Sandimmune

Calcineurin Inhibitors
Miscellaneous Ophthalmologicals for Dry Eye Disease

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
ORAL CAPSULES/LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.
TOPICAL: Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

bronchospasm / Rapid / 5.0-6.5
lymphoma / Delayed / 0-6.0
seizures / Delayed / 1.0-5.0
hyperkalemia / Delayed / 0-3.0
eczema vaccinatum / Delayed / 0-3.0
peptic ulcer / Delayed / 0-3.0
angioedema / Rapid / 0-3.0
skin cancer / Delayed / 1.0-3.0
heart failure / Delayed / 0-3.0
myocardial infarction / Delayed / 0-3.0
bone fractures / Delayed / 0-3.0
hearing loss / Delayed / 0-2.0
anaphylactoid reactions / Rapid / 0.1-0.1
nephrotoxicity / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
hemolytic-uremic syndrome / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
papilledema / Delayed / Incidence not known
visual impairment / Early / Incidence not known
GI bleeding / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
leukoencephalopathy / Delayed / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
pulmonary edema / Early / Incidence not known
new primary malignancy / Delayed / Incidence not known

hypertension / Early / 8.0-53.0
gingival hyperplasia / Delayed / 2.0-16.0
hypertriglyceridemia / Delayed / 15.0-15.0
edema / Delayed / 0-15.0
elevated hepatic enzymes / Delayed / 4.0-7.0
hyperbilirubinemia / Delayed / 1.0-7.0
stomatitis / Delayed / 5.0-7.0
dyspnea / Early / 1.0-6.5
leukopenia / Delayed / 0-6.0
hypomagnesemia / Delayed / 4.0-6.0
depression / Delayed / 1.0-6.0
conjunctival hyperemia / Early / 0-6.0
chest pain (unspecified) / Early / 1.0-6.0
blepharitis / Early / 1.0-5.0
epiphora / Early / 1.0-5.0
blurred vision / Early / 1.0-5.0
hyperuricemia / Delayed / 0-3.0
anemia / Delayed / 0-3.0
lymphadenopathy / Delayed / 0-3.0
bleeding / Early / 0-3.0
hypercholesterolemia / Delayed / 0-3.0
peripheral neuropathy / Delayed / 0-3.0
confusion / Early / 0-3.0
constipation / Delayed / 0-3.0
gastritis / Delayed / 0-3.0
esophagitis / Delayed / 0-3.0
dysphagia / Delayed / 0-3.0
glossitis / Early / 0-3.0
hot flashes / Early / 0-3.0
cataracts / Delayed / 0-3.0
urinary incontinence / Early / 0-3.0
hematuria / Delayed / 0-3.0
diabetes mellitus / Delayed / 0-3.0
hypoglycemia / Early / 0-3.0
goiter / Delayed / 0-3.0
migraine / Early / 0-3.0
candidiasis / Delayed / 1.0-2.9
conjunctivitis / Delayed / 0-2.0
hyperglycemia / Delayed / 0-2.0
skin ulcer / Delayed / 1.0-1.0
bullous rash / Early / 1.0-1.0
psoriasis / Delayed / 0-1.0
dysuria / Early / 1.0-1.0
hyperchloremic acidosis / Delayed / Incidence not known
gout / Delayed / Incidence not known
metabolic acidosis / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hyperlipidemia / Delayed / Incidence not known
hyperesthesia / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
encephalopathy / Delayed / Incidence not known
dysarthria / Delayed / Incidence not known
immunosuppression / Delayed / Incidence not known
BK virus-associated nephropathy / Delayed / Incidence not known
infertility / Delayed / Incidence not known
hyperprolactinemia / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known
ocular inflammation / Early / Incidence not known
wheezing / Rapid / Incidence not known

tremor / Early / 7.0-55.0
hirsutism / Delayed / 21.0-45.0
headache / Early / 1.0-25.0
infection / Delayed / 0-24.7
nausea / Early / 2.0-23.0
ocular pain / Early / 3.0-22.0
hypertrichosis / Delayed / 6.6-19.0
ocular irritation / Rapid / 17.0-17.0
abdominal pain / Early / 0-15.0
diarrhea / Early / 3.0-13.0
rash / Early / 7.0-12.0
dyspepsia / Early / 2.2-12.0
muscle cramps / Delayed / 2.0-12.0
paresthesias / Delayed / 1.0-11.0
rhinitis / Early / 0-11.0
vomiting / Early / 2.0-10.0
influenza / Delayed / 0-9.9
dizziness / Early / 1.0-8.0
sinusitis / Delayed / 0-8.0
ocular pruritus / Rapid / 8.0-8.0
cough / Delayed / 3.0-6.5
acne vulgaris / Delayed / 1.0-6.0
fatigue / Early / 3.0-6.0
foreign body sensation / Rapid / 6.0-6.0
arthralgia / Delayed / 1.0-6.0
flatulence / Early / 4.0-5.0
pharyngitis / Delayed / 3.0-5.0
flushing / Rapid / 0-5.0
ocular discharge / Delayed / 1.0-5.0
arthropathy / Delayed / 4.0-5.0
insomnia / Early / 1.0-4.0
alopecia / Delayed / 3.0-4.0
purpura / Delayed / 2.0-4.0
gingivitis / Delayed / 1.0-4.0
gynecomastia / Delayed / 0-4.0
increased urinary frequency / Early / 1.0-4.0
epistaxis / Delayed / 0-3.0
anxiety / Delayed / 0-3.0
libido decrease / Delayed / 0-3.0
vertigo / Early / 0-3.0
hypoesthesia / Delayed / 0-3.0
libido increase / Delayed / 0-3.0
emotional lability / Early / 0-3.0
drowsiness / Early / 0-3.0
urticaria / Rapid / 0-3.0
pruritus / Rapid / 0-3.0
xerosis / Delayed / 0-3.0
appetite stimulation / Delayed / 0-3.0
eructation / Early / 0-3.0
xerostomia / Early / 0-3.0
weight gain / Delayed / 0-3.0
dysgeusia / Early / 0-3.0
weight loss / Delayed / 0-3.0
anorexia / Delayed / 0-3.0
menstrual irregularity / Delayed / 1.0-3.0
asthenia / Delayed / 0-3.0
fever / Early / 1.0-3.0
malaise / Early / 0-3.0
myalgia / Early / 0-3.0
tinnitus / Delayed / 0-3.0
polyuria / Early / 0-3.0
nocturia / Early / 0-3.0
urinary urgency / Early / 0-3.0
folliculitis / Delayed / 1.0-2.9
hiccups / Early / 0-2.0
musculoskeletal pain / Early / 0-2.0
leukorrhea / Delayed / 1.0-1.0
lethargy / Early / Incidence not known
spermatogenesis inhibition / Delayed / Incidence not known
night sweats / Early / Incidence not known
weakness / Early / Incidence not known

Increased susceptibility to infection may result from immunosuppression. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection, especially herpes infection or varicella, can occur with immunosuppressive therapy. Patients should be instructed to report signs of infection promptly. Cyclosporine therapy requires an experienced clinician who is knowledgeable in immunosuppressive therapy or organ transplantation. Cyclosporine administration requires a specialized care setting with facilities equipped and staffed with adequate laboratory and supportive medical services.

Patients receiving immunosuppressants such as oral or injectable cyclosporine are at increased risk for the development of a new primary malignancy, such as lymphoma or skin cancer. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. In patients with psoriasis, the concomitant use of PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy is contraindicated because of the possibility of excessive immunosuppression and risk of malignancies. Also, psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy are at increased risk of developing skin cancer when taking cyclosporine. Patients should also be warned to avoid excessive sunlight (UV) exposure and wear sun protection. Patients should be evaluated before and during treatment for the presence of malignancies, and should be treated with cyclosporine only after complete resolution of suspicious lesions. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive therapies. Skin lesions not typical of psoriasis should be biopsied before starting cyclosporine treatment.

Cyclosporine in recommended dosages can cause nephrotoxicity. The risk of developing cyclosporine-induced nephrotoxicity increases with increasing doses of cyclosporine and duration of cyclosporine therapy. Neoral or Gengraf are contraindicated in patients with rheumatoid arthritis and psoriasis if abnormal renal function (such as renal disease, renal impairment, or renal failure) is present. All patients receiving nephrotoxic drugs concomitantly with systemic cyclosporine should be carefully monitored for worsening renal function. In all patients, serum creatinine should be monitored closely. It is not unusual for the serum creatinine and BUN to be elevated during systemic cyclosporine therapy for transplant rejection prophylaxis. The elevation of serum creatinine and BUN in renal transplant patients does not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. If patients are not monitored properly and doses are not adjusted correctly, systemic cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction. In psoriasis and rheumatoid arthritis patients, serum creatinine and BUN should be monitored every 2 weeks during the initial 3 months of cyclosporine therapy and then monthly if the patient is stable. If the serum creatinine is >= 25% above the rheumatoid arthritis or psoriasis patient's baseline, the level should be repeated within 2 weeks. If the change remains >= 25% above baseline, the cyclosporine dose should be reduced by 25—50%. If at any time the serum creatinine increases by >= 50% above baseline, cyclosporine dosage should be reduced by 25—50%. Cyclosporine should be discontinued if reversibility (within 25% of baseline) of the serum creatinine is not achieved after two dosage reductions. It is recommended to monitor the serum creatinine after a dosage increase or addition of a NSAID during cyclosporine treatment.

Systemic cyclosporine is contraindicated for use in patients with either psoriasis or rheumatoid arthritis who have uncontrolled hypertension. Because of its effects on the sympathetic nervous system, cyclosporine can elevate blood pressure. The risk of hypertension increases with increasing dose and duration of cyclosporine therapy. In any patient with treated hypertension prior to initiating systemic cyclosporine therapy, adjust the antihypertensive medication to control hypertension that may occur while receiving cyclosporine. Mild to moderate hypertension is more common than severe hypertension, and the incidence decreases over time. In renal, heart, or liver transplant patients treated with systemic cyclosporine, antihypertensive therapy may be required. However, since systemic cyclosporine may cause hyperkalemia, do not use potassium-sparing diuretics. Calcium-channel blockers, while effective treatment for cyclosporine-induced hypertension, may affect cyclosporine metabolism. Perform blood pressure measurements on at least two occasions to establish a baseline prior to beginning cyclosporine therapy in rheumatoid arthritis and psoriasis patients. After initiation of systemic cyclosporine treatment in rheumatoid arthritis and psoriasis patients, monitor blood pressure measurements every 2 weeks during the initial 3 months and then monthly once the patient is stable. In rheumatoid arthritis patients, it is recommended to monitor blood pressure after a dosage increase of NSAIDs. In psoriasis or rheumatoid arthritis patients, reduce the cyclosporine dosage by 25—50% if hypertension develops. If hypertension persists, further reduce the dose of cyclosporine or control blood pressure with antihypertensive agents. In most cases, blood pressure returns to baseline once cyclosporine is discontinued.

Cequa, Gengraf, Neoral, Restasis, Sandimmune, Verkazia

Rx

Immunosuppressive; cyclic polypeptide consisting of 11 amino acids
Used to prevent organ rejection and in various autoimmune conditions; ophthalmic 0.05% emulsion, 0.09% solution, and 0.1% solution used to treat keratoconjunctivitis (dry eye disease); 0.1% ophthalmic emulsion used to treat vernal keratoconjunctivitis
Microemulsion formulation (cyclosporine, USP (Modified)) has been introduced to improve the bioavailability

†Indicates off-label use

While specific guidelines are not available, patients with hepatic impairment may require a dosage reduction of cyclosporine. Cyclosporine concentrations should be closely monitored in these patients.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Abatacept: (Moderate) Concomitant use of immunosuppressives may potentially increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection.
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with cyclosporine is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Abrocitinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with abrocitinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with cyclosporine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acarbose: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible. Monitor the blood glucose.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine 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 cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine 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 cyclosporine 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 cyclosporine 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; Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine 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 moderate inhibitor like cyclosporine 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 cyclosporine 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.
Acetazolamide: (Minor) Acetazolamide may increase serum cyclosporine concentrations. If cyclosporine and acetazolamide are to be coadministered, monitor the patient for cyclosporine toxicity.
Acyclovir: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as acyclovir. Monitor renal function and fluid status carefully.
Adagrasib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with adagrasib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving cyclosporine along with adalimumab may be at a greater risk of developing an infection.
Adefovir: (Moderate) Chronic coadministration of adefovir with nephrotoxic drugs, such as cyclosporine, may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Cyclosporine itself can cause structural kidney damage. Monitor renal function and fluid status carefully during co-use.
Afatinib: (Moderate) If the concomitant use of cyclosporine 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 cyclosporine. 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 cyclosporine 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 cyclosporine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure of budesonide may also increase. Budesonide is a CYP3A4 substrate; cyclosporine is a CYP3A4 inhibitor. In the presence of another CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Aldesleukin, IL-2: (Moderate) Aldesleukin may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects with Aldesleukin, such as cyclosporine, may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
Aliskiren: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values.
Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of aliskiren with cyclosporine is not recommended because of significantly increased aliskiren blood concentrations and an increase in the number and/or intensity of adverse events such as headache, hot flushes, nausea, vomiting, and somnolence. Cyclosporine is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. As compared with aliskiren monotherapy, the maximum serum concentration (Cmax) of aliskiren was increased approximately 2.5-fold, and the systemic exposure was increased approximately 4.3-fold after a single 75 mg dose was given with a single cyclosporine 200 mg dose to healthy patients. Also, as compared with aliskiren receipt alone, prolongation of the median aliskiren elimination half-life (43 to 45 hours versus 26 hours) and the time to the maximum serum concentration (1.5 to 2 hours versus 0.5 hours) were noted. The mean systemic exposure and Cmax of cyclosporine were comparable to reported literature values.
Allopurinol: (Moderate) Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are used together. Reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol.
Alogliptin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Alogliptin; Pioglitazone: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
Alpelisib: (Major) Avoid coadministration of alpelisib with cyclosporine due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cyclosporine is a BCRP inhibitor.
Alpha-glucosidase Inhibitors: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible. Monitor the blood glucose.
Alprazolam: (Major) Avoid coadministration of alprazolam and cyclosporine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with cyclosporine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Alvimopan: (Moderate) Alvimopan is a substrate of P-glycoprotein (P-gp). Although the concomitant use of mild to moderate inhibitors of P-gp did not influence the pharmacokinetics of alvimopan, the concomitant use of strong P-gp inhibitors, such as cyclosporine, has not been studied. Coadministration of cyclosporine and alvimopan may result in elevated concentrations of alvimopan. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect of alvimopan.
Ambrisentan: (Major) When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose. Limit the adult dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine. Cyclosporine is a strong inhibitor of P-glycoprotein, OATP, and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-glycoprotein, OATP, and CYP3A4. Cyclosporine twice daily (targeting a trough concentration of 150 - 200 ng/mL) and ambrisentan (5 mg once daily) were coadministered in a 14-day repeated dose study in healthy volunteers. The AUC and Cmax of ambrisentan increased approximately 2-fold and 1.5-fold, respectively.
Amikacin: (Major) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as aminoglycosides.
Amiloride: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as amiloride, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Amiloride; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as amiloride, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Amiodarone: (Moderate) Cyclosporine is a CYP3A4 substrate. Amiodarone is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, which may reduce cyclosporine dosage requirements or cause cyclosporine toxicity.
Amlodipine: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
Amlodipine; Atorvastatin: (Major) FDA-approved labeling recommends avoiding coadministration of atorvastatin and cyclosporine. However, guidelines recommend limiting the atorvastatin dose to 10 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higher atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone. (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
Amlodipine; Benazepril: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
Amlodipine; Celecoxib: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Serum creatinine,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Amlodipine; Olmesartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
Amlodipine; Valsartan: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
Amobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Amoxicillin; Clarithromycin; Omeprazole: (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.
Amphotericin B lipid complex (ABLC): (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
Amphotericin B liposomal (LAmB): (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
Amphotericin B: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as amphotericin B, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully.
Angiotensin-converting enzyme inhibitors: (Moderate) Several cases of acute renal failure have been associated with the addition of angiotensin-converting enzyme (ACE) inhibitors to cyclosporine therapy in renal transplant patients. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of ACE could reduce renal function acutely. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with ACE inhibitors or potassium salts.
Apalutamide: (Moderate) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with apalutamide is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; apalutamide is a strong CYP3A4 inducer.
Aprepitant, Fosaprepitant: (Moderate) Avoid the concomitant use of cyclosporine with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; cyclosporine levels may also be affected. If coadministration cannot be avoided, use caution and monitor cyclosporine levels, as well as watching for an increase in cyclosporine- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Cyclosporine is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Cyclosporine 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 and may additionally increase plasma concentrations of cyclosporine. 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.
Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as cyclosporine, as the risk of renal impairment may be increased.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of cyclosporine. Patients receiving both a CYP2D6 inhibitor plus cyclosporine may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; cyclosporine is a moderate CYP3A inhibitor.
Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Therefore, armodafinil may induce the metabolism of medications which are substrates for CYP3A4 such as cyclosporine. Increased cyclosporine clearance and decreased cyclosporine concentrations can lead to loss of therapeutic effect. Cyclosporine concentrations should be monitored closely after the addition or discontinuation of armodafinil until a new steady-state level is achieved.
Asciminib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with asciminib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and asciminib is a weak CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine 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 moderate inhibitor like cyclosporine 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 cyclosporine 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.
Atazanavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Atazanavir; Cobicistat: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with cyclosporine. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and cyclosporine is an OATP inhibitor. 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.
Atorvastatin: (Major) FDA-approved labeling recommends avoiding coadministration of atorvastatin and cyclosporine. However, guidelines recommend limiting the atorvastatin dose to 10 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higher atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone.
Atorvastatin; Ezetimibe: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine. (Major) FDA-approved labeling recommends avoiding coadministration of atorvastatin and cyclosporine. However, guidelines recommend limiting the atorvastatin dose to 10 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higher atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone.
Atracurium: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Avacopan: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with avacopan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. For patients receiving both cyclosporine and letermovir, reduce the dose of avacopan to 30 mg once daily. Combination cyclosporine/letermovir acts as a strong CYP3A inhibitor; another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with cyclosporine due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Azilsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like azilsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with azilsartan.
Azilsartan; Chlorthalidone: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like azilsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with azilsartan.
Azithromycin: (Moderate) Caution is warranted with the concomitant use of azithromycin and cyclosporine as increased cyclosporine concentrations may occur. Dose adjustment of cyclosporine may be necessary; monitor cyclosporine serum concentrations during use with azithromycin and after discontinuation of azithromycin.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of bacitracin and other nephrotoxic agents. When possible, avoid concomitant administration of systemic bacitracin and other nephrotoxic drugs such as cyclosporine. Use of topically administrated preparations containing bacitracin, especially when applied to large surface areas, may have additive nephrotoxic potential with cyclosporine.
Barbiturates: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Baricitinib: (Major) Concomitant use of baricitinib with cyclosporine is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Basiliximab: (Minor) Because basiliximab is an immunosuppressant, additive effects may be seen with other immunosuppressives.
Belumosudil: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with belumosudil is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and belumosudil is a weak CYP3A inhibitor.
Belzutifan: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with belzutifan is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; belzutifan is a weak CYP3A inducer.
Bempedoic Acid; Ezetimibe: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with cyclosporine 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 cyclosporine 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 cyclosporine 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. Cyclosporine is an inhibitor of CYP3A4.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients taking cyclosporine. Additionally, closely monitor cyclosporine levels and monitor for cyclosporine-related adverse reactions; the dose of cyclosporine may need to be adjusted. Concurrent use may increase berotralstat and cyclosporine exposure and the risk of adverse effects related to both drugs. Berotralstat is a P-gp and BCRP substrate and moderate CYP3A4 and P-gp inhibitor; cyclosporine is a CYP3A4 and P-gp substrate and P-gp and BCRP inhibitor. Coadministration with cyclosporine increased berotralstat exposure by 69%.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving cyclosporine. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving cyclosporine. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; cyclosporine inhibits P-gp.
Bicalutamide: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with bicalutamide is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Bleomycin: (Minor) Previous treatment with nephrotoxic agents, like cyclosporine, may result in decreased bleomycin clearance if renal function has been impaired. Monitor for signs/symptoms of bleomycin toxicity in patients with concomittant or prior cyclosporine therapy.
Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as cyclosporine. The dose of the concomitant drug may need to be adjusted.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like cyclosporine; the risk of peripheral neuropathy may be additive.
Bosentan: (Contraindicated) The concomitant administration of bosentan and cyclosporine A is contraindicated. During the first day of coadministration with cyclosporine, trough concentrations of bosentan are increased by about 30-fold. Steady-state, bosentan plasma concentrations are 3- to 4-fold higher with concurrent cyclosporine administration. In addition, coadministration of bosentan at higher than approved doses (500-1000 mg PO twice daily) decreases the plasma concentrations of cyclosporine A (CYP3A4 substrate) by approximately 50%. In the cyclosporine interaction study, clinical toxicity has been observed, including: severe headache, nausea, vomiting, mild decreases in blood pressure, and small increases in heart rate; no serious adverse effects were reported.
Brigatinib: (Major) Avoid coadministration of brigatinib with cyclosporine if possible due to increased plasma exposure of brigatinib; cyclosporine concentrations may also be affected. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg). Monitor cyclosporine levels and adjust the dose as clinically appropriate. After discontinuation of cyclosporine, resume the brigatinib dose that was tolerated prior to initiation of cyclosporine. Brigatinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Additionally, cyclosporine is a P-glycoprotein (P-gp) substrate and a weak CYP3A substrate. Brigatinib inhibits P-gp in vitro and is also a weak CYP3A inducer.
Brincidofovir: (Moderate) Postpone the administration of cyclosporine 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 cyclosporine is necessary. Brincidofovir is an OATP1B1 substrate and cyclosporine is an OATP1B1 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with a single 600 mg oral cyclosporine dose.
Brodalumab: (Moderate) If brodalumab is initiated or discontinued in a patient taking cyclosporine, monitor cyclosporine concentrations; cyclosporine dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of cyclosporine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; cyclosporine is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and cyclosporine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure of budesonide may also increase. Budesonide is a CYP3A4 substrate; cyclosporine is a CYP3A4 inhibitor. In the presence of another CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and cyclosporine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure of budesonide may also increase. Budesonide is a CYP3A4 substrate; cyclosporine is a CYP3A4 inhibitor. In the presence of another CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and cyclosporine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure of budesonide may also increase. Budesonide is a CYP3A4 substrate; cyclosporine is a CYP3A4 inhibitor. In the presence of another CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine 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; cyclosporine inhibits CYP3A4.
Bupivacaine; Meloxicam: (Moderate) Monitor serum creatinine, potassium concentrations, and cyclosporine concentrations closely when systemic cyclosporine is given with meloxicam. Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs, particularly in a dehydrated patient. The effects of NSAIDs on the production of renal prostaglandins may also cause changes in the elimination of cyclosporine. Monitor patients closely for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Butabarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Butalbital; Acetaminophen: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Butalbital; Acetaminophen; Caffeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase. (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase. (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Cabozantinib: (Minor) Monitor for an increase in cabozantinib- and cyclosporine-related adverse events if concomitant use of is necessary; consider closer monitoring of cyclosporine serum concentrations. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and cyclosporine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as cyclosporine; however, the clinical relevance of this finding is unknown.
Canagliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Candesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like candesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with candesartan.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like candesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with candesartan.
Cannabidiol: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with cannabidiol is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with capmatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including cyclosporine, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
Carbamazepine: (Moderate) Carbamazepine can increase the clearance of cyclosporine by inducing cyclosporine metabolism.
Cardiac glycosides: (Major) Severe digitalis toxicity has been seen within days of starting cyclosporine in patients previously taking digoxin. Monitor serum digoxin concentrations if digoxin is used concomitantly with cyclosporine; a digoxin dosage reduction may be needed. Reduced clearance of digoxin has been observed when it is given concurrently with cyclosporine. Reduced clearance may be due to cyclosporine inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Inhibition of the P-gp-mediated renal tubular secretion of digoxin is the postulated mechanism for decreased renal clearance. A decrease in the apparent volume of distribution of digoxin has been reported after cyclosporine administration.
Carvedilol: (Moderate) Modest increases in mean trough cyclosporine concentrations may occur following initiation of carvedilol treatment. It is recommended that cyclosporine serum concentrations be monitored to individualize dosage.
Caspofungin: (Major) In two clinical studies, cyclosporine increased the systemic exposure (AUC) of caspofungin by approximately 35%. Cyclosporine concentrations are not altered by coadministration with caspofungin. Seven of 20 healthy subjects who received caspofungin (35 mg or 70 mg) in combination with cyclosporine (3 mg/kg or 4 mg/kg) developed transient elevations in alanine transaminase (ALT) up to 3 times the upper limit of normal. Elevations in aspartate transaminase (AST) paralleled ALT elevations but were of lesser magnitude. As determined retrospectively, 14 of 40 patients who received caspofungin and cyclosporine (1 to 290 days, median 17.5 days) had an ALT concentration elevation greater than 5 times the upper limit of normal or greater than 3 times the baseline value during concurrent therapy or the following 14 days. Five of the 14 cases and one case of elevated bilirubin were considered possibly related to concomitant therapy; no clinical evidence of hepatotoxicity or serious hepatic events occurred. The manufacturer recommends against the concomitant use of caspofungin with cyclosporine unless the potential benefit outweighs the risk. Monitor patients who develop abnormal liver enzyme concentrations; a risk versus benefit decision for therapy continuation is recommended.
Ceftriaxone: (Moderate) Cyclosporine serum concentrations may be increased if ceftriaxone is added. Although data are limited, ceftriaxone should be used cautiously in patients currently stabilized on cyclosporine. Vigilant serum cyclosporine serum concentration monitoring is warranted. Two case reports suggest that cyclosporine serum concentrations may rise if ceftriaxone is added. No changes in renal or hepatic function were observed in the 2 renal transplant patients. The mechanism of the potential interaction is unknown.
Celecoxib: (Moderate) Serum creatinine,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Celecoxib; Tramadol: (Moderate) Serum creatinine,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Cenobamate: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with cenobamate is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Moderate) Monitor serum cyclosporine concentrations when administered concurrently with ceritinib due to potential for elevated cyclosporine concentrations and cyclosporine-related adverse events; cyclosporine dosage adjustment may be necessary. Ceritinib is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
Chloramphenicol: (Moderate) Increased cyclosporine trough concentrations have been reported in patients receiving chloramphenicol increasing the risk for cyclosporine toxicity. Close monitoring of cyclosporine concentrations appears to be warranted; cyclosporine dosage adjustments may be necessary during concurrent therapy.
Chloroquine: (Major) Closely monitor the serum cyclosporine concentrations and adjust the dose of cyclosporine as appropriate after starting or stopping chloroquine therapy. Sudden increases in cyclosporine concentrations have been reported after the addition of chloroquine. Monitor patients for cyclosporine-related adverse events such as nephrotoxicity or hepatic toxicity. Discontinue chloroquine if necessary.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with cyclosporine 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 cyclosporine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cyclosporine is a moderate 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 cyclosporine 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 cyclosporine 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 cyclosporine 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.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Chlorthalidone; Clonidine: (Minor) Clonidine can inhibit cyclosporine-induced glomerular vasoconstriction and has been shown to offset cyclosporine-induced nephrotoxicity. Clonidine may adversely affect cyclosporine pharmacokinetics; limited data suggest that cyclosporine concentrations increase - dramatically, in some cases - when clonidine is added. Until more data are available, clinicians should use clonidine cautiously in patients stabilized on cyclosporine.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cholic Acid: (Major) Avoid concomitant use of cholic acid and inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine because there is a risk of increased accumulation of conjugated bile salts in the liver resulting in clinical symptoms. If concomitant use is unavoidable, then monitor serum transaminases and bilirubin closely.
Cidofovir: (Contraindicated) The administration of cidofovir with other potentially nephrotoxic agents, such as cyclosporine is contraindicated. Cyclosporine should be discontinued at least 7 days prior to beginning cidofovir. Monitor renal function and fluid status carefully during cyclosporine usage.
Cimetidine: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as cimetidine.
Ciprofloxacin: (Moderate) Monitor renal function during concomitant therapy. Cyclosporine serum concentrations should be monitored and suitable dosage adjustments made. Coadministration of ciprofloxacin and cyclosporine may result in elevated plasma cyclosporine concentrations. Cyclosporine is extensively metabolized by CYP3A4; ciprofloxacin is an inhibitor of CYP3A4. Additionally, some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving concomitant cyclosporine and ciprofloxacin therapy and may potentiate renal dysfunction. Cases of nephrotoxicity with and without increases in cyclosporine concentrations during concurrent cyclosporine and ciprofloxacin treatment have been reported.
Cisapride: (Contraindicated) Cisapride is metabolized by the CYP3A4 isoenzyme. QT prolongation and ventricular arrhythmias, including torsade de pointes and death, have occurred when inhibitors of CYP3A4 are coadministered with cisapride. Cyclosporine may have the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, should not be used with cisapride.
Cisatracurium: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Cisplatin: (Moderate) Closely monitor renal function if concomitant use with cisplatin and cyclosporine is necessary. Both drugs can cause nephrotoxicity, which may be exacerbated with the use of additional nephrotoxins.
Cladribine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Clarithromycin: (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.
Clindamycin: (Moderate) Concomitant use of cyclosporine and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and cyclosporine, an inhibitor of OAT protein (OATP), may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OATP inhibitors.
Clofazimine: (Moderate) Monitor for increased toxicity of cyclosporine if used concomitantly with clofazimine. Concomitant use may increase the concentration of cyclosporine, increasing the risk of adverse effects. Cyclosporine is a CYP3A4 substrate that has a narrow therapeutic range; in vitro data suggest clofazimine inhibits CYP3A4.
Clonidine: (Minor) Clonidine can inhibit cyclosporine-induced glomerular vasoconstriction and has been shown to offset cyclosporine-induced nephrotoxicity. Clonidine may adversely affect cyclosporine pharmacokinetics; limited data suggest that cyclosporine concentrations increase - dramatically, in some cases - when clonidine is added. Until more data are available, clinicians should use clonidine cautiously in patients stabilized on cyclosporine.
Cobicistat: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic cyclosporine therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cyclosporine is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cyclosporine, resume cobimetinib at the previous dose. Use an alternative to cyclosporine in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cyclosporine is a moderate inhibitor of CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a 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 cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with cyclosporine 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 cyclosporine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cyclosporine 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. Cyclosporine is a moderate inhibitor of CYP3A4.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and cyclosporine 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. Cyclosporine 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 cyclosporine 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.
Colesevelam: (Moderate) Colesevelam decreases the Cmax and AUC of cyclosporine by 44% and 34%, respectively. The manufacturer recommends administration of cyclosporine at least 4 hours before colesevelam. Additionally, cyclosporine serum concentrations should be monitored.
Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function during concurrent use. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including cyclosporine, may increase serum concentrations of either drug.
Colistin: (Major) Theoretically, chronic coadministration may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function during concurrent use. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including cyclosporine, may increase serum concentrations of either drug.
Conivaptan: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with conivaptan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
Crizotinib: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with crizotinib; additionally, monitor for an increase in crizotinib-related adverse reactions. Use of these medications together may result in elevated serum concentrations of both drugs, causing an increased risk for treatment-related adverse events. Crizotinib Is a CYP3A substrate and moderate inhibitor. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and is also a moderate CYP3A4 inhibitor.
Cyclophosphamide: (Moderate) Closely monitor cyclosporine concentrations if coadministration with cyclophosphamide is necessary. Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.
Dabigatran: (Major) Avoid concomitant use of dabigatran and cyclosporine. Increased serum concentrations of dabigatran and an increased risk of bleeding are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with cyclosporine, a P-gp inhibitor. P-gp inhibition is a major independent factor that results in increased exposure to dabigatran.
Dalfopristin; Quinupristin: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with dalfopristin; quinupristin. Use of these medications together resulted in a 63% increase in exposure of cyclosporine, which may increase the risk for cyclosporine-related toxicity. Dalfopristin; quinupristin is a weak inhibitor of CYP3A4 and cyclosporine is a CYP3A4 substrate.
Danazol: (Major) Close monitoring of cyclosporine concentrations is required when danazol is given concurrently with cyclosporine. Danazol has been reported to increase concentrations of cyclosporine. Danazol is an inhibitor of CYP3A4 while cyclosporine is a substrate of CYP3A4. In a patient stabilized on cyclosporine, the addition of danazol 200 mg every 8 hours yielded a 38% increase in the cyclosporine blood concentration and necessitated a cyclosporine dosage reduction from 250 mg twice daily to 200 mg twice daily.
Dapagliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with cyclosporine. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darunavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Darunavir; Cobicistat: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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.
Daunorubicin Liposomal: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressants may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g., daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
Daunorubicin Liposomal; Cytarabine Liposomal: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressants may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g., daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
Daunorubicin: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressants may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g., daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
Deferasirox: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as cyclosporine. If these drugs are used together, monitor patients for a decrease in the effects of cyclosporine.
Deferoxamine: (Moderate) Although not specifically studied, reduced serum concentrations of deferoxamine may occur in patients taking other CYP3A4 substrates such as cyclosporine. If these drugs are used together, monitor patients for a decrease in the effects of cyclosporine. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including cyclosporine, may increase the risk of acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and cyclosporine concomitantly.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with cyclosporine. 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; cyclosporine is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as cyclosporine, should be expected with concurrent use of delavirdine.
Dexamethasone: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with dexamethasone is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; dexamethasone is a weak CYP3A inducer.
Dichlorphenamide: (Moderate) Use dichlorphenamide and systemic cyclosporine together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Diclofenac: (Major) Significant interactions may occur between systemic cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac. Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of diclofenac, especially in a dehydrated patient. Although concomitant administration of diclofenac does not affect cyclosporine blood concentrations, a doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function have been noted. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range. The mechanism of the interaction may be inhibition of diclofenac metabolism, as diclofenac is a substrate for and cyclosporine an inhibitor of CYP3A4. NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine. Interactions with skin and eye products containing these drugs are not expected. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Diclofenac; Misoprostol: (Major) Significant interactions may occur between systemic cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac. Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of diclofenac, especially in a dehydrated patient. Although concomitant administration of diclofenac does not affect cyclosporine blood concentrations, a doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function have been noted. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range. The mechanism of the interaction may be inhibition of diclofenac metabolism, as diclofenac is a substrate for and cyclosporine an inhibitor of CYP3A4. NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine. Interactions with skin and eye products containing these drugs are not expected. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Diflunisal: (Moderate) Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with diflunisal, a nonsteroidal antiinflammatory drug (NSAID). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Nonsteroidal antiinflammatory drugs (NSAIDs) may also mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine.
Digoxin: (Major) Severe digitalis toxicity has been seen within days of starting cyclosporine in patients previously taking digoxin. Monitor serum digoxin concentrations if digoxin is used concomitantly with cyclosporine; a digoxin dosage reduction may be needed. Reduced clearance of digoxin has been observed when it is given concurrently with cyclosporine. Reduced clearance may be due to cyclosporine inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Inhibition of the P-gp-mediated renal tubular secretion of digoxin is the postulated mechanism for decreased renal clearance. A decrease in the apparent volume of distribution of digoxin has been reported after cyclosporine administration.
Diltiazem: (Moderate) Diltiazem inhibits CYP3A4 metabolism and thereby increases cyclosporine serum concentrations. Cyclosporine dosage reduction (20 to 50%) may be required when diltiazem therapy is initiated to prevent cyclosporine toxicity.
Diphenhydramine; Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Diphenhydramine; Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Disulfiram: (Major) Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Docetaxel: (Major) Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine may enhance the efficacy of the certain chemotherapy agents including docetaxel, paclitaxel, and vinca alkaloids by inhibiting this protein. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation. The addition of cyclosporine may also enhance the efficacy and/or toxicity of these chemotherapy regimens by other mechanisms. The addition of cyclosporine may increase the AUC values of these chemotherapy agents due to a decrease in either chemotherapy metabolism or clearance, or due to an increase in the intracellular concentrations of the chemotherapy agent.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like cyclosporine, 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) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressants may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g., doxorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of doxorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to doxorubicin therapy may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of doxorubicinol, or an increase in intracellular doxorubicin concentrations. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone; coma and/or seizures have also been described.
Doxorubicin: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressants may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g., doxorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of doxorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to doxorubicin therapy may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in cleara nce of parent drug, a decrease in metabolism of doxorubicinol, or an increase in intracellular doxorubicin concentrations. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone; coma and/or seizures have also been described.
Dronabinol: (Major) Use caution if coadministration of dronabinol with cyclosporine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence) as well as increased cyclosporine levels. Dronabinol is a CYP2C9 and 3A4 substrate; cyclosporine is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. Dronabinol is also highly bound to plasma proteins and may displace and increase the free fraction of other concomitantly administered protein-bound drugs such as cyclosporine.
Dronedarone: (Contraindicated) The concomitant use of dronedarone and cyclosporine is contraindicated. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A and P-gp. Cyclosporine is a substrate and strong inhibitor of CYP3A4 and is a substrate for P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. No data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of cyclosporine have not been described, although an increase in cyclosporine serum concentrations is possible.
Dulaglutide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including dulaglutide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to cyclosporine. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. Monitor cyclosporine concentrations if dupilumab is initiated or discontinued in a patient taking cyclosporine; cyclosporine dose adjustments may be needed.
Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as cyclosporine. 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; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and cyclosporine during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; cyclosporine is also a substrate and moderate inhibitor of CYP3A.
Edoxaban: (Moderate) Coadministration of edoxaban and cyclosporine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cyclosporine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as cyclosporine. Monitoring of serum cyclosporine concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as cyclosporine. Monitoring of serum cyclosporine concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as cyclosporine. Monitoring of serum cyclosporine concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
Elacestrant: (Major) Avoid concomitant use of elacestrant and cyclosporine due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. The exposure of cyclosporine may also be increased. Elacestrant is a CYP3A substrate and P-gp inhibitor; cyclosporine is a P-gp substrate and moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cyclosporine 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. Cyclosporine inhibits both OATP1B1 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.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cyclosporine 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. Cyclosporine inhibits both OATP1B1 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.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with cyclosporine is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Cyclosporine is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP1B1). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with cyclosporine. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with cyclosporine; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. In addition, coadministration may increase the systemic exposure of cyclosporine. Appropriate monitoring should be used; adjust the cyclosporine dosage as necessary. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate), ivacaftor is a weak P-gp inhibitor, and cyclosporine is a moderate CYP3A inhibitor and P-gp substrate. (Major) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. More careful monitoring of cyclosporine blood concentrations may be warranted. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-gp; cyclosporine is a CYP3A and P-gp substrate. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with cyclosporine; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; cyclosporine is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of cyclosporine and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of cyclosporine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Monitor therapeutic cyclosporine concentrations closely and adjust the dosage as necessary. The coadministration of eliglustat with both cyclosporine and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Cyclosporine is a moderate CYP3A inhibitor and P-glycoprotein (P-gp) substrate; eliglustat is a CYP3A and CYP2D6 substrate and a P-gp inhibitor. Coadministration of eliglustat with CYP3A inhibitors, such as cyclosporine, may increase 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. In addition, coadministration of eliglustat with P-gp substrates (e.g., cyclosporine) may result in increased concentrations of the concomitant drug. Although specific recommendations are not available, when eliglustat is given in combination with digoxin, another narrow therapeutic index P-gp substrate, an empiric digoxin dosage reduction of 30% followed by careful monitoring is recommended.
Eluxadoline: (Major) When administered concurrently with cyclosporine, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cyclosporine is an OATP inhibitor. Use of these drugs together results in a 4.4-fold increase in exposure (AUC) and a 6.2-fold increase in maximum plasma concentration of eluxadoline. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Emapalumab: (Moderate) Monitor for decreased efficacy of cyclosporine and adjust the dose as needed during coadministration with emapalumab. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Empagliflozin; Linagliptin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Empagliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
Emtricitabine; Tenofovir alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
Enasidenib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with enasidenib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of encorafenib and cyclosporine due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of cyclosporine. If cyclosporine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cyclosporine. Encorafenib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Entecavir: (Moderate) In a small pilot study of entecavir in HBV-infected liver transplant recipients on stable doses of cyclosporine, entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients. Monitor renal function.
Entrectinib: (Major) Avoid coadministration of entrectinib with cyclosporine due to 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 200 mg PO once daily. If cyclosporine is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cyclosporine. Entrectinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
Enzalutamide: (Major) Closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with enzalutamide is necessary. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Cyclosporine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Eprosartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like eprosartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with eprosartan.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like eprosartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with eprosartan.
Erdafitinib: (Major) Avoid coadministration of cyclosporine with erdafitinib due to the risk of increased plasma concentrations of cyclosporine. If concomitant use is unavoidable, separate erdafitinib administration by at least 6 hours before or after administration of cyclosporine; monitor cyclosporine levels. Cyclosporine is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and erdafitinib is a P-gp inhibitor.
Ertugliflozin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Erythromycin: (Major) Erythromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Additionally, erythromycin has been associated with inhibition of P-glycoprotein, which leads to decreased intestinal metabolism and increased oral absorption of cyclosporine. It has been recommend to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolide 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.
Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as cyclosporine, may result in decreased serum concentrations of the substrate. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy until a new steady-state cyclosporine concentration is achieved when eslicarbazepine is added to an existing cyclosporine regimen; conversely, if eslicarbazepine is discontinued, cyclosporine concentrations could increase.
Esterified Estrogens; Methyltestosterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Estrogens: (Moderate) Estrogens in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance can increase cyclosporine concentrations. Additionally, estrogens are metabolized by CYP3A4; cyclosporine inhibits CYP3A4 and may increase estrogen concentrations and estrogen-related side effects. The patient's cyclosporine concentrations should be monitored closely; monitor clinical status including blood pressure and renal and hepatic function. Be alert for complaints of estrogen-related side effects (e.g., nausea, fluid retention, breast tenderness).
Ethanol: (Major) Advise patients to avoid consuming red wine with cyclosporine. In a healthy volunteer study involving non-modified cyclosporine, consuming red wine while taking cyclosporine decreased cyclosporine peak and overall exposure by 38% and 30% respectively. The effect of other forms of alcohol and the impact to modified cyclosporine dosage forms in unknown.
Ethotoin: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
Etodolac: (Moderate) Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
Etonogestrel: (Moderate) Coadministration may result in increased serum concentrations of cyclosporine or etonogestrel. There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity, and/or hepatotoxicity. If etonogestrel is initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. In addition, coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cyclosporine may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Moderate) Coadministration may result in increased serum concentrations of cyclosporine or etonogestrel. There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity, and/or hepatotoxicity. If etonogestrel is initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. In addition, coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cyclosporine may increase the serum concentration of etonogestrel.
Etoposide, VP-16: (Moderate) Monitor for an increase in etoposide-related adverse reactions if concomitant use of cyclosporine results in cyclosporine levels greater than 2,000 ng/mL. Concomitant administration of high-dose cyclosporine (concentrations greater than 2,000 ng/mL) with oral etoposide increased etoposide exposure by 80% with a 38% decrease in total body clearance of etoposide compared to etoposide alone.
Etravirine: (Major) Coadministration with etravirine may result in altered cyclosporine concentrations. Coadminister these drugs with caution, carefully monitor cyclosporine concentrations and make dosage adjustments as needed.
Everolimus: (Major) Coadministration of everolimus with cyclosporine requires an everolimus dose reduction for some indications and close monitoring for others; also, closely monitor cyclosporine whole blood trough concentrations as appropriate and adjust the dose as necessary to remain in the recommended therapeutic range. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of cyclosporine and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, as well as a weak CYP3A4 inhibitor. Cyclosporine is a moderate CYP3A4 and P-gp inhibitor, as well as a CYP3A4 substrate. In a single-dose study, coadministration cyclosporine increased the AUC of everolimus by 168% (range, 46% to 365%) and the Cmax by 82% (range, 25% to 158%). Concurrent use may also increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events.
Exenatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including exenatide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Ezetimibe: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Ezetimibe; Simvastatin: (Contraindicated) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1. (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Fedratinib: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with fedratinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Fedratinib is a moderate inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Felodipine: (Major) Cyclosporine may competitively inhibit the first-pass metabolism of felodipine by cytochrome P450 3A4 in the gut wall, resulting in an increased bioavailability of felodipine. The concomitant administration of cyclosporine and felodipine significantly increases the peak felodipine plasma concentration (151%) and AUC (58%). The combination resulted in a greater decrease in mean diastolic blood pressure over 24 hours than either drug alone. Patients should avoid taking felodipine with cyclosporine; separate doses by at least two hours. Patients receiving cyclosporine should be monitored for potential risk of felodipine dose-related adverse effects (e.g., flushing, edema). Felodipine has been shown to have minimal effects on cyclosporine blood concentrations.
Fenofibrate: (Moderate) The use of fibric acid derivatives, such as fenofibrate, may potentiate the risk for renal dysfunction with cyclosporine. During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) and cyclosporine levels should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
Fenoprofen: (Moderate) Pharmacodynamic interactions consisting of additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine 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 cyclosporine 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 cyclosporine 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.
Fidaxomicin: (Minor) Cyclosporine, a P-glycoprotein (PGP) inhibitor, significantly increased the serum concentrations of fidaxomicin and its microbiologically active metabolite, OP-1118 (both PGP substrates); however, the serum concentrations of both fidaxomicin and OP-1118 were still in the ng/ml range. The manufacturer states a dosage adjustment is not necessary. The mean serum Cmax for fidaxomicin increased from 4.67 ng/ml when fidaxomicin was used alone to 19.4 ng/ml when administered with cyclosporine, while the mean AUC increased from 59.5 ng-h/ml for fidaxomicin alone to 114 ng-h/ml when administered with cyclosporine. The mean serum Cmax for OP-1118 increased from 10.6 ng/ml when fidaxomicin was used alone to 100 ng/ml when administered with cyclosporine, while the mean AUC increased from 106 ng-h/ml for fidaxomicin alone to 438 ng-h/ml when administered with cyclosporine. These concentrations are still well below the fecal concentrations demonstrated with a 10 day course of fidaxomicin.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or cyclosporine; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as cyclosporine, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Major) Fluconazole inhibits the CYP3A4 metabolism of cyclosporine, resulting in significant increases in cyclosporine plasma concentrations. If these drugs are used together, monitor serum creatinine and cyclosporine concentrations, and adjust cyclosporine dosage accordingly. Renal transplant patients stabilized on cyclosporine for at least 6 months and on a stable cyclosporine dose for at least 6 weeks received fluconazole 200 mg PO daily for 14 days. Cyclosporine AUC, Cmax, Cmin were increased by 92%, 60%, and 157%, respectively. In addition, the apparent cyclosporine clearance decreased by 45%.
Fludarabine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Fluoxetine: (Moderate) Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of cyclosporine.
Flurbiprofen: (Moderate) Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
Fluvastatin: (Major) Do not exceed 40 mg/day of fluvastatin when coadministered with cyclosporine. The risk of developing myopathy/rhabdomyolysis increases when fluvastatin is used concomitantly with cyclosporine. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. The fluvastatin AUC was increased by 90% with the concomitant cyclosporine administration.
Fluvoxamine: (Moderate) Fluvoxamine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity or require the downward dosage adjustment of cyclosporine. Until more data are available, cyclosporine concentrations should be monitored very carefully any time fluvoxamine is prescribed.
Food: (Major) The oral bioavailability of non-modified cyclosporine is highly variable and food interactions are possible. Administration with high-fat content meals increases both bioavailability and clearance; however, the AUC does not change significantly. In general, food will decrease the absorption of modified cyclosporine. It is important to take cyclosporine consistently with or without food to ensure uniform cyclosporine concentrations.
Fosamprenavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Foscarnet: (Major) The risk of renal toxicity may be increased if foscarnet is used in conjunction with other nephrotoxic agents such as cyclosporine. Monitor renal function and fluid status carefully during cyclosporine usage.
Fosphenytoin: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
Fostamatinib: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with fostamatinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Fostamatinib is a weak inhibitor of CYP3A4 as well as the drug transporter P-glycoprotein (P-gp); cyclosporine is a sensitive substrate of CYP3A4 and a substrate of P-gp.
Furosemide: (Moderate) Coadministration of furosemide and cyclosporine increases the risk of gouty arthritis. This is a result of furosemide-induced hyperuricemia and the impairment of renal urate excretion by cyclosporine.
Futibatinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with futibatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Ganciclovir: (Moderate) Use caution and monitor renal function when ganciclovir is coadministered with cyclosporine because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
Gemfibrozil: (Moderate) The use of fibric acid derivatives, such as gemfibrozil, may potentiate the risk for renal dysfunction with cyclosporine. During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) and cyclosporine levels should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
Gentamicin: (Major) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as aminoglycosides.
Gilteritinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with gilteritinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and gilteritinib is a P-gp inhibitor.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir in patients requiring stable cyclosporine doses more than 100 mg per day is not recommended as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is partially metabolized by CYP3A4, and is a substrate of the drug transporters P-glycoprotein (P-gp), OATP1B1, and BCRP; cyclosporine is an inhibitor of CYP3A4, P-gp, OATP1B1, and BCRP. Additionally, cyclosporine is a P-gp substrate and glecaprevir is a P-gp inhibitor; concentrations of cyclosporine may also be increased. In drug interaction studies, coadministration of cyclosporine with glecaprevir resulted in an approximately 5-fold increase in the AUC of glecaprevir. (Major) Coadministration of pibrentasvir in patients requiring stable cyclosporine doses more than 100 mg per day is not recommended as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of the drug transporters P-glycoprotein (P-gp) and BCRP; cyclosporine is an inhibitor of P-gp and BCRP. Additionally, cyclosporine is a P-gp substrate and pibrentasvir is a P-gp inhibitor; concentrations of cyclosporine may also be increased. In drug interaction studies, coadministration of cyclosporine with pibrentasvir resulted in an approximately 2-fold increase in the AUC of pibrentasvir.
Glipizide; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Glyburide; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Glycerol Phenylbutyrate: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with glycerol phenylbutyrate is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; glycerol phenylbutyrate is a weak CYP3A inducer.
Golimumab: (Moderate) If golimumab is initiated or discontinued in a patient taking cyclosporine, monitor the cyclosporine concentration; cyclosporine dose adjustment may be needed. Monitor closely for additive immunosuppression and for infection. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during golimumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine.
Grapefruit juice: (Major) Grapefruit juice inhibits the enterocyte CYP3A4 isoenzyme and increases cyclosporine serum concentrations. Thus, grapefruit and grapefruit juice consumption by patients receiving cyclosporine should be avoided. Grapefruit juice contains compounds that can inhibit P-450 isozymes and the p-glycoproteins lining the intestinal wall. Administration of either formulation of cyclosporine with grapefruit juice significantly increased cyclosporine concentrations and AUC compared to administration with either orange juice or water. Separating dose of grapefruit juice from cyclosporine may not eliminate the interaction completely, as the inhibitory effect of grapefruit juice can last for several hours. Patients stabilized on cyclosporine should avoid large changes (i.e., either increases or decreases) in their daily intake of grapefruit juice. Do not mix cyclosporine oral solution with grapefruit juice.
Griseofulvin: (Moderate) Griseofulvin has been reported to reduce cyclosporine serum concentrations. Although very few reports of this interaction are known, the sequelae from this combination are significant. Closely monitor cyclosporine levels during concurrent treatment with griseofulvin. An increase in cyclosporine dose may be necessary if griseofulvin is added. The cyclosporine dosage may need to decreased if griseofulvin is discontinued.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine 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 cyclosporine 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 cyclosporine 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) Cyclosporine 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. Upon cyclosporine discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and cyclosporine is a moderate CYP3A4 inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine 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 cyclosporine 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 cyclosporine 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.
Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like cyclosporine. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Hydantoins: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine 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 cyclosporine 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 cyclosporine 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 cyclosporine 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 cyclosporine 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 cyclosporine 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. (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine 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 cyclosporine 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 cyclosporine 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.
Hydroxychloroquine: (Major) Closely monitor serum cyclosporine concentrations and adjust the dose of cyclosporine as appropriate after starting or stopping hydroxychloroquine therapy. Increased serum concentrations of cyclosporine have been noted when coadministered with hydroxychloroquine. Monitor patients for cyclosporine-related adverse events such as nephrotoxicity or hepatic toxicity.
Ibandronate: (Moderate) Theoretically, coadministration of intravenous ibandronate with other potentially nephrotoxic drugs like cyclosporine may increase the risk of developing nephrotoxicity.
Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and cyclosporine as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
Ibrutinib: (Major) If ibrutinib is coadministered with cyclo sporine, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if cyclosporine is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Monitor cyclosporine levels and observe patients for symptoms of cyclosporine toxicity. Ibrutinib is a 3A4 substrate and a P-glycoprotein (P-gp) inhibitor in vitro; cyclosporine is a CYP3A4 inhibitor and a P-gp substrate with a narrow therapeutic index. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Ibuprofen; Famotidine: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine 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 moderate inhibitor like cyclosporine 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 cyclosporine 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. (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Ibuprofen; Pseudoephedrine: (Moderate) Serum creatinine, potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with cyclosporine, a CYP3A substrate, as cyclosporine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Imatinib: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme. Concurrent administration of cyclosporine and imatinib may result in increased concentrations of cyclosporine due to decreased metabolism. Monitoring of cyclosporine concentrations is warranted.
Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like cyclosporine. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Indinavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Indomethacin: (Moderate) Additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Infigratinib: (Major) Avoid concomitant use of infigratinib and cyclosporine. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor.
Infliximab: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If infliximab is initiated or discontinued in a patient taking cyclosporine, monitor the cyclosporine concentration; cyclosporine dose adjustment may be needed.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and cyclosporine due to the risk of glomerulonephritis and nephrotoxicity.
Insulin Degludec; Liraglutide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including liraglutide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Insulin Glargine; Lixisenatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including lixisenatide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Insulins: (Moderate) Cyclosporine may cause hyperglycemia. Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving insulin.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Irbesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like irbesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with irbesartan.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like irbesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with irbesartan.
Isavuconazonium: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with isavuconazonium. Use of these drugs together results in elevated cyclosporine serum concentrations and an increased risk for adverse reactions, such as renal toxicity. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration. Isavuconazole, the active moiety of isavuconazonium, is an inhibitor of hepatic isoenzyme CYP3A4 as well as the drug transporter P-glycoprotein (P-gp); cyclosporine is a substrate of CYP3A4 and P-gp. Additionally, isavuconazole is a sensitive substrate of CYP3A4 while cyclosporine is an inhibitor of this enzyme; elevated isavuconazole serum concentrations may also occur.
Isoniazid, INH: (Minor) Cyclosporine is a CYP3A4 substrate. Coadministration with a CYP3A4 inhibitor, such as isoniazid, may decrease the metabolism and clearance of cyclosporine, resulting in increased serum concentrations and, thus, potentially causing cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced cyclosporine dosage requirements may be needed. Conversely, if isoniazid is discontinued, cyclosporine concentrations could decrease. Monitor serum cyclosporine concentrations carefully if isoniazid is used concomitantly and upon discontinuation.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers. (Minor) Cyclosporine is a CYP3A4 substrate. Coadministration with a CYP3A4 inhibitor, such as isoniazid, may decrease the metabolism and clearance of cyclosporine, resulting in increased serum concentrations and, thus, potentially causing cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced cyclosporine dosage requirements may be needed. Conversely, if isoniazid is discontinued, cyclosporine concentrations could decrease. Monitor serum cyclosporine concentrations carefully if isoniazid is used concomitantly and upon discontinuation.
Isoniazid, INH; Rifampin: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers. (Minor) Cyclosporine is a CYP3A4 substrate. Coadministration with a CYP3A4 inhibitor, such as isoniazid, may decrease the metabolism and clearance of cyclosporine, resulting in increased serum concentrations and, thus, potentially causing cyclosporine toxicity (e.g., nephrotoxicity, hepatotoxicity, or seizures). Reduced cyclosporine dosage requirements may be needed. Conversely, if isoniazid is discontinued, cyclosporine concentrations could decrease. Monitor serum cyclosporine concentrations carefully if isoniazid is used concomitantly and upon discontinuation.
Istradefylline: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with istradefylline 40 mg daily. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor and P-gp inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Itraconazole: (Major) Monitor cyclosporine serum concentrations and adjust dose as needed if coadministration of itraconazole is necessary. Cyclosporine concentrations may be significantly increased in the presence of itraconazole. Itraconazole is a strong CYP3A4 and P-glycoprotein(P-gp) inhibitor; cyclosporine is a CYP3A4/P-gp substrate.
Ivabradine: (Major) Avoid coadministration of ivabradine and cyclosporine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; cyclosporine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. More careful monitoring of cyclosporine blood concentrations may be warranted. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-gp; cyclosporine is a CYP3A and P-gp substrate.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with cyclosporine due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of cyclosporine is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor.
Ketoconazole: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with ketoconazole is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-gp substrate and ketoconazole is a strong CYP3A4 and P-gp inhibitor.
Ketoprofen: (Moderate) Additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Ketorolac: (Moderate) Additive decreases in renal function have been reported between cyclosporine and nonsteroidal anti-inflammatory drugs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
Lanreotide: (Moderate) Monitor cyclosporine levels if coadministration of cyclosporine with lanreotide is necessary; adjust the dose of cyclosporine as necessary to maintain therapeutic drug concentrations. Concomitant administration of lanreotide with cyclosporine may decrease the absorption of cyclosporine.
Lansoprazole; Amoxicillin; Clarithromycin: (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.
Lapatinib: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with lapatinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Larotrectinib: (Moderate) Monitor for increase in adverse reactions from both drugs if concomitant use of larotrectinib and cyclosporine is necessary. Closely monitor cyclosporine whole blood trough concentrations as appropriate and adjust the dose as needed. Concomitant use may increase the exposure of both drugs. Larotrectinib is a CYP3A substrate and weak CYP3A inhibitor; cyclosporine is a CYP3A substrate and moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lasmiditan: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with lasmiditan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of cyclosporine and ledipasvir. Both ledipasvir and cyclosporine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, cyclosporine is a breast cancer resistance protein (BCRP) inhibitor; ledipasivr is a BCRP substrate. Taking these drugs together may increase plasma concentrations of both drugs. According to the manufacturer, no significant interactions were observed when these medications were administered concurrently during drug interaction studies.
Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with cyclosporine as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cyclosporine is a P-gp and moderate CYP3A4 inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and cyclosporine as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with lenacapavir is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor.
Lesinurad; Allopurinol: (Moderate) Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are used together. Reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol.
Letermovir: (Major) Decrease the dose of letermovir to 240 mg once daily if coadministered with cyclosporine. Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of letermovir and adjust the dose of cyclosporine accordingly. Coadministration result in increased exposure to both drugs. If cyclosporine is initiated after starting letermovir, decrease the next dose of letermovir to 240 mg once daily. If cyclosporine is discontinued after starting letermovir, increase the next dose of letermovir to 480 mg once daily. If cyclosporine dosing is interrupted due to high cyclosporine concentrations, no dose adjustment of letermovir is needed.
Levamlodipine: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
Levoketoconazole: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with ketoconazole is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-gp substrate and ketoconazole is a strong CYP3A4 and P-gp inhibitor.
Levothyroxine: (Moderate) Serum trough cyclosporine concentrations appear to be reduced by concurrent oral cyclosporine and levothyroxine use. Claosely monitor cyclosporine concentrations with concomitant levothyroxine therapy. Among 10 patients who took cyclosporine (Neoral) capsules twice daily for at least a year and oral levothyroxine 100 mcg daily for at least 3 months, the trough serum cyclosporine concentration was significantly lower as compared with values from 30 patients who only took cyclosporine. The mechanism of the interaction may be decreased oral cyclosporine absorption. Cyclosporine is a substrate of P-glycoprotein (P-gp), and levothyroxine appears to be an inducer of intestinal P-gp.
Levothyroxine; Liothyronine (Porcine): (Moderate) Serum trough cyclosporine concentrations appear to be reduced by concurrent oral cyclosporine and levothyroxine use. Claosely monitor cyclosporine concentrations with concomitant levothyroxine therapy. Among 10 patients who took cyclosporine (Neoral) capsules twice daily for at least a year and oral levothyroxine 100 mcg daily for at least 3 months, the trough serum cyclosporine concentration was significantly lower as compared with values from 30 patients who only took cyclosporine. The mechanism of the interaction may be decreased oral cyclosporine absorption. Cyclosporine is a substrate of P-glycoprotein (P-gp), and levothyroxine appears to be an inducer of intestinal P-gp.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Serum trough cyclosporine concentrations appear to be reduced by concurrent oral cyclosporine and levothyroxine use. Claosely monitor cyclosporine concentrations with concomitant levothyroxine therapy. Among 10 patients who took cyclosporine (Neoral) capsules twice daily for at least a year and oral levothyroxine 100 mcg daily for at least 3 months, the trough serum cyclosporine concentration was significantly lower as compared with values from 30 patients who only took cyclosporine. The mechanism of the interaction may be decreased oral cyclosporine absorption. Cyclosporine is a substrate of P-glycoprotein (P-gp), and levothyroxine appears to be an inducer of intestinal P-gp.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine 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; cyclosporine inhibits CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine 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; cyclosporine inhibits CYP3A4.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and cyclosporine 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; cyclosporine inhibits CYP3A4.
Linagliptin; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Liraglutide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including liraglutide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Lixisenatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including lixisenatide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Lomitapide: (Major) Concomitant use of lomitapide and cyclosporine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Cyclosporine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and cyclosporine is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp inhibitor; cyclosporine is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor.
Lonapegsomatropin: (Moderate) Somatropin may increase the activity of cytochrome-mediated metabolism of cyclosporine clearance.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with cyclosporine. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and cyclosporine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with cyclosporine. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and cyclosporine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Lorlatinib: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with lorlatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; it is also a substrate of P-glycoprotein (P-gp). Lorlatinib is a weak CYP3A4 inducer and a moderate inducer of P-gp.
Losartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like losartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with losartan.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like losartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with losartan.
Lovastatin: (Major) Avoid the concurrent use of cyclosporine and lovastatin. Cyclosporine may increase the risk of myopathy, rhabdomyolysis and acute renal failure in patients taking lovastatin. In uncontrolled clinical studies of lovastatin, myopathy was reported more frequently in patients receiving concomitant therapy with cyclosporine. Cyclosporine may reduce the clearance of the HMG-CoA reductase inhibitors (statins), Cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors, presumably due to CYP3A4 inhibition.
Lumacaftor; Ivacaftor: (Major) Concomitant use of cyclosporine and lumacaftor; ivacaftor is not recommended. If concurrent use cannot be avoided, monitor cyclosporine serum concentrations closely and adjust the dose accordingly. Lumacaftor; ivacaftor may decrease the systemic exposure of cyclosporine. In return, cyclosporine may increase ivacaftor exposure, although the clinical significance of this interaction is unclear. Cyclosporine is a substrate and moderate inhibitor of CYP3A. Lumacaftor is a strong inducer of CYP3A, and ivacaftor is CYP3A substrate. In addition, the exposure of cyclosporine may be altered via P-glycoprotein (P-gp) transport. Cyclosporine is P-gp substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit P-gp.
Lumacaftor; Ivacaftor: (Major) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. More careful monitoring of cyclosporine blood concentrations may be warranted. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-gp; cyclosporine is a CYP3A and P-gp substrate.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of cyclosporine is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and cyclosporine due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor.
Mannitol: (Major) Avoid use of mannitol and cyclosporine, if possible. Concomitant administration of nephrotoxic drugs, such as cyclosporine, increases the risk of renal failure after administration of mannitol.
Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and cyclosporine as increased maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A, P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP1B), and multidrug resistance-associated protein (MRP2). Cyclosporine is a CYP3A4, P-gp, OATP1B1, and MRP2 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Maribavir: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with maribavir is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-gp substrate and maribavir is a P-gp and weak CYP3A4 inhibitor.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting cyclosporine therapy. Avoid initiation of cyclosporine in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable cyclosporine therapy. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with mavacamten is necessary. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions, and may decrease cyclosporine exposure resulting in decreased efficacy. Mavacamten is a substrate and moderate inducer of CYP3A and cyclosporine is a substrate and moderate inhibitor of CYP3A; it has a narrow therapeutic index. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Meclofenamate Sodium: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Mefenamic Acid: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Cyclosporine is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
Meloxicam: (Moderate) Monitor serum creatinine, potassium concentrations, and cyclosporine concentrations closely when systemic cyclosporine is given with meloxicam. Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs, particularly in a dehydrated patient. The effects of NSAIDs on the production of renal prostaglandins may also cause changes in the elimination of cyclosporine. Monitor patients closely for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Melphalan Flufenamide: (Major) Concomitant use of melphalan and cyclosporine may result in additive nephrotoxicity. Severe renal impairment was reported in patients who received a single dose of melphalan 140 to 250 mg/m2 IV followed by standard oral doses of cyclosporine. If these agents are used together, closely monitor renal function (e.g., serum creatinine, BUN); consider a dosage reduction of cyclosporine or melphalan or switch to alternate treatment in patients who develop renal impairment.
Melphalan: (Major) Concomitant use of melphalan and cyclosporine may result in additive nephrotoxicity. Severe renal impairment was reported in patients who received a single dose of melphalan 140 to 250 mg/m2 IV followed by standard oral doses of cyclosporine. If these agents are used together, closely monitor renal function (e.g., serum creatinine, BUN); consider a dosage reduction of cyclosporine or melphalan or switch to alternate treatment in patients who develop renal impairment.
Mercaptopurine, 6-MP: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Metformin; Repaglinide: (Major) Use of cyclosporine with repaglinide results in increased repaglinide exposure and an increased risk for hypoglycemia. Limit the repaglinide daily dose to 6 mg/day and increase the frequency of glucose monitoring. Cyclosporine has additionally been associated with hyperglycemia and may independently alter blood glucose, via a directe effect on beta cells in the pancreas. Monitor closely for alterations in glycemic control. Cyclosporine inhibits the metabolism of repaglinide by inhibiting the drug transporter OATP1B1, which is an active hepatic uptake transporter, and also inhibits CYP3A4. In a drug interaction study, cyclosporine increased low-dose repaglinide exposures by 2.5 fold. Increased repaglinide concentrations were also noted among healthy patients who took oral cyclosporine 100 mg daily for 2 days; after a single 0.25 mg repaglinide dose, the mean AUC for repaglinide increased 244% (range, 119% to 533%) as compared with control data. (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Metformin; Rosiglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Metformin; Saxagliptin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Metformin; Sitagliptin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Methazolamide: (Minor) Acetazolamide may increase serum cyclosporine concentrations. Data are not available regarding an interaction between cyclosporine and other carbonic anhydrase inhibitors (e.g., methazolamide), although monitoring is warranted.
Methohexital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Methotrexate: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as methotrexate, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully. Additionally, concurrent administration of methotrexate and cyclosporine in patients with rheumatoid arthritis can elevate methotrexate concentrations and decrease the levels of the 7-hydroxy-methotrexate metabolite. Of 20 patients with rheumatoid arthritis that received methotrexate and cyclosporine, the mean peak methotrexate concentration increased 26%, the mean methotrexate AUC increased 18%, and the AUC of the 7-hydroxy-methotrexate metabolite decreased 80% as compared with patients that received methotrexate alone. Cyclosporine concentrations do not appear to be altered, but data is from only 6 patients. Monitoring of methotrexate and cyclosporine concentrations during concurrent cyclosporine therapy is recommended.
Methylprednisolone: (Moderate) Convulsions have been reported during concurrent use of cyclosporine and high dose methylprednisolone. In addition, mutual inhibition of metabolism occurs with concurrent use of cyclosporine and methylprednisolone; therefore, the potential for adverse events associated with either drug may be increased. Coadministration should be approached with caution.
Methyltestosterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Metoclopramide: (Moderate) Monitor cyclosporine concentrations and adjust the dose as needed if concomitant use of metoclopramide is necessary. Metoclopramide alters gastric motility resulting in increased absorption of cyclosporine.
Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving cyclosporine, drug concentration monitoring should be performed and the cyclosporine dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as cyclosporine.
Metronidazole: (Major) Monitor serum concentrations of cyclosporine when coadministered with systemic metronidazole. Concomitant use with metronidazole may increase the serum concentrations of cyclosporine; thereby, increasing the risk of side effects. Also, medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after metronidazole is discontinued. Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Micafungin: (Moderate) Leukopenia, neutropenia, anemia, and thrombocytopenia have been associated with micafungin. In theory, patients who are taking immunosuppressive agents such as cyclosporine concomitantly with micafungin may have additive risks for infection or other side effects. However, the manufacturer has listed no particular precautions for co-use of micafungin with cyclosporine. Concurrent administration of micafungin and cyclosporinel did not alter the pharmacokinetic parameters of micafungin. Furthermore, there was no effect of a single or multiple doses of micafungin on cyclosporine pharmacokinetic parameters.
Mifepristone: (Contraindicated) Coadministration of cyclosporine is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome. Mifepristone, a CYP3A4 inhibitor, is likely to increase cyclosporine concentrations and adverse effects, since cyclosporine is a CYP3A4 substrate with a narrow therapeutic index. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Miglitol: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible. Monitor the blood glucose.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with cyclosporine and monitor hemoglobin and for adverse reactions. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with mitapivat is necessary. Coadministration increases mitapivat concentrations and may have an unpredictable effect on cyclosporine. Mitapivat is a CYP3A substrate and weak inducer and P-gp inhibitor and cyclosporine is a CYP3A substrate and moderate inhibitor and P-gp substrate. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with mitotane is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; mitotane is a strong CYP3A inducer.
Mitoxantrone: (Major) Concurrent use of mitoxantrone with other agents which cause bone marrow or immune suppression such as other immunosuppressives may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of mitoxantrone by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to mitoxantrone therapy may increase the intracellular concentrations of mitoxantrone leading to increased efficacy and side effects.
Mivacurium: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and cyclosporine; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Concurrent use may also decrease cyclosporine exposure resulting in decreased efficacy. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with mobocertinib is necessary. Mobocertinib is a CYP3A substrate and weak CYP3A inducer; cyclosporine is a CYP3A substrate and moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Modafinil: (Moderate) Modafinil can increase the clearance of cyclosporine by inducing cyclosporine metabolism. Increased cyclosporine clearance and decreased cyclosporine concentrations can lead to loss of therapeutic effect or organ rejection. Cyclosporine concentrations should be monitored closely after the addition of modafinil until a new steady-state level is achieved.
Mycophenolate: (Moderate) Because mycophenolate mofetil is an immunosuppressant, additive affects may be seen with other immunosuppressives, such as cyclosporine.
Nabumetone: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Nafcillin: (Moderate) Nafcillin can increase the clearance of cyclosporine by inducing cyclosporine metabolism. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy until a new steady-state cyclosporine concentration is achieved when nafcillin is added to an existing cyclosporine regimen.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with cyclosporine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; cyclosporine is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and cyclosporine due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with cyclosporine is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. In vitro, the metabolism of paclitaxel is inhibited by cyclosporine at concentrations that exceed those found in vivo following normal therapeutic doses.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and cyclosporine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adv erse effects. Sirolimus is a CYP3A and P-gp substrate and cyclosporine is a moderate CYP3A and P-gp inhibitor.
Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Naproxen; Esomeprazole: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Naproxen; Pseudoephedrine: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. The safety and efficacy of natalizumab in combination with immunosuppressants has not been evaluated. Multiple sclerosis (MS) patients receiving chronic immunosuppressant therapy should not ordinarily be treated with natalizumab. Also, natalizumab for Crohn's disease should not be used in combination with cyclosporine.
Nateglinide: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
Nebivolol; Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
Nefazodone: (Major) Both nefazodone and cyclosporine are substrates and inhibitors of CYP3A4. Nefazodone is known to increase cyclosporine serum concentrations by inhibiting cyclosporine metabolism. A single case report is noted of increasing cyclosporine concentrations after the addition of nefazodone; the cyclosporine concentration returned to previous levels after the discontinuation of nefazodone. The manufacturer has also received reports of this interaction. In some cases cyclosporine levels have been seven-times their baseline after nefazodone administration. Because of the potential toxicity of cyclosporine, nefazodone should be used cautiously, if at all, in patients receiving cyclosporine. Monitoring of serum cyclosporine concentrations is recommended.
Nelfinavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Neomycin: (Minor) Because the systemic absorption of neomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of cyclosporine and systemic neomycin may increase the risk of nephrotoxicity or ototoxicity.
Neratinib: (Major) Avoid concomitant use of cyclosporine with neratinib due to an increased risk of neratinib-related toxicity; cyclosporine exposure may also increase. Neratinib is a CYP3A4 substrate and cyclosporine is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Nevirapine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with nevirapine is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; nevirapine is a weak CYP3A inducer.
Niacin; Simvastatin: (Contraindicated) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1.
Nicardipine: (Moderate) Coadministration of nicardipine and cyclosporine may result in elevated plasma cyclosporine concentrations. Monitor plasma concentrations of cyclosporine closely, and adjust the dose as necessary. Cyclosporine is extensively metabolized by CYP3A4; nicardipine is an inhibitor of CYP3A4.
Nifedipine: (Moderate) Cyclosporine may increase nifedipine blood concentrations when given concomitantly. Concurrent use of cyclosporine and nifedipine has been associated with increased severity and frequency of gingival hyperplasia; patients receiving these drugs together should be instructed to follow strict oral hygiene. Patients with severe gingival hyperplasia should be promptly referred for evaluation. Nifedipine has been shown to have minimal effects on cyclosporine blood concentrations.
Nilotinib: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, and cyclosporine, a CYP3A4 substrate and inhibitor with a narrow therapeutic range, may result in increased nilotinib and/or cyclosporine levels. A dose reduction of either agent may be necessary if these drugs are used together; monitor patients for nilotinib and cyclosporine toxicity (e.g., cyclosporine concentrations to help avoid graft failure or drug-related toxicity and QT interval prolongation).
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cyclosporine, 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. Cyclosporine is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) Before prescribing ritonavir-boosted nirmatrelvir for a patient receiving cyclosporine, the patient's specialist provider(s) should be consulted, given the significant drug-drug interaction potential and because close monitoring may not be feasible. If this is not feasible, consider an alternative COVID-19 therapy. Coadministration may increase cyclosporine exposure resulting in increased toxicity. Cyclosporine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with cyclosporine due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and cyclosporine is a CYP3A4 inhibitor.
Non-Ionic Contrast Media: (Moderate) Because the use of other nephrotoxic drugs, including cyclosporine, is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, when possible, cyclosporine should be withheld during radiopaque contrast agent administration.
Obeticholic Acid: (Major) Avoid coadministration of obeticholic acid, an inhibitor of the bile salt efflux pump (BSEP) with other BSEP inhibitors, such as cyclosporine; if coadministration is necessary, monitor serum transaminases and bilirubin. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms.
Octreotide: (Major) Octreotide may induce cyclosporine metabolism, thereby increasing the clearance of cyclosprone. In addition, administration of octreotide to patients receiving oral cyclosporine has been shown to decrease the oral bioavailability of cyclosporine. Since oral cyclosporine is administered in an olive oil vehicle, the mechanism of this interaction is thought to be due to the decreased absorption of fat by octreotide. If octreotide is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if octreotide is discontinued, cyclosporine concentrations could increase.
Odevixibat: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with odevixibat is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; odevixibat is a weak CYP3A inducer.
Olanzapine; Fluoxetine: (Moderate) Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of cyclosporine.
Olaparib: (Major) Avoid coadministration of olaparib with cyclosporine due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after cyclosporine is discontinued. Olaparib is a CYP3A substrate and cyclosporine is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
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 cyclosporine is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and cyclosporine may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If cyclosporine 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 cyclosporine is a moderate CYP3A4 inhibitor.
Olmesartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like olmesartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with olmesartan.
Olutasidenib: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with olutasidenib is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A and has a narrow therapeutic index; olutasidenib is a weak CYP3A inducer.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and cyclosporine. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Additionally, closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate as concomitant use may also decrease cyclosporine exposure resulting in decreased efficacy. Omaveloxolone is a CYP3A substrate and weak CYP3A inducer and cyclosporine is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
Oritavancin: (Moderate) Avoid use of oritavancin with drugs that have a narrow therapeutic window, such as cyclosporine. Cyclosporine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of cyclosporine may be reduced if these drugs are administered concurrently. Monitor for lack of cyclosporine efficacy.
Orlistat: (Major) Orlistat decreases the absorption of fat by inhibiting gastrointestinal lipases and as cyclosporine is dependent on lipid absorption, especially the Sandimmune formulation, the absorption of cyclosporine is inhibited. Caution is advised with the concomitant use of orlistat and cyclosporine therapy. More frequent cyclosporine concentration monitoring may be needed. To reduce the chance of a drug-drug interaction, cyclosporine should be administered at least 2 hours before or after orlistat in patients taking both drugs; although, as noted, separation of administration times may not always alter the course of the interaction.
Osilodrostat: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with osilodrostat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Osilodrostat is a weak inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Osimertinib: (Moderate) Monitor cyclosporine levels if coadministration with osimertinib is necessary; adjust the dose of cyclosporine if clinically appropriate. Cyclosporine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase cyclosporine exposure.
Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with cyclosporine due to the risk of increased oxaliplatin-related adverse reactions. Cyclosporine is known to be potentially nephrotoxic; because platinum-containing drugs like oxaliplatin are eliminated primarily through the kidney, oxaliplatin clearance may be decreased by coadministration with nephrotoxic agents.
Oxandrolone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Oxaprozin: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Oxcarbazepine: (Moderate) Oxcarbazepine and its active metabolite, MHD, are dose-dependent inducers of the hepatic CYP3A4/5 isoenzymes thereby having the potential to lower the plasma levels of medications metabolized through these pathways, including cyclosporine.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine 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 moderate inhibitor like cyclosporine 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 cyclosporine 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.
Oxymetholone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Paclitaxel: (Major) In vitro, the metabolism of paclitaxel is inhibited by cyclosporine, but cyclosporine concentrations used exceeded those found in vivo following normal therapeutic doses used in transplantation. Additionally, cyclosporine blocks the multidrug resistance (MDR) P-glycoprotein, which is a mechanism of resistance to naturally occurring (non-synthetic) chemotherapy agents. These agents could enhance paclitaxel's activity and toxicity. Paclitaxel has poor oral availability due to its high affinity for P-glycoprotein present in high levels in the GI tract. In clinical studies, oral paclitaxel has been given in combination with cyclosporine to improve the bioavailability of paclitaxel, due to cyclosporine-induced blockade of P-glycoprotein located in the in GI tract. The bioavailability of oral paclitaxel was 8-fold higher when given in combination with cyclosporine than after oral paclitaxel alone. Therapeutic concentrations were achieved within 7.4 hours, comparable to an equivalent IV dose.
Pacritinib: (Major) Avoid concurrent use of pacritinib with cyclosporine due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Cyclosporine exposure may also increase. Pacritinib is a CYP3A substrate, a weak CYP3A4 inhibitor, and a P-gp inhibitor; cyclosporine is a moderate CYP3A inhibitor, a CYP3A4 substrate, and a P-gp substrate. The manufacturer of cyclosporine recommends closely monitoring cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with a weak CYP3A4 inhibitor is necessary.
Palbociclib: (Moderate) Monitor cyclosporine levels and watch for cyclosporine-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while cyclosporine is a CYP3A4 substrate with narrow therapeutic index.
Palovarotene: (Major) Avoid concomitant use of palovarotene and cyclosporine due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Pamidronate: (Moderate) Coadministration of pamidronate with other nephrotoxic drugs, including cyclosporine, may increase the risk of developing nephrotoxicity following pamidronate administration, even in patients who have normal renal function.
Pancuronium: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Paromomycin: (Minor) Because the systemic absorption of oral paromomycin is minimal, the risk of this interaction is expected to be low; however, the combined use of cyclosporine and paromomycin may increase the risk of nephrotoxicity or ototoxicity.
Pasireotide: (Major) Pasireotide and cyclosporine coadministration may decrease the relative bioavailability of cyclosporine. Patients taking both of these drugs should have their cyclosporine concentrations monitored; if needed, adjust the cyclosporine dosage to maintain therapeutic concentrations.
Pazopanib: (Major) Avoid administering pazopanib with strong breast cancer resistance protein (BCRP) inhibitors, such as cyclosporine. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a CYP3A4, P-glycoprotein (P-gp), and BCRP substrate, and cyclosporine, a CYP3A4, P-gp, and BCRP inhibitor and CYP3A4 substrate, may result in altered pazopanib and/or cyclosporine concentrations.
Peginterferon Alfa-2b: (Moderate) Concomitant use of immunosuppressive agents, such as cyclosporine, with peginterferon alfa-2b warrants the therapeutic monitoring of the immunosuppressant in appropriate populations as the effect on immunosuppressant concentrations is unknown.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and cyclosporine 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 cyclosporine is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of cyclosporine. Pemigatinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentamidine: (Moderate) Additive nephrotoxicity may be seen with the combination of pentamidine and other agents that cause nephrotoxicity, including cyclosporine.
Pentobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Pentostatin: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Perindopril; Amlodipine: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and cyclosporine due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease cyclosporine 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. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; cyclosporine is a CYP3A substrate and moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Phenytoin: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
Pioglitazone: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
Pioglitazone; Glimepiride: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
Pioglitazone; Metformin: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity. Also, any drug that deteriorates the renal status of the patient is likely to alter metformin concentrations in the body, so renal function should be carefully monitored during the use of cyclosporine and metformin together.
Piroxicam: (Moderate) Additive decreases in renal function have been reported between cyclosporine and NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Pirtobrutinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with pirtobrutinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and pirtobrutinib is a P-gp and weak CYP3A inhibitor.
Pitavastatin: (Contraindicated) Coadministration of pitavastatin and cyclosporine is contraindicated due to significantly increased pitavastatin exposure and risk for myopathy or rhabdomyolysis. In a drug interaction study, concurrent use of cyclosporine increased the pitavastatin Cmax and AUC by 6.6- and 4.6-fold, respectively.
Polymyxin B: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, as cyclosporine itself can cause structural kidney damage and there is potential for additive nephrotoxicity. Systemic polymyxin B should generally not be used concurrently or sequentially with other drugs that have the potential for nephrotoxicity or neurotoxicity. Monitor renal function and fluid status carefully during co-use.
Posaconazole: (Major) The interactions between cyclosporine and systemic azole antifungals can be significant. Posaconazole may inhibit cyclosporine CYP3A4-mediated metabolism, which may result in increased cyclosporine blood concentrations. Cyclosporine concentrations may increase within 1 to 3 days after starting azole antifungal therapy, and may persist for > 1 week after discontinuing antifungal treatment. Posaconazole appears to inhibit cyclosporine metabolism in a dose-dependent fashion; higher doses result in greater inhibition of cyclosporine metabolism than do lower doses. Increased cyclosporine serum concentrations occurred when posaconazole was given to patients stabilized on cyclosporine. Reduce cyclosporine doses to three-fourths the original dose when initiating therapy with posaconazole. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and cyclosporine as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and cyclosporine as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations.
Potassium: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and cyclosporine are used together. Concomitant use may increase the risk of hyperkalemia.
Pralsetinib: (Major) Avoid concomitant use of cyclosporine with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A and P-gp substrate and cyclosporine is a combined moderate CYP3A and P-gp inhibitor. Coadministration increased the overall exposure of pralsetinib by 81%.
Pramlintide: (Moderate) Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents. Cyclosporine has been reported to cause hyperglycemia or exacerbate diabetes mellitus; this effect appears to be dose-related and caused by direct beta-cell toxicity.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Pravastatin: (Major) FDA-approved labeling recommends limiting the dose of pravastatin to 20 mg/day if coadministered with cyclosporine. However, guidelines recommend limiting the pravastatin dose to 40 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. During pharmacokinetic trials, a single dose of cyclosporine increased the AUC and Cmax of pravastatin by 282% and 327%, respectively. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving 100 post-transplant (cardiac or renal) patients treated for up to 2 years with pravastatin (10 to 40 mg) and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies.
Pretomanid: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with pretomanid is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and pretomanid is a P-gp inhibitor.
Primidone: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and cyclosporine 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. Cyclosporine 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 cyclosporine 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.
Protease inhibitors: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Purine analogs: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Quinine: (Moderate) Quinine is a substrate of P-glycoprotein (PGP), and cyclosporine is a PGP substrate and inhibitor. Therefore, quinine concentrations could be increased with coadministration. Monitor patients for increased side effects of quinine if these drugs are given together.
Rabeprazole: (Minor) Rabeprazole may inhibit the metabolism of cyclosporine, a CYP3A4 substrate.
Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as cyclosporine, may lead to increases in the serum concentrations of ramelteon.
Ranitidine: (Minor) Although data are conflicting, cautious use of ranitidine and cyclosporine is warranted; cyclosporine can cause nephrotoxicity, and ranitidine is substantially excreted by the kidney. The risk of toxic reactions to ranitidine may be greater in patients with impaired renal function; ranitidine dose reduction is needed for renal impairment.
Ranolazine: (Contraindicated) Cyclosporine inhibits the cytochrome P450 3A4 (CYP3A4) isoenzyme. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism by cyclosporine could lead to increased ranolazine plasma concentrations. In addition, ranolazine is a substrate of P-glycoprotein (P-gp); inhibitors of P-gp may increase the absorption of ranolazine and should be coadministered with caution. When possible, it is prudent to avoid coadministration of ranolazine with cyclosporine due to the potential for increased plasma concentrations of ranolazine, which may result in QT prolongation and increase the risk for proarrhythmias. If necessary to coadminister these drugs, it is prudent to monitor the individual patient response to ranolazine therapy closely, including an evaluation of the ECG effects and antianginal benefits during coadministration.
Red Yeast Rice: (Contraindicated) Since compounds in red yeast rice are chemically similar to and possess actions similar to lovastatin, patients should avoid this dietary supplement if they currently take cyclosporine, a drug known to increase the risk of myopathy when coadministered with HMG-CoA reductase inhibitors.
Relugolix: (Major) Avoid concomitant use of relugolix and oral cyclosporine. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer cyclosporine at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and cyclosporine is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral cyclosporine. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer cyclosporine at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and cyclosporine is a P-gp inhibitor.
Repaglinide: (Major) Use of cyclosporine with repaglinide results in increased repaglinide exposure and an increased risk for hypoglycemia. Limit the repaglinide daily dose to 6 mg/day and increase the frequency of glucose monitoring. Cyclosporine has additionally been associated with hyperglycemia and may independently alter blood glucose, via a directe effect on beta cells in the pancreas. Monitor closely for alterations in glycemic control. Cyclosporine inhibits the metabolism of repaglinide by inhibiting the drug transporter OATP1B1, which is an active hepatic uptake transporter, and also inhibits CYP3A4. In a drug interaction study, cyclosporine increased low-dose repaglinide exposures by 2.5 fold. Increased repaglinide concentrations were also noted among healthy patients who took oral cyclosporine 100 mg daily for 2 days; after a single 0.25 mg repaglinide dose, the mean AUC for repaglinide increased 244% (range, 119% to 533%) as compared with control data.
Revefenacin: (Major) Coadministration of revefenacin with cyclosporine is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cyclosporine is an inhibitor of OATP1B1/1B3.
Ribociclib: (Moderate) Monitor cyclosporine concentrations if coadministration with ribociclib is necessary; adjust the dose of cyclosporine if necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
Ribociclib; Letrozole: (Moderate) Monitor cyclosporine concentrations if coadministration with ribociclib is necessary; adjust the dose of cyclosporine if necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
Rifabutin: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
Rifampin: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
Rifamycins: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
Rifapentine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with rifamycins is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; rifamycins are CYP3A4 inducers.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cyclosporine 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 cyclosporine is a P-gp inhibitor. Coadministration with cyclosporine increased rifaximin overall exposure by 124-fold.
Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with cyclosporine; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; cyclosporine is a moderate CYP3A4 inhibitor and a P-gp inhibitor.
Ritlecitinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with ritlecitinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Rivaroxaban: (Minor) The coadministration of rivaroxaban and cyclosporine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these drugs are coadministered to patients with normal renal function. Cyclosporine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 mL/minute [HR (95% CI): 1.05 (0.77, 1.42)].
Rocuronium: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Rolapitant: (Major) Avoid the concurrent use of cyclosporine and rolapitant if possible; if coadministration is necessary, monitor cyclosporine levels and watch for cyclosporine-related adverse effects. Cyclosporine is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Additionally, cyclosporine is an inhibitor of CYP3A4 and rolapitant is a CYP3A4 substrate. Theoretically this could increase rolapitant concentrations, but this effect is not expected to be clinically relevant.
Romidepsin: (Moderate) Romidepsin is a substrate for P-glycoprotein (P-gp). Cyclosporine is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
Rosiglitazone: (Moderate) Cyclosporine has been reported to cause hyperglycemia; this effect appears to be dose-related and caused by direct beta-cell toxicity. Therefore, a pharmacodynamic interaction is possible with all antidiabetic agents and cyclosporine. Patients should be monitored for worsening glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents.
Rosuvastatin: (Major) Do not exceed a rosuvastatin dose of 5 mg once daily when coadministered with cyclosporine. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1) and breast cancer resistance protein (BCRP) and cyclosporine is an inhibitor of these transporters. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. The rosuvastatin AUC was increased 7-fold in the presence of cyclosporine.
Rosuvastatin; Ezetimibe: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine. (Major) Do not exceed a rosuvastatin dose of 5 mg once daily when coadministered with cyclosporine. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1) and breast cancer resistance protein (BCRP) and cyclosporine is an inhibitor of these transporters. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis. The rosuvastatin AUC was increased 7-fold in the presence of cyclosporine.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Rucaparib: (Moderate) Monitor cyclosporine levels and watch for cyclosporine-related adverse reactions if coadministration with rucaparib is necessary. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and rucaparib is a weak CYP3A4 inhibitor. Concomitant use may increase plasma concentrations of cyclosporine.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cyclosporine, may occur during concurrent use with rufinamide.
Sacubitril; Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
Salicylates: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like cyclosporine may lead to additive nephrotoxicity.
Saquinavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Sarilumab: (Moderate) Monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with sarilumab is necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cyclosporine is a CYP3A4 substrate and a narrow therapeutic index drug.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Phenobarbital may induce cyclosporine metabolism, thereby increasing the clearance of cyclosporine. It is likely that other barbiturates would interact similarly with cyclosporine; however no supportive data are available. If phenobarbital is added to an existing cyclosporine regimen, monitor cyclosporine concentrations closely to avoid loss of clinical efficacy until a new steady-state concentration is achieved. Conversely, if phenobarbital is discontinued, cyclosporine concentrations could increase.
Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking cyclosporine, monitor cyclosporine concentrations; cyclosporine dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. These interactions remain theoretical. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Coadministration may result in increased serum concentrations of cyclosporine or segesterone. There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity, and/or hepatotoxicity. If segesterone is initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. In addition, coadministration of segesterone and moderate CYP3A4 inhibitors such as cyclosporine may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and cyclosporine due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. Concurrent use may also increase cyclosporine exposure; closely monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate. If cyclosporine is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of cyclosporine. Selpercatinib is a CYP3A4 substrate, a weak CYP3A4 inhibitor, and a P-gp inhibitor. Cyclosporine is a CYP3A4 substrate, a moderate CYP3A4 inhibitor, and a P-gp substrate. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events.
Selumetinib: (Major) Avoid coadministration of selumetinib and cyclosporine 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 cyclosporine is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cyclosporine. Selumetinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Semaglutide: (Moderate) Consider increased clinical or laboratory monitoring for oral cyclosporine administered with oral semaglutide as the absorption of cyclosporine may be altered. Semaglutide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications. Be sure to administer oral semaglutide as directed, separately from other oral medications. This absorption interaction does not occur with subcutaneous semaglutide or IV cyclosporine. Patients should also be monitored for worsening of glycemic control when any form of systemic cyclosporine is initiated in patients receiving antidiabetic agents, including semaglutide. Cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity and the effects may be dose-related.
Sertraline: (Moderate) Although a causal relationship has not been established, the combination of cyclosporine and sertraline is suspected of causing serotonin syndrome in a renal transplant patient. Sertraline serum concentrations may have increased due to possible CYP3A4 inhibition by cyclosporine.
Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of cyclosporine from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because cyclosporine has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
Silodosin: (Major) In vitro data indicate that silodosin is a P-glycoprotein substrate. The manufacturer of silodosin recommends against concurrent use of silodosin and potent P-gp inhibitors such as cyclosporine.
Siltuximab: (Moderate) Monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cyclosporine is a CYP3A4 substrate and a narrow therapeutic index drug.
Simvastatin: (Contraindicated) The use of simvastatin with is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Cyclosporine increases the AUC of statins when administered concomitantly, and the risk for myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Although the mechanism is not fully understood, it is presumably due to inhibition of CYP3A4 and/or OAT1B1 by cyclosporine; simvastatin is a substrate of CYP3A4 and OAT1B1.
Siponimod: (Moderate) Concomitant use of siponimod and cyclosporine 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; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and immunosuppressives should be avoided. Concurrent administration of immunosuppressives with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving immunosuppressives may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of immunosuppressives prior to initiating therapy with sipuleucel-T.
Sirolimus: (Moderate) Administer oral sirolimus 4 hours after oral cyclosporine. Simultaneous oral coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. While the effect of this interaction is diminished when administered separately, additional sirolimus dosage reductions may be required in some patients. Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate. Simultaneous coadministration has been observed to increase sirolimus overall exposure by 148% to 230%; separating administration by 4 hours has been observed to increase sirolimus overall exposure by 33% to 80%.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and cyclosporine. Monitor serum transaminases, bilirubin, and cyclosporine concentrations if coadministration cannot be avoided; the dose of cyclosporine may need to be adjusted. Cyclosporine may inhibit canalicular membrane bile acid transporters, such as the bile salt export pump (BSEP), resulting in excessive accumulation of conjugated bile salts in the liver. Concomitant use may also alter cyclosporine exposure. Cyclosporine is a CYP3A and P-gp substrate and sodium phenylbutyrate; taurursodiol is a weak CYP3A inducer and P-gp inhibitor. The net effect on cyclosporine exposure is unknown.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with cyclosporine. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Velpatasvir is also a substrate for the Breast Cancer Resistance Protein (BCRP). Cyclosporine is a BCRP inhibitor. In addition, cyclosporine is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and cyclosporine. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Cyclosporine is also an inhibitor of the Organic Anion Transporting Polypeptides 1B1 (OATP1B1 ), Breast Cancer Resistance Protein (BCRP), and CYP3A4; voxilaprevir is a substrate of OATP1B1, BCRP, and CYP3A4. (Moderate) Use caution when administering velpatasvir with cyclosporine. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Velpatasvir is also a substrate for the Breast Cancer Resistance Protein (BCRP). Cyclosporine is a BCRP inhibitor. In addition, cyclosporine is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Somatropin, rh-GH: (Moderate) Somatropin may increase the activity of cytochrome-mediated metabolism of cyclosporine clearance.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and cyclosporine; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and cyclosporine is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Moderate) Monitor for an increase in cyclosporine plasma concentrations and cyclosporine-related adverse reactions if coadministration with sorafenib is necessary. Cyclosporine is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotorasib: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with sotorasib is necessary. Concurrent use may alter cyclosporine exposure resulting in decreased efficacy or increased toxicity. Cyclosporine is a CYP3A4 and P-gp substrate and has a narrow therapeutic index; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Sparsentan: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with sparsentan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Additionally, monitor for an increase in sparsentan-related adverse effects as concomitant use may also increase sparsentan exposure. Concomitant use increased sparsentan overall exposure by 70%. Cyclosporine is a P-gp substrate and moderate CYP3A inhibitor and sparsentan is a CYP3A substrate and P-gp inhibitor.
Spironolactone: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as spironolactone, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations. Additionally, closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions as concurrent use may increase cyclosporine exposure. The dose of cyclosporine may need to be adjusted. Cyclosporine is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as spironolactone, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations. Additionally, closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions as concurrent use may increase cyclosporine exposure. The dose of cyclosporine may need to be adjusted. Cyclosporine is a CYP3A substrate and spironolactone is a weak CYP3A inhibitor.
St. John's Wort, Hypericum perforatum: (Contraindicated) Clinical interactions between cyclosporine and St. John's wort, Hypericum perforatum have been reported. It appears that St. John's wort may increase the metabolism of cyclosporine through induction of the hepatic CYP3A4 isoenzyme. Clinically, decreased cyclosporine concentrations resulting from the concurrent administration of St. John's wort have led to reports of acute heart transplant rejection. A similar report of subtherapeutic cyclosporine concentrations has been noted in a kidney-pancreas transplant patient who self-medicated with St. John's wort. Graft loss has occurred. St. John's wort in all forms, including teas, should be avoided in patients treated with cyclosporine.
Stiripentol: (Moderate) Consider a dose adjustment of cyclosporine when coadministered with stiripentol. Coadministration may alter plasma concentrations of cyclosporine resulting in an increased risk of adverse reactions and/or decreased efficacy. Cyclosporine is a CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with dalfopristin; quinupristin. Use of these medications together resulted in a 63% increase in exposure of cyclosporine, which may increase the risk for cyclosporine-related toxicity. Dalfopristin; quinupristin is a weak inhibitor of CYP3A4 and cyclosporine is a CYP3A4 substrate.
Streptomycin: (Major) Cyclosporine should be used cautiously with nephrotoxic drugs, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as streptomycin. Monitor renal function and fluid status carefully during cyclosporine usage.
Succinylcholine: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if cyclosporine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine 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 moderate CYP3A4 inhibitor like cyclosporine 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 cyclosporine 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: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with sulfadiazine. Use of these drugs together may result in decreased cyclosporine serum concentrations and the potential for decreased efficacy. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid the concomitant use of sulfamethoxazole; trimethoprim and cyclosporine. There have been reports of significant, but reversible nephrotoxicity with coadministration in renal transplant patients. In addition, there are case reports of reduced exposure to cyclosporine in patients receiving concomitant sulfonamides. Monitor renal function and cyclosporine concentrations if concomitant use is required.
Sulfasalazine: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with sulfasalazine. Use of these drugs together may result in decreased cyclosporine serum concentrations and the potential for decreased efficacy. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
Sulfonylureas: (Moderate) Sulfonylureas may increase concentrations of cyclosporine. Retrospective data from 6 adults with post-renal transplant diabetes mellitus and normal hepatic and renal function before and after glyburide initiation were examined. The mean plasma cyclosporine concentration from 5 months of data before glyburide use was 212.3 +/- 66.4 ng/ml. In contrast, the mean plasma cyclosporine concentration from 5 months of data during glyburide use was 334.8 +/- 65.8 ng/ml. Until more data are available, when glyburide is added to cyclosporine therapy, monitor cyclosporine concentrations and adjust cyclosporine dosage as necessary. Also, monitor patients for increased cyclosporine toxicity (renal dysfunction, neurotoxicity). In addition, cyclosporine has been reported to cause hyperglycemia. Cyclosporine may have direct beta-cell toxicity, the effects of which may be dose-related. Patients should be monitored for worsening of glycemic control if cyclosporine is initiated in patients receiving antidiabetic agents.
Sulindac: (Moderate) Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of sulindac. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling.
Sumatriptan; Naproxen: (Moderate) Serum creatinine ,potassium concentrations, and cyclosporine concentrations should be closely monitored when systemic cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of NSAIDs. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with cyclosporine. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Contraindicated) Concurrent use of cyclosporine and tacrolimus may increase the risk of nephrotoxicity due to synergistic or additive effects. Concomitant tacrolimus and cyclosporine usage is not recommended. When switching patients from cyclosporine to tacrolimus, wait at least 24 hours after the last dose of cyclosporine before beginning tacrolimus therapy. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be delayed until the concentration falls into the normal range.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of cyclosporine is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; cyclosporine is a P-gp and BCRP inhibitor.
Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as cyclosporine. 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; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with cyclosporine as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Additionally, concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If cyclosporine is discontinued, wait at least 3 half-lives of cyclosporine before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Teduglutide: (Moderate) Teduglutide may increase absorption of cyclosporine because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of cyclosporine is recommended.
Telavancin: (Minor) Concurrent or sequential use of telavancin with other potentially nephrotoxic drugs such as cyclosporine may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
Telmisartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like telmisartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with telmisartan.
Telmisartan; Amlodipine: (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like telmisartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with telmisartan.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like telmisartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with telmisartan.
Telotristat Ethyl: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with telotristat is necessary. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; telotristat is a weak CYP3A4 inducer.
Temozolomide: (Minor) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Temsirolimus: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of temsirolimus with cyclosporine is necessary; monitor cyclosporine levels. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use may lead to increased concentrations of both cyclosporine and temsirolimus.
Teniposide: (Minor) Concurrent use of teniposide or etoposide with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Tenofovir Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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 Alafenamide: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Additionally, monitoring for changes in renal function is advised if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions. Also, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. 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: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus.
Tepotinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with tepotinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and tepotinib is a P-gp inhibitor.
Terbinafine: (Moderate) Terbinafine has been found to increase the clearance of cyclosporine. As decreased cyclosporine serum concentrations and thus, an increased risk of organ rejection are possible, monitoring of cyclosporine concentrations is recommended during terbinafine use.
Testolactone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Testosterone: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with cyclosporine; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. In addition, coadministration may increase the systemic exposure of cyclosporine. Appropriate monitoring should be used; adjust the cyclosporine dosage as necessary. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate), ivacaftor is a weak P-gp inhibitor, and cyclosporine is a moderate CYP3A inhibitor and P-gp substrate. (Major) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. More careful monitoring of cyclosporine blood concentrations may be warranted. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-gp; cyclosporine is a CYP3A and P-gp substrate.
Thioguanine, 6-TG: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Ticagrelor: (Moderate) Coadministration of ticagrelor and cyclosporine results in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor. No dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Ticlopidine: (Moderate) Ticlopidine decreases cyclosporine concentrations. It is prudent to monitor cyclosporine concentrations if ticlopidine therapy is initiated or discontinued.
Tigecycline: (Moderate) Monitor cyclosporine serum trough concentrations during treatment with tigecycline to avoid cyclosporine toxicity. Concomitant use of cyclosporine and tigecycline may lead to an increase in serum trough concentrations of cyclosporine.
Tinidazole: (Moderate) Monitor for signs of calcineurin-inhibitor associated toxicities during coadministration of tinidazole and cyclosporine. Data suggest that another nitroimidazole has the potential to increase cyclosporine concentrations.
Tipranavir: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
Tirzepatide: (Moderate) Patients should be monitored for worsening of glycemic control if therapy with cyclosporine is initiated in patients receiving antidiabetic agents, including tirzepatide. Cyclosporine has been reported to cause hyperglycemia. It may have direct beta-cell toxicity; the effects may be dose-related.
Tobramycin: (Major) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as aminoglycosides.
Tocilizumab: (Moderate) Monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cyclosporine is a CYP3A4 substrate and narrow therapeutic index drug.
Tofacitinib: (Major) Concomitant use of tofacitinib with cyclosporine is not recommended. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and tofacitinib is a CYP3A4 substrate. Increased systemic exposure of tofacitinib has been noted with concurrent cyclosporine administration, and dosage adjustment may be necessary. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Tolmetin: (Moderate) Additive decreases in renal function may occur with coadministration of NSAIDs and cyclosporine. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
Tolvaptan: (Major) Avoid coadministration of cyclosporine when tolvaptan is administered for hyponatremia; a reduction in the tolvaptan dose according to clinical response may be required if coadministration cannot be avoided. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with cyclosporine. In ADPKD patients receiving tolvaptan 90 mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Topotecan: (Major) Avoid coadministration of cyclosporine with oral topotecan due to increased topotecan exposure; cyclosporine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and cyclosporine is a P-gp inhibitor. Oral administration of topotecan within 4 hours of cyclosporine increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Trandolapril; Verapamil: (Moderate) Coadministration of verapamil with cyclosporine can lead to increased cyclosporine concentrations and toxicity. Verapamil inhibits CYP3A4 metabolism and thereby can increase the serum concentrations of cyclosporine. Verapamil should be used cautiously in patients stabilized on cyclosporine; cyclosporine dosage reduction may be required.
Tretinoin, ATRA: (Moderate) Patients should be closely monitored for tretinoin toxicity if concurrent therapy with cyclosporine is necessary; increased tretinoin exposure is possible, which may increase risks for adverse reactions. Cyclosporine is a moderate CYP3A4 inhibitor and tretinoin is metabolized by the hepatic CYP450 system. In a small study of patients stabilized on oral tretinoin therapy, a 72% increase in mean tretinoin plasma AUC was observed when a strong CYP3A4 inhibitor was given 1 hour before the tretinoin dose. To date there no data to determine if cyclosporine increases the toxicity of tretinoin capsules.
Triamterene: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as triamterene, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Triamterene; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of cyclosporine and potassium-sparing diuretics, such as triamterene, due to the risk of hyperkalemia. If concomitant use is necessary, closely monitor serum potassium concentrations.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with cyclosporine and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor.
Trofinetide: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with trofinetide is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Tucatinib: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with tucatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with cyclosporine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4, BCRP, and P-gp substrate; cyclosporine is a moderate CYP3A4 inhibitor and a BCRP and P-gp inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Upadacitinib: (Major) Do not use upadacitinib in combination with potent immunosuppressants such as cyclosporine. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and upadacitinib is a CYP3A4 substrate. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Ustekinumab: (Moderate) Upon initiation of usetkinumab in patients who are receiving cyclosporine, consider monitoring cyclosporine drug concentrations and adjusting the cyclosporine dose if clinically indicated, due to potential changes in CYP450 activity as inflammation is treated. The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF, IFN) during chronic inflammation. Thus, ustekinumab, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes, which might affect CYP450 substrates with a narrow therapeutic index.
Valacyclovir: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as valacyclovir. Monitor renal function and fluid status carefully.
Valganciclovir: (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with cyclosporine because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
Valsartan: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan.
Vancomycin: (Minor) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as vancomycin. Renal function should be monitored closely and vancomycin doses should be adjusted according to vancomycin serum concentrations.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with cyclosporine due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Vecuronium: (Moderate) Concomitant use of neuromuscular blockers and cyclosporine may prolong neuromuscular blockade.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and cyclosporine may result in altered concentrations of cyclosporine and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with cyclosporine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of cyclosporine. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cyclosporine is a CYP3A4 (moderate) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Verapamil: (Moderate) Coadministration of verapamil with cyclosporine can lead to increased cyclosporine concentrations and toxicity. Verapamil inhibits CYP3A4 metabolism and thereby can increase the serum concentrations of cyclosporine. Verapamil should be used cautiously in patients stabilized on cyclosporine; cyclosporine dosage reduction may be required.
Viloxazine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with viloxazine is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
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 cyclosporine is necessary. Vinblastine is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Moderate) Use cyclosporine and vincristine together with caution; concomitant use may result in increased vincristine plasma concentrations and increased vincristine toxicity. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and vincristine is a CYP3A4 and P-gp substrate. Early onset and/or increased severity of neuromuscular adverse events have been reported when vincristine was administered with a strong CYP3A4 and P-gp inhibitor.
Vincristine: (Moderate) Use cyclosporine and vincristine together with caution; concomitant use may result in increased vincristine plasma concentrations and increased vincristine toxicity. Cyclosporine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and vincristine is a CYP3A4 and P-gp substrate. Early onset and/or increased severity of neuromuscular adverse events have been reported when vincristine was administered with a strong CYP3A4 and P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cyclosporine is necessary. Vinorelbine is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor.
Vonoprazan; Amoxicillin: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with vonoprazan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (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. (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with vonoprazan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and cyclosporine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with cyclosporine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) The interactions between cyclosporine and systemic azole antifungals, including voriconazole, can be significant. Voriconazole may inhibit the metabolism and lead to increased concentrations of cyclosporine. Plasma cyclosporine concentrations should be monitored closely if voriconazole is added. Reduce cyclosporine doses by one-half when initiating therapy with voriconazole due to voriconazole-induced inhibition of CYP3A4. When voriconazole is discontinued, cyclosporine concentrations should be carefully monitored and the dose increased as needed. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
Voxelotor: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with voxelotor is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with cyclosporine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cyclosporine is a moderate 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.
Yellow Fever Vaccine, Live: (Contrain dicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Zafirlukast: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with zafirlukast is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 substrate and zafirlukast is a weak CYP3A4 inhibitor.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with cyclosporine. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of cyclosporine, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Zoledronic Acid: (Moderate) Since zoledronic acid is eliminated by the kidney, coadministration of zoledronic acid with other nephrotoxic drugs, such as cyclosporine, may increase serum concentrations of either zoledronic acid and/or these coadministered drugs.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and cyclosporine 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.

Cequa Ophthalmic Sol: 0.09%
Cyclosporine, Modified/Gengraf/Neoral/Sandimmune Oral Sol: 1mL, 100mg
Cyclosporine/Cyclosporine, Modified/Gengraf/Neoral/Sandimmune Oral Cap: 25mg, 50mg, 100mg
Cyclosporine/Klarity-C/Restasis/Verkazia Ophthalmic Emulsion: 0.05%, 0.1%
Cyclosporine/Sandimmune Intravenous Inj Sol: 1mL, 50mg

4 drops/day per affected eye for 0.1% ophthalmic emulsion; 2 drops/day per affected eye for 0.05% ophthalmic emulsion and 0.09% ophthalmic solution. For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations.

4 drops/day per affected eye for 0.1% ophthalmic emulsion; 2 drops/day per affected eye for 0.05% ophthalmic emulsion and 0.09% ophthalmic solution. For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations.

16 to 17 years: 4 drops/day per affected eye for 0.1% ophthalmic emulsion; 2 drops/day per affected eye for 0.05% ophthalmic emulsion. For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the 0.09% ophthalmic solution.
13 to 16 years: 4 drops/day per affected eye for 0.1% ophthalmic emulsion. For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the 0.05% ophthalmic emulsion or 0.09% ophthalmic solution.

4 to 12 years: 4 drops/day per affected eye for 0.1% ophthalmic emulsion. For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the 0.05% ophthalmic emulsion or 0.09% ophthalmic solution.
1 to 3 years: For systemic formulations, the maximum dosage is dependent on indication, route of therapy, and cyclosporine serum concentrations. Safety and efficacy have not been established for the ophthalmic emulsions or solution.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Cyclosporine induces immunosuppression by inhibiting the first phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early gene products (e.g., interleukins IL-2, IL-3, and IL-4, tumor necrosis factor alpha, and interferon gamma) that allow T-cells to progress from the G0 to G1 phases. Cyclosporine binds to an immunophilin termed cyclophilin. Immunophilins (e.g., cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein regulation. The cyclosporine-cyclophilin complex then binds to and inhibits the calcium-calmodulin activated phosphatase calcineurin. The calcineurin enzyme catalyzes critical dephosphorylation reactions necessary for early lymphokine gene transcription, and subsequent early activation of T-cells. Calcineurin inhibition results in blockade of signal transduction of the nuclear factor of activated T-cells (NF-AT). The blockade of signal transduction results in failure to activate NF-AT regulated genes. NF-AT activated genes include those required for B-cell activation including interleukin (IL)-4 and CD40 ligand and those required for T-cell activation including IL-2 and interferon gamma. Cyclosporine does not affect suppressor T-cells or T-cell independent, antibody-mediated immunity.
 
In patients with vernal keratoconjunctivitis or whose tear production is suppressed due to inflammation associated with keratoconjunctivitis sicca (dry eye disease), ophthalmic cyclosporine is thought to act as a partial immunomodulator by blocking release of pro-inflammatory cytokines such as IL-2. The exact mechanism of action is unknown. In dry eye syndrome, lymphocytes can aggregate and damage the lacrimal gland causing fibrosis and loss of tear production. Cyclosporine is thought to reverse this process by causing apoptosis of lymphocytes allowing for tear production.

Cyclosporine is administered orally, intravenously, or ophthalmically. Cyclosporine is extremely hydrophobic. First-pass metabolism, mode of administration, formulation, and drug interactions all affect cyclosporine absorption.
 
Cyclosporine is a substrate and inhibitor of P-glycoprotein, which is an energy-dependent drug-efflux pump located in intestinal epithelium and the blood brain barrier. There appears to be overlap between inhibitors and/or substrates of cytochrome P450 (CYP) 3A4 and P-glycoprotein. The P-glycoprotein efflux of cyclosporine from intestinal cells back into the gut lumen allows for CYP3A4 metabolism prior to absorption, thus limiting cyclosporine availability. When cyclosporine is administered with inhibitors of both CYP3A4 and P-glycoprotein (e.g., diltiazem, erythromycin, or ketoconazole) increased cyclosporine bioavailability leads to increased cyclosporine concentrations.
 
Cyclosporine is distributed widely throughout the body, crosses the placenta, and is found in breast milk. Preferential uptake of cyclosporine occurs in the liver, pancreas, and adipose tissue, while it penetrates the CNS poorly. In blood, the distribution of cyclosporine is concentration dependent; as the hemocrit rises, the cyclosporine concentration in plasma decreases. Approximately 22 to 47% of cyclosporine is found in plasma, 4 to 9% in lymphocytes, 5 to 12% in granulocytes, and 41 to 58% in erythrocytes. At high drug concentrations the binding to lymphocytes and erythrocytes becomes saturated. In plasma, cyclosporine is approximately 90% bound to lipoproteins. In addition, binding to erythrocytes and lipoproteins is temperature dependent. As the temperature increases, binding to lipoproteins increases; however, binding to erythrocytes increases as the temperature decreases. Other medications that may affect the binding of cyclosporine to lipoproteins may modify the clinical response to cyclosporine. Cyclosporine is metabolized extensively by the CYP3A enzyme system in the liver and to a lesser extent in the gastrointestinal tract and kidney. Agents that affect the CYP3A system may significantly alter the metabolism of cyclosporine. At least 25 metabolites of cyclosporine have been identified, some of which are biologically active. Although most cyclosporine metabolites show only 10 to 20% of the immunosuppressive activity of the parent drug, they do contribute to toxicity. The major metabolites of cyclosporine are M1, M9, and M4N, resulting from oxidation at the 1-beta, 9-gamma, and 4-N-desmethylated positions. The percentage of dose present as M1, M9, or M4N is similar when either cyclosporine (Modified) or cyclosporine (Nonmodified) is administered. At steady state, concentrations and AUCs of cyclosporine metabolites may exceed that of cyclosporine. Mean AUCs for blood concentrations of these metabolites are 70%, 21%, and 7.5% respectively, of blood cyclosporine concentrations. The elimination half-life of cyclosporine is highly variable. In patients with normal hepatic function the average half-life ranges from 16 to 27 hours, but can vary from 10-40 hours. Elimination of cyclosporine and its metabolites is principally through the bile and feces. Cyclosporine undergoes enterohepatic recycling. Only 6% of the cyclosporine dose is excreted renally, of which 0.1% is excreted as unchanged cyclosporine. Although cyclosporine blood levels are widely used to assist dosing, accurate interpretation is hampered by variation in absorption, variation in protein binding, sampling error, type of assay, cross-reactivity of metabolites, enterohepatic recycling of drug, and drug interactions.

Use of oral and intravenous formulations of cyclosporine during pregnancy should only be considered if the potential benefits to the mother justify the potential risks to the fetus; consider discontinuation of cyclosporine therapy in psoriasis patients. Prior to drug administration, females of childbearing age should be counseled about the potential risks of cyclosporine therapy and about appropriate contraceptive measures. Ophthalmic products do not produce significant concentrations of cyclosporine in the blood; thus maternal use of these formulations are not expected to result in fetal drug exposure. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. There are no adequate and well-controlled studies of cyclosporine during pregnancy. In animal models, cyclosporine has been shown to be embryotoxic and fetotoxic when given in maternally toxic doses. In pregnant transplant recipients who are being treated with immunosuppressants, the risk of premature births is increased. Outcomes of 116 pregnancies in women (mostly transplant patients) receiving cyclosporine throughout the entire gestational period showed premature birth (gestational period of 28 to 36 weeks) in 47% and low birth weight for gestational age in 28% of pregnancies. Sixteen fetal losses occurred. Most of the pregnancies were complicated by disorders including preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility and fetoplacental dysfunction. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Neonatal complications occurred in 27%. A limited number of observations in children up to approximately 7 years of age exposed to cyclosporine in utero is available. Renal function and blood pressure in these children were normal. Additionally, for an adult weighing 70 kg, the maximum daily oral dose of cyclosporine would deliver about 1 gram of alcohol (approximately 6% of the amount of alcohol contained in a standard drink), while the daily IV dose would deliver approximately 15% of the amount of alcohol contained in a standard drink. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to cyclosporine; information about the registry can be obtained at www.transplantpregnancyregistry.org or by calling 1-877-955-6877.

When administered systemically, cyclosporine is excreted into breast milk. The American Academy of Pediatrics considers cyclosporine a cytotoxic drug that may interfere with the cellular metabolism of a nursing infant. Cyclosporine preparations also contain ethanol, which will be present in human milk at levels similar to that found in maternal serum. There is no information on the presence of cyclosporine in human milk following topical administration or the effects of ophthalmic cyclosporine on the breastfed infant or milk production. Ophthalmic products produce low or undetectable blood concentrations, making it unlikely that clinically relevant amounts of the drug would be excreted into breast milk. Utilize caution when administering ophthalmic products to nursing women. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.