pramlintide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Pravastatin: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively.
Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include clarithromycin.
Primidone: (Major) Coadministration of primidone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. Primidone is metabolized in the liver to produce phenobarbital and PEMA. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Probenecid: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and clarithromycin in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Clarithromycin can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken clarithromycin in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day. (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
Procainamide: (Major) Clarithromycin should be used cautiously with procainamide. Procainamide and clarithromycin are both associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
Prochlorperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Phenothiazines, like prochlorperazine, have been reported to prolong the QT interval, while clarithromycin is associated with an established risk for QT prolongation and TdP.
Progesterone: (Moderate) Use caution if coadministration of clarithromycin with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Quazepam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
Quetiapine: (Major) Avoid concurrent use of quetiapine and clarithromycin due to the potential for additive effects on the QT interval and torsade de pointes (TdP) and the potential for greatly increased quetiapine exposure. Clarithromycin is a potent inhibitor of CYP3A4 that is expected to signficantly reduce metabolism of quetiapine. If administration of clarithromycin is required in a patient taking quetiapine, reduce the quetiapine dose to one sixth of the current dose. Monitor for quetiapine-related side effects. If clarithromycin is discontinued, increase the quetiapine dose by 6-fold. Clarithromycin has an established causal association with QT prolongation and TdP (torsade de pointes). Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Quinidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Quinidine (including dextromethorphan; quinidine) and disopyramide are also associated with QT prolongation and TdP. There have been post-marketing reports of TdP occurring with the coadministration of clarithromycin and quinidine or disopyramide. If used concomitantly, monitor ECGs for QT prolongation and consider monitoring serum concentrations of quinidine or disopyramide.
Quinine: (Major) Concurrent use of quinine with clarithromycin should be avoided due to the risk for QT prolongation and torsade de pointes (TdP). Both quinine and clarithromycin have been associated with prolongation of the QT interval. In addition, because both clarithromycin and quinine are substrates and inhibitors of CYP3A4; coadministration may result in elevated plasma concentration of both drugs, causing an increased risk for adverse events.
Quizartinib: (Major) Avoid concomitant use of clarithromycin with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. Concomitant use may also increase the risk for torsade de pointes (TdP) and QT/QTc prolongation. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quizartinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Ramelteon: (Moderate) Use caution with concurrent use of ramelteon and strong inhibitors of CYP3A4, such as clarithromycin. Because ramelteon is partially metabolized via CYP3A4, an increase in exposure of ramelteon is expected. An increase in ramelteon AUC by approximately 84% and Cmax by 36% was noted when coadministered with a strong CYP3A4 inhibitor (ketoconazole). Similar increases were noted in M-II pharmacokinetics. Patients should be monitored for increased ramelteon side effects. Also use caution with concurrent use of combinations containing clarithromycin, such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Red Yeast Rice: (Contraindicated) Clarithromycin potently inhibits the metabolism of certain HMG Co-A reductase inhibitors ('statins') via the CYP3A4 isoenzyme and increase the risk of myopathy and rhabdomyolysis. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, it should not be used in combination with clarithromycin.
Regorafenib: (Major) Avoid coadministration of regorafenib with clarithromycin due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Relugolix: (Major) Avoid coadministration of clarithromycin with relugolix. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Also, concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. Relugolix therapy may be interrupted for up to 14 days if a short course of clarithromycin is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of clarithromycin with relugolix. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Also, concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. Relugolix therapy may be interrupted for up to 14 days if a short course of clarithromycin is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
Repaglinide: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Dosage reduction of repaglinide may be needed. Careful monitoring of glucose is recommended.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as clarithromycin, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with clarithromycin because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increase in potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; clarithromycin is an inhibitor of OATP1B1 and OATP1B3.
Ribociclib: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with clarithromycin due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib. Ribociclib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that has an established risk for QT prolongation and torsade de pointes (TdP). Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Major) The combination of rifabutin and clarithromycin should be avoided. Clarithromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. The metabolism of rifabutin is inhibited by clarithromycin, possibly through inhibition of CYP3A4. Inhibition of rifabutin metabolism results in significant increases in rifabutin serum concentrations and adverse reactions. Also, rifabutin increases the metabolism of clarithromycin resulting in significant decreases in clarithromycin concentrations thereby reducing the antimicrobial efficacy of clarithromycin. As compared with the plasma concentration obtained with clarithromycin monotherapy, the clarithromycin plasma concentration was reduced by 63% when rifabutin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 2 +/- 1.5 mcg/ml when given in combination with rifabutin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups.
Rifampin: (Major) Avoid coadministration of lansoprazole with rifampin due to the risk of decreased lansoprazole plasma concentrations which may decrease efficacy. Lansoprazole is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. (Major) Clarithromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. As compared with the plasma concentration obtained with clarithromycin 500 mg twice daily as monotherapy, the clarithromycin plasma concentration was reduced by 87% when rifampin 600 mg daily was coadministered. Specifically, as monotherapy, the mean serum clarithromycin concentration was 5.4 +/- 2.1 mcg/ml. The mean serum clarithromycin concentration was 0.7 +/- 0.6 mcg/ml when given in combination with rifampin. The mean serum concentrations of 14-OH clarithromycin were similar between the two groups. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers.
Rifapentine: (Major) Avoid concomitant use of lansoprazole and rifapentine as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with rifapentine is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and clarithromycin is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Rimegepant: (Major) Avoid coadministration of rimegepant with clarithromycin; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; clarithromycin is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with clarithromycin. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risedronate: (Moderate) Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use PPIs in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
Risperidone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with risperidone. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Clarithromycin is associated with an established risk for QT prolongation and TdP. Risperidone has been associated with a possible risk for QT prolongation and/or TdP; however, data are currently lacking to establish causality in association with TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritonavir: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
Rivaroxaban: (Moderate) Pharmacokinetic data suggests coadministration of rivaroxaban with clarithromycin is unlikely to affect bleeding risk. However, coadministration of rivaroxaban with other combined P-gp and strong CYP3A4 inhibitors has resulted in increased rivaroxaban exposure and is not recommended. Educate patients about the signs and symptoms of bleeding if concurrent use of clarithromycin with rivaroxaban is necessary; patients with renal impairment may be at greater risk with this combination.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and clarithromycin, a strong CYP3A4 inhibitor and a P-gp inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, romidepsin has been reported to prolong the QT interval. Clarithromycin may also prolong the QT interval. If romidepsin and the clarithromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
Rosiglitazone: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with clarithromycin. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and clarithromycin is an OATP1B1/3 inhibitor.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with clarithromycin in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of clarithromycin in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily; alternatively, ruxolitinib therapy may be interrupted for the duration of clarithromycin use. Ruxolitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with clarithromycin. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites or could displace other highly protein-bound drugs such as penicillins. An enhanced effect of the displaced drug may occur.
Saquinavir: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and clarithromycin is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as clarithromycin. In addition to the potential for arrhythmias, because saquinavir and clarithromycin are both CYP3A4 inhibitors and substrates, clinically significant increases in the plasma concentrations of both drugs are seen with concurrent use. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (Fortovase and Invirase; 1200mg three times daily) resulted in a 177% increase in saquinavir AUC, a 45% increase in clarithromycin AUC, and a 24% decrease in the clarithromycin 14-OH metabolite AUC. (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended.
Secobarbital: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
Secretin: (Major) Discontinue use of proton pump inhibitors before administering secretin. Patients who are receiving proton pump inhibitors at the time of stimulation testing may be hyperresponsive to secretin stimulation, falsely suggesting gastrinoma. The time required for serum gastrin concentrations to return to baseline after discontinuation of a proton pump inhibitor is specific to the individual drug.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Coadministration of segesterone and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and clarithromycin due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If clarithromycin is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of clarithromycin. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%. (Major) Avoid coadministration of selpercatinib with lansoprazole due to the risk of decreased selpercatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, selpercatinib must be taken with food. Coadministration under fasting conditions with another proton pump inhibitor decreased selpercatinib exposure by 69%; however, concomitant use increased selpercatinib exposure by 2% or less when it was administered with a meal.
Selumetinib: (Major) Avoid coadministration of selumetinib and clarithromycin due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If clarithromycin is discontinued, resume the original selumetinib dose after 3 elimination half-lives of clarithromycin. Selumetinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Semaglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sertraline: (Major) Concomitant use of sertraline and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
SGLT2 Inhibitors: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sildenafil: (Major) Coadministration of clarithromycin is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving clarithromycin. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Clarithromycin is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. Clarithromycin inhibits CYP3A4 and may cause significant increases in silodosin plasma concentrations. Concurrent use is contraindicated.
Simvastatin: (Contraindicated) The concurrent use of clarithromycin and simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis. If no alternative to a short course of clarithromycin therapy is available, simvastatin use must be suspended during clarithromycin treatment. Simvastatin is metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving clarithromycin due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Clarithromycin has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and clarithromycin may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and clarithromycin. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and clarithromycin is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Sitagliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sodium Benzoate; Sodium Phenylacetate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and clarithromycin. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Major) Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. (Moderate) Use caution when administering velpatasvir with clarithromycin. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of P-glycoprotein (P-gp) and CYP3A4. Clarithromycin is a CYP3A4 and P-gp inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and clarithromycin due to the potential for increased voxilaprevir exposure. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3); clarithromycin is an OATP1B1/1B3 inhibitor. (Major) Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. (Moderate) Use caution when administering velpatasvir with clarithromycin. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of P-glycoprotein (P-gp) and CYP3A4. Clarithromycin is a CYP3A4 and P-gp inhibitor.
Solifenacin: (Major) Avoid coadministration of clarithromycin with solifenacin if possible due to the risk of QT prolongation; plasma concentrations of solifenacin may also increase. If concomitant use is unavoidable, do not administer more than than solifenacin 5 mg per day in adults; do not exceed the initial starting dose in pediatric patients. Periodically monitor ECGs and electrolytes; an interruption of clarithromycin therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Solifenacin is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold. Both drugs have been associated with dose- or concentration-dependent QT prolongation, and torsade de pointes (TdP) was reported in postmarketing experience with solifenacin although causality was not determined. (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and clarithromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Clarithromycin is a strong CYP3A4 inhibitor; sonidegib is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Sorafenib: (Major) Avoid coadministration of sorafenib with clarithromycin due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
Sotalol: (Major) Concomitant use of sotalol and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions. (Major) Consider alternatives to clarithromycin if treatment with sotorasib is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Sparsentan: (Major) Avoid concomitant use of sparsentan and clarithromycin. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%. (Major) Avoid concurrent use of sparsentan and proton pump inhibitors (PPIs) due to the risk for decreased sparsentan exposure which may reduce its efficacy. Medications that affect gastric pH may reduce sparsentan absorption.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%. (Moderate) St. John's Wort appears to induce CYP3A4 and may lead to increased systemic clearance of clarithromycin, a CYP3A4 substrate. Additionally, clarithromycin may increase serum concentrations of St. John's Wort due to CYP3A4 inhibition. Postmarketing reports of interactions have been noted.
Stiripentol: (Moderate) Consider a dose reduction of lansoprazole when coadministered with stiripentol. Coadministration may increase plasma concentrations of lansoprazole resulting in an increased risk of adverse reactions. Lansoprazole is a sensitive CYP2C19 substrate. In vitro data predicts inhibition of CYP2C19 by stiripentol potentially resulting in clinically significant interactions.
Sucralfate: (Moderate) Sucralfate has been shown to delay absorption and reduce the bioavailability of lansoprazole by about 17%. Lansoprazole should be taken no less than 30 minutes before sucralfate if these drugs are to be used concomitantly.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if clarithromycin must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If clarithromycin is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfadiazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfasalazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfonamides: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Sulfonylureas: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sunitinib: (Major) Avoid coadministration of clarithromycin with sunitinib due to increased sunitinib exposure as well as the risk of QT prolongation and torsade de pointes (TdP). Sunitinib is a CYP3A4 substrate that can cause QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and TdP. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and clarithromycin is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) A reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended if coadministered with clarithromycin as concurrent use may result in increased tacrolimus exposure and additive QT prolongation. Additional tacrolimus dosage reductions may be required. Despite an initial reduction in tacrolimus dose, a rapid, sharp increase in tacrolimus levels has been reported during coadministration with clarithromycin. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; clarithromycin is a strong CYP3A4 inhibitor. Both tacrolimus and clarithromycin are associated with an established risk of QT prolongation and torsade de pointes (TdP). Use this combination with caution. (Moderate) Tacrolimus is metabolized via the hepatic cytochrome P-450 (CYP) 3A4. Lansoprazole may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations. In addition to being a CYP3A4 substrate, lansoprazole is also a CYP2C19 substrate. Patients who are intermediate or poor CYP2C19 metabolizers as compared to those patients who are efficient CYP2C19 metabolizers may have more dramatic increases in their tacrolimus whole blood concentrations. Increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
Tadalafil: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Talazoparib: (Major) Avoid coadministration of clarithromycin with talazoparib when used for the treatment of breast cancer due to increased talazoparib exposure. If concomitant use is unavoidable, reduce the dose of talazoparib to 0.75 mg PO once daily. If clarithromycin is discontinued, wait at least 3 to 5 half-lives of clarithromycin before increasing the dose of talazoparib to the prior dose used before clarithromycin therapy. A talazoparib dose reduction is not necessary for patients with prostate cancer; monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a P-gp substrate and clarithromycin is a P-gp inhibitor. In clinical trials, coadministration with clarithromycin increased talazoparib exposure by 45%.
Tamoxifen: (Major) Concomitant use of tamoxifen and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of clarithromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as clarithromycin, should be avoided.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as clarithromycin, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with clarithromycin as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with telavancin. Both telavancin and clarithromycin are associated with QT prolongation, while clarithromycin is also associated with an established risk for TdP.
Telmisartan; Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Temsirolimus: (Major) Avoid coadministration of clarithromycin with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of clarithromycin before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
Tenofovir Alafenamide: (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering clarithromycin. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; clarithromycin is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered. (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering lansoprazole. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19; lansoprazole is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Major) Concurrent use of tetrabenazine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tetrabenazine causes a small increase in the corrected QT interval (QTc), while clarithromycin is associated with an established risk for QT prolongation and TdP.
Tetracyclines: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
Tezacaftor; Ivacaftor: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with clarithromycin; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); clarithromycin is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectiv ely.
Theophylline, Aminophylline: (Major) Clarithromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for aminophylline products states that aminophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when aminophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Major) Clarithromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. The labeling for theophylline products states that theophylline clearance may be decreased by up to 35% when clarithromycin is prescribed concurrently; these interactions can be clinically important. These interactions are particularly significant when theophylline serum concentrations are already in the high therapeutic range (i.e., > 15 mcg/ml). If clarithromycin is used with aminophylline or theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity. Of the macrolides, azithromycin may be an alternative since it does not inhibit cytochrome P450 enzymes; no dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered. (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Aminophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued. (Minor) Concomitant use of theophylline, a CYP1A2 and CYP3A substrate, and lansoprazole has led to a small increase in theophylline clearance. Theophylline may require dosage adjustment when therapy with lansoprazole is initiated or discontinued.
Thiazide diuretics: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Thiazolidinediones: (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with clarithromycin which, when combined with a thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and clarithromycin if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; clarithromycin is a strong CYP3A4 inhibitor.
Thyroid hormones: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as clarithromycin. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with clarithromycin substantially increases ticagrelor exposure which may increase the bleeding risk.
Tipranavir: (Major) The coadministration of tipranavir and ritonavir with clarithromycin results in increased tipranavir and clarithromycin concentrations, and a decreased concentration of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance 30-60 ml/min, the dose of clarithromycin should be reduced by 50 percent; for patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75 percent. (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Tipranavir markedly induces the hepatic cytochrome P-450 enzyme CYP2C19, an enzyme responsible for the metabolism of PPIs. However, since tipranavir is not given unless it is co-prescribed with ritonavir, a known marked enzyme inhibitor, a reduction in PPI metabolism may be unlikely to occur. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If tipranavir and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Tirzepatide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with clarithromycin is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with clarithromycin. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolazamide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Tolbutamide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with clarithromycin. Concurrent use may increase tolterodine exposure. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Topotecan: (Major) Avoid coadministration of clarithromycin with oral topotecan due to increased topotecan exposure; clarithromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and clarithromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Avoid coadministration of clarithromycin with toremifene if possible due to the risk of increased toremifene exposure resulting in additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Torsemide: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and loop diuretic use due to risk for hypomagnesemia.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to the risk of increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Trandolapril; Verapamil: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Trazodone: (Major) Avoid coadministration of trazodone with clarithromycin due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Clarithromycin may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Clarithromycin is considered a strong inhibitor of this isoenzyme. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects.
Triclabendazole: (Major) Concomitant use of triclabendazole and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with trifluoperazine. Clarithromycin is associated with an established risk for QT prolongation and TdP, while trifluoperazine (a phenothiazine) is associated with a possible risk for QT prolongation.
Triptorelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Androgen deprivation therapy may also prolong the QT/QTc interval.
Trospium: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Tucatinib: (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with tucatinib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Typhoid Vaccine: (Major) Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and clarithromycin is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and clarithromycin is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
Upadacitinib: (Major) During concomitant use of upadacitinib and clarithromycin reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as clarithromycin. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Valproic Acid, Divalproex Sodium: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor magnesium concentration before and periodically during concomitant lansoprazole and thiazide diuretic use due to risk for hypomagnesemia.
Vandetanib: (Major) Avoid coadministration of vandetanib with clarithromycin due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with clarithromycin due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; clarithromycin is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold. Use of these drugs together may increase the risk for QT prolongation or vardenafil-related side effects. Clarithromycin has an established risk of QT prolongation and torsade de pointes. Vardenafil may produce an increase in QTc interval at both therapeutic and supratherapeutic doses.
Vemurafenib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as clarithromycin. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of clarithromycin with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of clarithromycin. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; clarithromycin is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Concomitant use of venlafaxine and clarithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Avoid coadministration of clarithromycin and verapamil, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving verapamil therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Verapamil is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension.
Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as clarithromycin. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with clarithromycin is necessary. Vinblastine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
Vincristine: (Major) Increased concentrations of vincristine are likely. Consider if alternative antibiotic therapy is appropriate. Monitor for vincristine-related side effects, including neurotoxicity, if these drugs must be used together. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vincristine is a CYP3A4 and P-gp substrate. Postmarketing reports of interactions, including serious toxicity, between clarithromycin or similar macrolides and vinca alkaloids have been noted.
Vinorelbine: (Moderate) Consider if an alternative to clarithromycin is appropriate in patients who will undergo vinorelbine therapy. Monitor for vinorelbine-related side effects, including neurotoxicity and neutropenia, if these drugs must be used together. Increased concentrations of vinorelbine are likely. Clarithromycin is a potent inhibitor of CYP3A4 and also inhibits P-gp. Vinorelbine is a CYP3A4 and P-gp substrate. Reports of interactions, including serious toxicity, between clarithromycin and vinca alkaloids have been noted.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and clarithromycin is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Additive QT prolongation may also occur. Voclosporin is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and clarithromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with clarithromycin, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. If these drugs are given together, closely monitor for prolongation of the QT interval and other adverse effects such as drowsiness, fatigue, dry mouth, nausea, or insomnia. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy. (Moderate) Voriconazole is an inhibitor of the CYP3A and CYP2C19 isozymes and may theoretically reduce the metabolism of substrates of these enzymes, including lansoprazole.
Vorinostat: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin should be used cautiously with other medications which may prolong the QT interval including vorinostat.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with clarithromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clarithromycin is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor the INR in patients receiving warfarin with proton pump inhibitors. Increases in INR may lead to abnormal bleeding. Adjust the warfarin dose to maintain the target INR. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Zafirlukast: (Moderate) Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as clarithromycin, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with clarithromycin. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of clarithromycin, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 183% when coadministered with clarithromycin.
Zavegepant: (Major) Avoid concomitant use of zavegepant and clarithromycin. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and clarithromycin is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Ziprasidone: (Major) Concomitant use of ziprasidone and clarithromycin should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with clarithromycin is necessary. Zolpidem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and clarithromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

Amoxicillin Trihydrate;Clarithromycin;Lansoprazole/Amoxicillin;Clarithromycin;Lansoprazole/Prevpac Oral Cap DR Pellets: 500-500-30mg
Amoxicillin Trihydrate;Clarithromycin;Lansoprazole/Amoxicillin;Clarithromycin;Lansoprazole/Prevpac Oral Cap: 500-500-30mg
Amoxicillin Trihydrate;Clarithromycin;Lansoprazole/Amoxicillin;Clarithromycin;Lansoprazole/Prevpac Oral Tab: 500-500-30mg

Adults

Lansoprazole 60 mg/day PO; amoxicillin 2 g/day PO; clarithromycin 1 g/day PO.

Geriatric

Lansoprazole 60 mg/day PO; amoxicillin 2 g/day PO; clarithromycin 1 g/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Amoxicillin and clarithromycin have demonstrated in vitro activity against most susceptible strains of Helicobacter pylori. Significant in vitro activity against H. pylori has also been demonstrated for lansoprazole; but the clinical significance of this finding has not been established. The use of combination therapy is necessary for successful eradication of H. pylori and to avoid the development of resistance. The relative contribution of systemic versus local antimicrobial activity against H. pylori for the components of Prevpac therapy has not been established. The acid-suppressive therapy of the proton pump inhibitor (PPI) lansoprazole is also required concurrently for ulcer healing.
Lansoprazole: Lansoprazole inhibits gastric acid secretion which is believed to enhance the effect of antimicrobial agents eradicating H. pylori. It is a substituted benzimidazole which suppresses gastric acid secretion by inhibiting the H+/K+ ATPase enzyme system of gastric parietal cells. A significant increase in gastric pH and decrease in basal acid output follow oral administration of lansoprazole. In hypersecretory conditions, lansoprazole has a marked effect on gastric acid secretion, both basal- and pentagastrin-stimulated. Lansoprazole exerts an inhibitory effect on gastric acid for at least 24 hours. Lansoprazole does not antagonize H2 or cholinergic receptors.
Amoxicillin: Beta-lactam antibiotics such as amoxicillin are mainly bactericidal. Like other penicillins, amoxicillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of amoxicillin, as well as the other penicillins, against a particular organism depends on their ability to gain access to and bind with the necessary PBP. The aminopenicillins are able to penetrate gram-negative bacteria more readily than are the natural penicillins or penicillinase-resistant penicillins due to the presence of a free amino group within the structure. Like all beta-lactam antibiotics, the ability of amoxicillin to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.
Clarithromycin: Clarithromycin binds to the 50 S subunit of the 70 S ribosome, thereby blocking RNA-mediated bacterial protein synthesis. Clarithromycin can be bacteriostatic or bactericidal in action, depending on the concentration as well as the particular organism and its inoculum. In addition, it appears that an alkaline pH facilitates bacterial cell penetration, since clarithromycin exists in an unionized state in this environment. H. pylori resistance can develop during clarithromycin therapy; therefore combination antimicrobial therapy is necessary. H. pylori resistance to clarithromycin in the US ranges from about 7% to 11%.

The components of Prevpac therapy (lansoprazole capsules, amoxicillin capsules, and clarithromycin immediate-release tablets) are administered orally. The pharmacokinetics of the individual drugs when coadministered have not been studied. Studies have shown no clinically significant interactions of lansoprazole and amoxicillin or lansoprazole and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of lansoprazole, amoxicillin, and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information below is based on administration of each agent alone.
Lansoprazole: Lansoprazole is about 97% bound to plasma protein. Lansoprazole is believed to be transformed into 2 active inhibitors of acid secretion in the gastric parietal cells. Hepatic metabolism of lansoprazole is extensive. The 2 identified hepatic metabolites of lansoprazole have little antisecretory activity. Plasma elimination half-life, which is less than 2 hours, is not related to gastric antisecretory effect, which lasts more than 24 hours. Elimination is believed to occur via biliary excretion. Almost no unchanged lansoprazole is detected in urine after single-dose administration. After administration of a single dose of radio-labeled lansoprazole, one-third of the administered radiation was excreted in urine and two-thirds in the feces.
Amoxicillin: Approximately 20% of circulating amoxicillin is protein-bound. Amoxicillin is widely distributed into most body tissues and fluids, excluding the brain and spinal fluid except when meninges are inflamed. Amoxicillin does cross the placenta. A small percentage is excreted in breast milk. The unchanged drug and its metabolites are excreted into the urine primarily via tubular secretion and glomerular filtration. In adults, approximately 60% of an orally administered dose is excreted in the urine primarily via tubular secretion and glomerular filtration within 6-8 hours; concurrent administration of probenecid prolongs urinary excretion. In patients with normal renal function, the elimination half-life of amoxicillin is 1 to 1.5 hours.
Clarithromycin: Protein binding is approximately 42% to 70%. Both clarithromycin and the 14-OH metabolite distribute readily into body tissues and fluids. There are no data on CSF penetration. Due to high intracellular concentrations, tissue concentrations are higher than serum concentrations. Clarithromycin is metabolized to 14-OH clarithromycin, and roughly 20% of a 250 mg dose is converted to this metabolite during first-pass metabolism. The elimination half-life is 5 to 7 hours when administered as 500 mg every 8 to 12 hours. Roughly 30% of the dose is excreted in the urine as clarithromycin after a 500 mg dose every 12 hours. The renal clearance is relatively independent of the dose and approximates the glomerular filtration rate. 14-OH clarithromycin accounts for 10% to 15% of the dose in urine after either a 250 mg or 500 mg tablet every 12 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4,CYP2C19, P-gP
Lansoprazole: Lansoprazole is a substrate of the cytochrome P450 system via the CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is a substrate and inhibitor of the P-glycoprotein (P-gP) transport system.
Clarithromycin: Clarithromycin is an inhibitor of both CYP3A4 isoenzymes and P-glycoprotein (P-gP). It is a substrate of CYP3A4. It is also potentially a substrate of P-gP, but data are in vitro only. Clarithromycin does not have any significant inhibitory effects on CYP1A2, CYP2C9, and CYP2D6.

Oral Route

Lansoprazole: Lansoprazole capsules contain enteric-coated granules that release drug after they leave the stomach. Absorption is rapid; mean peak plasma levels occur after about 1.7 hours and peak concentrations are proportional to the oral dose administered. The absolute bioavailability is over 80%, which can be reduced by 50% if lansoprazole is given 30 minutes after food. The time to reach Cmax is also delayed by 3.5 to 3.7 hours when administered with food.
Amoxicillin: Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed. Peak concentrations are reached 1 to 2 hours after administration.
Clarithromycin: Clarithromycin immediate-release tablets are rapidly absorbed from the GI tract. Bioavailability of the 250 mg immediate-release clarithromycin formulation is roughly 50%. For a single 500 mg dose, food slightly delays absorption and increases the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of absorption. Food does not affect the formation of the active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly increase the extent of metabolite formation; this is indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin may be given without regard to food.

Pregnancy

Lansoprazole; amoxicillin; clarithromycin is not recommended for use during pregnancy unless no alternative therapy is appropriate. Except in very unusual cases, H. pylori eradication treatment can generally be deferred until after delivery.[45899] If pregnancy occurs while taking clarithromycin, advise the patient of the potential risk to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, in pregnant animals administered oral clarithromycin. Observational studies in pregnant women also demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations.[28238] [62176] [65012] [62177] In a prospective, multi-center trial (n = 511) of women exposed to macrolides (including clarithromycin) during the first trimester, the rates for major congenital defects were 1.8% for clarithromycin vs. 2.4% in the comparator group (p = 0.8, OR 0.76, 95% CI 0.25 to 2.27).[56584] Other studies of women exposed to a macrolide have not reported major birth defects with clarithromycin.[56583] [56585] Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with amoxicillin use have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Reproduction studies with amoxicillin have been performed in mice and rats (5 and 10 times the human dose 2 g human dose for mice and rats, respectively, 3 and 6 times the 3 g human dose for mice and rats, respectively). There was no evidence of harm to the fetus due to amoxicillin. For lansoprazole, available data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment. Animal reproductive studies at doses up to 40 times the recommended human dose based on body surface area, revealed no evidence of impaired fertility or fetal harm. It is not known if lansoprazole crosses the human placenta; its low molecular weight (359) suggests that it has the potential to do so. Cases of inadvertent exposure and therapeutic use of lansoprazole in early gestation in humans suggest a low risk to the fetus. In a prospective study, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs. There was no difference in the rate of major malformations between women exposed to PPIs and the control group, (RR = 1.04, 95% CI 0.25 to 4.21). In a retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. In a meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women, there were no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs for major malformations (OR =1.12, 95% CI 0.86 to 1.45) and for spontaneous abortions (OR = 1.29, 95% CI 0.84 to 1.97).

Discontinue breast-feeding or lansoprazole; amoxicillin; clarithromycin pack, taking into account the potential risk to the infant vs. the potential benefit to the mother. It is not known whether lansoprazole is excreted into human breast milk; lansoprazole and its metabolites are excreted in the milk of rats. Due to the limited data available during lactation, lansoprazole and other proton pump inhibitors (PPIs) are generally not recommended for use during breast-feeding. Clarithromycin and its active metabolite are excreted in human milk. No data are available to assess the effects of clarithromycin or its metabolite on milk production. A study in 12 lactating women estimated that infants exclusively breastfed during maternal consumption of clarithromycin would be exposed at a rate that equates to less than 2% of the maternal weight-adjusted dose and less than 1% of the normal pediatric dose through milk consumption. Another study showed that clarithromycin is transferred to human milk in concentrations that are roughly 25% of maternal serum concentrations. A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (6 were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence. Amoxicillin is excreted in breast milk and may rarely cause diarrhea, candidiasis, and skin rash or penicillin-sensitization in breast-feeding infants; however, previous American Academy of Pediatrics (AAP) recommendations considered amoxicillin use in lactation as low risk.