Invirase

Protease Inhibitors

Oral Administration

Administer orally within 2 hours after a full meal.
Saquinavir mesylate must be coadministered with ritonavir; administer saquinavir mesylate and ritonavir at the same time.

Severe

eczema vaccinatum / Delayed / 2.0-2.0
torsade de pointes / Rapid / 0-1.0
AV block / Early / 0-1.0
GI obstruction / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
intracranial bleeding / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
seizures / Delayed / Incidence not known
visual impairment / Early / Incidence not known

Moderate

lipodystrophy / Delayed / 5.0-5.0
hyperglycemia / Delayed / 3.0-3.0
diabetes mellitus / Delayed / 3.0-3.0
constipation / Delayed / 2.0-2.0
hyperbilirubinemia / Delayed / 4.0
gastritis / Delayed / Incidence not known
hyperamylasemia / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
erythema / Early / Incidence not known
bullous rash / Early / Incidence not known
peripheral vasoconstriction / Rapid / Incidence not known
hypertension / Early / Incidence not known
phlebitis / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
hyperlipidemia / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
hypertriglyceridemia / Delayed / Incidence not known
bleeding / Early / Incidence not known
hematoma / Early / Incidence not known
anemia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
ascites / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
confusion / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
depression / Delayed / Incidence not known
psychosis / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
PR prolongation / Rapid / Incidence not known
dyspnea / Early / Incidence not known
dehydration / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known
edema / Delayed / Incidence not known
nephrolithiasis / Delayed / Incidence not known

Mild

diarrhea / Early / 8.0-18.0
nausea / Early / 11.0-11.0
vomiting / Early / 7.0-10.0
abdominal pain / Early / 6.0-6.0
fatigue / Early / 6.0-6.0
infection / Delayed / 3.0-5.0
rash / Early / 3.0-3.0
pruritus / Rapid / 3.0-3.0
influenza / Delayed / 3.0-3.0
sinusitis / Delayed / 3.0-3.0
fever / Early / 3.0-3.0
xerosis / Delayed / 2.0-2.0
back pain / Delayed / 2.0-2.0
dysgeusia / Early / Incidence not known
xerostomia / Early / Incidence not known
eructation / Early / Incidence not known
flatulence / Early / Incidence not known
anorexia / Delayed / Incidence not known
dyspepsia / Early / Incidence not known
acne vulgaris / Delayed / Incidence not known
diaphoresis / Early / Incidence not known
alopecia / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
gynecomastia / Delayed / Incidence not known
Cushingoid features / Delayed / Incidence not known
tremor / Early / Incidence not known
hypoesthesia / Delayed / Incidence not known
drowsiness / Early / Incidence not known
dizziness / Early / Incidence not known
anxiety / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
headache / Early / Incidence not known
insomnia / Early / Incidence not known
syncope / Early / Incidence not known
cough / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
lethargy / Early / Incidence not known
arthralgia / Delayed / Incidence not known
myalgia / Early / Incidence not known
tinnitus / Delayed / Incidence not known

Invirase

Rx

Protease inhibitor (PI)
Used to treat HIV-1 infections in combination with ritonavir and other antiretroviral agents
Only use when 'boosted' with ritonavir; PR and QT prolongation (including TdP) reported

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents. Oral dosage Adults (Treatment-naive patients OR patients switching from a delavirdine- or rilpivirine-containing regimen)

500 mg PO twice daily with ritonavir 100 mg PO twice daily for the first 7 days. After 7 days, may increase to the standard dose of 1,000 mg PO twice daily with ritonavir 100 mg PO twice daily.

Adults (Treatment-experienced patients)

1,000 mg PO twice daily with ritonavir 100 mg PO twice daily for patients switching immediately (no washout period) from another ritonavir-containing regimen or from a NNRTI-based regimen (NOT including delavirdine or rilpivirine). No additional ritonavir is needed for patients already taking ritonavir 100 mg PO twice daily as part of their antiretroviral regimen.

Adolescents 17 years (Treatment-naive patients OR patients switching from a delavirdine- or rilpivirine-containing regimen)

500 mg PO twice daily with ritonavir 100 mg PO twice daily for the first 7 days. After 7 days, may increase to the standard dose of 1,000 mg PO twice daily with ritonavir 100 mg PO twice daily.

Adolescents 17 years (Treatment-experienced patients)

1,000 mg PO twice daily with ritonavir 100 mg PO twice daily for patients switching immediately (no washout period) from another ritonavir-containing regimen or from a NNRTI-based regimen (NOT including delavirdine or rilpivirine). No additional ritonavir is needed for patients already taking ritonavir 100 mg PO twice daily as part of their antiretroviral regimen.

Children and Adolescents 2 to 16 years weighing 15 kg or more† (Treatment-experienced patients)

50 mg/kg/dose PO with ritonavir 2.5 mg/kg/dose (Max: 100 mg/dose) PO twice daily is recommended in the HIV guidelines based on limited data. Pediatric dosing recommendations that are both safe and effective have not been established. Two studies, involving a total of 68 children between the ages of 4 months and 16 years, have evaluated use of saquinavir (50 mg/kg/dose PO twice daily) with either ritonavir 2.5 to 3 mg/kg/dose PO twice daily or lopinavir; ritonavir 230 mg/57.5 mg per m2/dose PO twice daily. In these studies, the respective saquinavir combination therapies resulted in HIV-1 RNA concentrations less than 50 copies/mL in 61% and 66% of patients treated. However, pharmacokinetic data from one of the studies showed steady state saquinavir exposures that were higher than historical data in adults and within the range associated with QT and PR prolongation; pharmacokinetic data from the other study could not be validated. The FDA-approved labeling states that data for doses less than 50 mg/kg are not available and reducing the dose to minimize the risk for QT prolongation will likely decrease efficacy; therefore, dosing recommendations that are both effective and below the QT/PR prolongation threshold could not be determined. HIV guidelines recommend that adolescents in late puberty (i.e., Sexual Maturity Rating [SMR] Stage 4 or 5) should follow adult dosing schedules.

Children 2 years and older weighing less than 15 kg† (Treatment-experienced patients)

50 mg/kg/dose PO with ritonavir 3 mg/kg/dose PO twice daily is recommended in the HIV guidelines based on limited data. Pediatric dosing recommendations that are both safe and effective have not been established. Two studies, involving a total of 68 children between the ages of 4 months and 16 years, have evaluated use of saquinavir (50 mg/kg/dose PO twice daily) with either ritonavir 2.5 to 3 mg/kg/dose PO twice daily or lopinavir; ritonavir 230 mg/57.5 mg per m2/dose PO twice daily. In these studies, the respective saquinavir combination therapies resulted in HIV-1 RNA concentrations less than 50 copies/mL in 61% and 66% of patients treated. However, pharmacokinetic data from 1 of the studies showed steady state saquinavir exposures that were higher than historical data in adults and within the range associated with QT and PR prolongation; pharmacokinetic data from the other study could not be validated. The FDA-approved labeling states that data for doses less than 50 mg/kg are not available and reducing the dose to minimize the risk for QT prolongation will likely decrease efficacy; therefore, dosing recommendations that are both effective and below the QT/PR prolongation threshold could not be determined.

Hepatic Impairment

The use of saquinavir 'boosted' with ritonavir is contraindicated in patients with severe hepatic impairment. No dosage adjustment is necessary for adult patients with mild or moderate hepatic impairment based on limited data. There have been reports of worsening liver disease in patients with underlying hepatitis B or C, hepatic cirrhosis, chronic alcoholism, or other underlying hepatic abnormalities; use with caution in these patients.

Renal Impairment

No dosage adjustment is necessary for patients with renal impairment as less than 1% of saquinavir is eliminated renally. Use in patients with severe renal impairment or end-stage renal disease (ESRD) has not been studied; use caution when administering to these patients.

Abarelix: (Contraindicated) The FDA recommends that saquinavir boosted with ritonavir should not be used in combination with other drugs that may prolong the QT interval. Abarelix has a low, but possible risk for QT prolongation and torsades de pointes.
Abemaciclib: (Major) If coadministration with saquinavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If saquinavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of saquinavir. Abemaciclib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Abrocitinib: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with abrocitinib is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and saquinavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acarbose: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with saquinavir 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 saquinavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If saquinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Saquinavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of saquinavir is necessary. If saquinavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like saquinavir 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 saquinavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Contraindicated) Avoid concomitant use of adagrasib and saquinavir. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of saquinavir with a drug that increases saquinavir concentrations and prolongs the QT interval, such as adagrasib, is contraindicated per the manufacturer of saquinavir. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for saquinavir-related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A and P-gp inhibitor, saquinavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals like the protease inhibitors, are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of saquinavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until saquinavir has cleared from the circulation (approximately 3 half-lives of saquinavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; saquinavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of saquinavir 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 saquinavir. 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 saquinavir 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: (Major) Avoid coadministration of saquinavir and orally administered budesonide and use inhaled formulations with caution. Saquinavir may inhibit CYP3A4 metabolism of budesonide, resulting in increased plasma budesonide concentrations and reduced serum cortisol concentrations. Theoretically, inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to budesonide, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Aldesleukin, IL-2: (Moderate) Both saquinavir boosted with ritonavir and aldesleukin are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with aldesleukin may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If the protease inhibitor is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like protease inhibitors can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If the protease inhibitor is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Contraindicated) Concurrent use of alfuzosin and protease inhibitors is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. When coadministered with another strong CYP3A inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with saquinavir is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and saquinavir should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alosetron: (Moderate) Concomitant use of alosetron with saquinavir may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; boosted saquinavir is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alpha-glucosidase Inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Alprazolam: (Contraindicated) Coadministration of saquinavir boosted with ritonavir and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with saquinavir/ritonavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and saquinavir/ritonavir are strong CYP3A4 inhibitors. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiodarone: (Contraindicated) The concurrent use of amiodarone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Amiodarone and saquinavir are both substrates and inhibitors of CYP3A4. The coadministration of saquinavir/ritonavir and amiodarone results in increased plasma concentrations of both amiodarone and saquinavir, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as all Class III antiarrhythmics.
Amisulpride: (Major) Avoid coadministration of amisulpride and saquinavir boosted with ritonavir due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG at baseline and during therapy if coadministration cannot be avoided. Amisulpride causes dose- and concentration- dependent QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Amitriptyline: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with saquinavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and clarithromycin is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as clarithromycin. In addition to the potential for arrhythmias, because saquinavir and clarithromycin are both CYP3A4 inhibitors and substrates, clinically significant increases in the plasma concentrations of both drugs are seen with concurrent use. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (Fortovase and Invirase; 1200mg three times daily) resulted in a 177% increase in saquinavir AUC, a 45% increase in clarithromycin AUC, and a 24% decrease in the clarithromycin 14-OH metabolite AUC. (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include saquinavir.
Apalutamide: (Major) Coadministration of saquinavir with apalutamide is not recommended as there is a potential for decreased saquinavir concentrations, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; apalutamide exposure may also increase. Saquinavir is a sensitive CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
Apixaban: (Major) Reduce the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as saquinavir boosted with ritonavir. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and saquinavir plus ritonavir. Concomitant administration of saquinavir plus ritonavir and apixaban results in increased exposure to apixaban which increases the risk of bleeding.
Apomorphine: (Major) Concurrent use of saquinavir and apomorphine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of saquinavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased saquinavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in saquinavir- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Saquinavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Saquinavir 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 saquinavir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Concomitant use of aripiprazole and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, saquinavir is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Major) Concomitant use of aripiprazole and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP3A and CYP2D6 substrate, saquinavir is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. QT prolongation should also be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported.
Artemether; Lumefantrine: (Contraindicated) The concurrent use of saquinavir boosted with ritonavir and artemether; lumefantrine should be avoided if possible due to the potential for life threatening arrhythmias such as torsades de pointes TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of both components of artemether; lumefantrine. During coadministration, elevated serum concentrations of artemether; lumefantrine can occur; thus, caution is warrented due to the potential for increased side effects, including QT prolongation. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as artemether; lumefantrine. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring. (Major) The concurrent use of saquinavir boosted with ritonavir and artemether; lumefantrine should be avoided if possible due to the potential for life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of both components of artemether; lumefantrine. During coadministration, elevated serum concentrations of artemether; lumefantrine can occur; thus, caution is warrented due to the potential for increased side effects, including QT prolongation. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as artemether; lumefantrine. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring (see Saquinavir Contraindications).
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with saquinavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor.
Asenapine: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as asenapine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Aspirin, ASA; Omeprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of saquinavir is necessary. If saquinavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like saquinavir 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 saquinavir 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: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and atazanavir is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir boosted with ritonavir prolongs the QT and PR intervals in a dose-dependent fashion, and the impact of coadministering the combination with other drugs that prolong the PR interval, such as atazanavir, is not known. In addition, administration of atazanavir (300 mg daily) with saquinavir (1600 mg daily) and ritonavir (100 mg daily) resulted in an increased saquinavir AUC (by 60%). When administered with atazanavir, and in the presence of a high fat meal, there is a 4- to 7-fold increase in the AUC of saquinavir (soft-gelatin capsules, Fortovase).
Atazanavir; Cobicistat: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and atazanavir is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir boosted with ritonavir prolongs the QT and PR intervals in a dose-dependent fashion, and the impact of coadministering the combination with other drugs that prolong the PR interval, such as atazanavir, is not known. In addition, administration of atazanavir (300 mg daily) with saquinavir (1600 mg daily) and ritonavir (100 mg daily) resulted in an increased saquinavir AUC (by 60%). When administered with atazanavir, and in the presence of a high fat meal, there is a 4- to 7-fold increase in the AUC of saquinavir (soft-gelatin capsules, Fortovase). (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Atogepant: (Major) Avoid use of atogepant and saquinavir when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with saquinavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and saquinavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of saquinavir and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with saquinavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with saquinavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of saquinavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Concomitant use of avanafil and saquinavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; saquinavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; saquinavir would be expected to have similar effects.
Avapritinib: (Major) Avoid coadministration of avapritinib with saquinavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with saquinavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after saquinavir is discontinued. Axitinib is a CYP3A4/5 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and saquinavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Azithromycin: (Major) Avoid coadministration of azithromycin with saquinavir boosted with ritonavir due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Barbiturates: (Major) Coadministration with phenobarbital and, potentially, other barbiturates may increase the metabolism of saquinavir and lead to decreased saquinavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If saquinavir and barbiturates are used together, the patient must be closely monitored for antiviral efficacy.
Basiliximab: (Moderate) Both saquinavir boosted with ritonavir and basiliximab are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with basiliximab may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as saquinavir boosted with ritonavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, saquinavir/ritonavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT and torsade de pointes (TdP). If these drugs must be administered together, obtain serum electrolyte concentrations and a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with saquinavir 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 saquinavir 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 saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking saquinavir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor for an increase in saquinavir-related adverse reactions as concurrent use may increase exposure. Berotralstat is a P-gp substrate and P-gp and moderate CYP3A4 inhibitor; saquinavir is a CYP3A4 and P-gp substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
Betamethasone: (Moderate) Consider an alternative corticosteroid that is less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly for long-term use, in patients receiving saquinavir. Coadministration may significantly increase betamethasone exposure increasing the risk for Cushing's syndrome and adrenal suppression. Saquinavir is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving saquinavir. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving saquinavir. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; saquinavir inhibits P-gp.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bortezomib: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such saquinavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity.
Bosentan: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Bosutinib: (Major) Avoid concomitant use of bosutinib and saquinavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with saquinavir if possible due to increased plasma exposure of brigatinib which may result in an increase in brigatinib-related adverse reactions; saquinavir exposure may also increase. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of saquinavir, resume the brigatinib dose that was tolerated prior to initiation of saquinavir. Brigatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Saquinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with saquinavir ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; saquinavir boosted with ritonavir is a strong inhibitor of CYP3A4.
Budesonide: (Major) Avoid coadministration of saquinavir and orally administered budesonide and use inhaled formulations with caution. Saquinavir may inhibit CYP3A4 metabolism of budesonide, resulting in increased plasma budesonide concentrations and reduced serum cortisol concentrations. Theoretically, inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to budesonide, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Budesonide; Formoterol: (Major) Avoid coadministration of saquinavir and orally administered budesonide and use inhaled formulations with caution. Saquinavir may inhibit CYP3A4 metabolism of budesonide, resulting in increased plasma budesonide concentrations and reduced serum cortisol concentrations. Theoretically, inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to budesonide, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid coadministration of saquinavir and orally administered budesonide and use inhaled formulations with caution. Saquinavir may inhibit CYP3A4 metabolism of budesonide, resulting in increased plasma budesonide concentrations and reduced serum cortisol concentrations. Theoretically, inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to budesonide, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Bupivacaine; Lidocaine: (Contraindicated) The concurrent use of systemic lidocaine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. These drugs used together may result in large increases in lidocaine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as lidocaine.
Buprenorphine: (Major) Buprenorphine should be avoided in combination with saquinavir. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as saquinavir may decrease the clearance of buprenorphine further increasing the risk of QT prolongation and prolonged or increased opioid effects. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Buprenorphine; Naloxone: (Major) Buprenorphine should be avoided in combination with saquinavir. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as saquinavir may decrease the clearance of buprenorphine further increasing the risk of QT prolongation and prolonged or increased opioid effects. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Buspirone: (Moderate) When buspirone is administered with an inhibitor of CYP3A4 like saquinavir, a lower dose of buspirone is recommended. Dose adjustment of either drug should be based on clinical assessment.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with saquinavir if possible due to increased cabazitaxel exposure. If concomitant use is

unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and saquinavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with saquinavir 2 to 3 days after discontinuation of saquinavir. Cabozantinib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with saquinavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with saquinavir. Saquinavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Minor) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
Canagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control if protease inhibitor therapy is initiated.
Canagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Cannabidiol: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with cannabidiol is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with saquinavir is necessary. Capmatinib is a CYP3A substrate and P-glycoprotein (P-gp) inhibitor. Saquinavir is a strong CYP3A4 inhibitor and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Inhibitors of P-gp may increase saquinavir exposure.
Carbamazepine: (Major) Carbamazepine increases the metabolism of the protease inhibitors, including saquinavir, and may lead to decreased efficacy of these medications. An alternative anticonvulsant should be considered when possible. Treatment failures have been reported with other protease inhibitors when carbamazepine was used concomitantly. In addition, saquinavir boosted with ritonavir is a potent CYP3A inibitor and coadministration may result in increased serum concentrations of carbamazepine. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and carbamazepine are unknown. If used concomitantly, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or carbamazepine toxicity.
Carvedilol: (Moderate) Altered concentrations of saquinavir and/or carvedilol may occur during coadministration. Carvedilol and saquinavir are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
Ceritinib: (Contraindicated) Coadministration of saquinavir with ceritinib is contraindicated due to the risk of QT prolongation; increased exposure to both drugs is also possible. Ceritinib is a CYP3A4 substrate and a strong CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Saquinavir is a sensitive CYP3A4 substrate, as well as a strong CYP3A4 inhibitor. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). If concomitant use is unavoidable, the manufacturer of ceritinib recommends decreasing the dose of ceritinib by approximately one-third when administered in combination with strong CYP3A4 inhibitors, rounding to the nearest multiple of 150 mg and monitoring for ceritinib-related adverse reactions. After posaconazole is discontinued, resume the dose of ceritinib taken prior to initiating posaconazole. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chloramphenicol: (Moderate) Both saquinavir boosted with ritonavir and chloramphenicol are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with chloramphenicol may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
Chlordiazepoxide: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chlordiazepoxide; Amitriptyline: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Chlordiazepoxide; Clidinium: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chloroquine: (Major) Avoid coadministration of chloroquine with saquinavir boosted with ritonavir due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with saquinavir 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 saquinavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If saquinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Saquinavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpromazine: (Contraindicated) Concurrent use of chlorpromazine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Chlorpromazine is also associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
Ciclesonide: (Major) Saquinavir may inhibit CYP3A4 metabolism of ciclesonide, resulting in increased plasma ciclesonide concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to ciclesonide, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Cidofovir: (Moderate) Additive adverse effects may be seen when cidofovir is given with other agents that cause neutropenia. Patients receiving anti-retroviral protease inhibitors in combination with cidofovir may have an increased risk of iritis or uveitis.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with protease inhibitors and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a strong CYP3A inhibitor increased the cilostazol AUC by 117%. Coadministration with a moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Cimetidine: (Moderate) The concurrent use of saquinavir boosted with ritonavir and cimetidine should be avoided if possible due to the potential for life-threatening cardiac arrhythmias such as torsades de pointes (TdP). Cimetidine is an inhibitor of several CYP isoenzymes including CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Increased plasma concentrations of saquinavir may occur during coadministration; saquinavir boosted with ritonavir has been found to cause dose-dependent QT and PR prolongation. The interaction between saquinavir not boosted with ritonavir and cimetidine has not been found to produce clinically relevant effects, although some patients could experience and increase in adverse effects if saquinavir and cimetidine are coadministered.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of saquinavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Concomitant use of protease inhibitors and cisapride is contraindicated; use increases cisapride exposure and the risk for cisapride-related adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concomitant use of cisapride with CYP3A inhibitors also is disallowed under the Propulsid Limited Access Program.
Citalopram: (Major) Concurrent use of citalopram and saquinavir boosted with ritonavir should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, specific ECG monitoring is recommended. Citalopram causes dose-dependent QT interval prolongation. Saquinavir boosted with ritonavir also increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. In addition, the concurrent use of saquinavir boosted with ritonavir and citalopram or escitalopram should be avoided if possible due to the potential for elevated plasma concentrations of citalopram or escitalopram. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of citalopram and escitalopram. In addition, citalopram and escitalopram are also metabolized by CYP2D6, an isoenzyme that may be inhibited by ritonavir. Because both citalopram and escitalopram are metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease the clearance of these SSRIs. No clinical studies have been performed; however, caution is advised if citalopram or escitalopram are coadministered with saquinavir/ritonavir.
Clarithromycin: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and clarithromycin is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as clarithromycin. In addition to the potential for arrhythmias, because saquinavir and clarithromycin are both CYP3A4 inhibitors and substrates, clinically significant increases in the plasma concentrations of both drugs are seen with concurrent use. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (Fortovase and Invirase; 1200mg three times daily) resulted in a 177% increase in saquinavir AUC, a 45% increase in clarithromycin AUC, and a 24% decrease in the clarithromycin 14-OH metabolite AUC.
Clofazimine: (Major) Concomitant use of clofazimine and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with protease inhibitors; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Clorazepate: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate, and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Clozapine: (Contraindicated) Concurrent use of clozapine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Cobicistat: (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with saquinavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; saquinavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval including promethazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Codeine; Promethazine: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval including promethazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. (Moderate) Concomitant use of codeine with saquinavir 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 saquinavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If saquinavir 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. Saquinavir is a strong inhibitor of CYP3A4.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and saquinavir 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. Saquinavir 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 saquinavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Conivaptan: (Contraindicated) Coadministration of conivaptan and saquinavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase saquinavir exposure and risk for saquinavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A and P-gp inhibitor; saquinavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Bazedoxifene: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. (Minor) Coadministration of medroxyprogesterone, a CYP3A substrate with saquinavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and saquinavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; saquinavir boosted with ritonavir is a strong CYP3A inhibitor.
Crizotinib: (Contraindicated) The concurrent use of saquinavir and crizotinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP); increased plasma concentrations of both drugs may also occur, which may increase the incidence and severity of adverse reactions. If an alternative is not available and concomitant use is unavoidable for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of saquinavir. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclophosphamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
Cyclosporine: (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.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with saquinavir, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like saquinavir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with saquinavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and saquinavir; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of saquinavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; saquinavir is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as saquinavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of saquinavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
Danazol: (Moderate) Both saquinavir boosted with ritonavir and danazol are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with danazol may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
Dapagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. Limit the saxagliptin dose to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as saquinavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapsone: (Major) Concurrent administration of oral dapsone and saquinavir boosted with ritonavir is not recommended, due to the potential for elevated dapsone concentrations and risk of dapsone-related side effects (i.e., hemolytic anemia, methemoglobinemia, or peripheral neuropathy). The metabolism of dapsone is mediated by CYP3A4, coadministration of drugs that inhibit CYP3A4, such as saquinavir boosted with ritonavir, may cause decreased clearance of dapsone.
Daridorexant: (Major) Avoid concomitant use of daridorexant and saquinavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with saquinavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with saquinavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Saquinavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir: (Major) Coadministration of darunavir and saquinavir results in decreased exposure to darunavir (26% decrease in AUC). Appropriate dosage adjustments for this combination have not been established. Coadministration, with or without additional low-dose ritonavir, is not recommended.
Darunavir; Cobicistat: (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Major) Coadministration of darunavir and saquinavir results in decreased exposure to darunavir (26% decrease in AUC). Appropriate dosage adjustments for this combination have not been established. Coadministration, with or without additional low-dose ritonavir, is not recommended.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Major) Coadministration of darunavir and saquinavir results in decreased exposure to darunavir (26% decrease in AUC). Appropriate dosage adjustments for this combination have not been established. Coadministration, with or without additional low-dose ritonavir, is not recommended.
Dasatinib: (Contraindicated) Concurrent use of dasatinib and saquinavir boosted with ritonavir is contraindicated due to the potential for life threatening arrhythmias such as torsade de pointes (TdP). Increased dasatinib exposure may also occur. Saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor that causes dose-dependent QT and PR prolongation. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with saquinavir. 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; saquinavir boosted with ritonavir is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval like degarelix. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Appropriate dosing recommendations for concomitant administration of delavirdine and saquinavir boosted with ritonavir have not been established; thus, use of these drugs together is not recommended. If this combination is prescribed, frequent monitoring of hepatic enzymes should be performed; in a small, preliminary study, elevated hepatic enzymes occurred in 13% of subjects during the first several weeks of using delavirdine and saquinavir in combination. Both delavirdine and saquinavir HGC (Invirase) boosted with ritonavir are inhibitors of CYP3A4; coadministration of delavirdine and saquinavir HGC results in increased saquinavir plasma concentration. The effect on delavirdine pharmacokinetic parameters is not well established. There are insufficient data to support any dosing recommendations for the combination of delavirdine and saquinavir HGC boosted with ritonavir. Delavirdine (400 mg three times daily) in combination with saquinavir (soft gelatin capsules, SGC) (1000 mg three times daily) increased mean saquinavir Cmax (98%), AUC (121%), and Cmin (199%), relative to saquinavir-SGC (1200 mg three times daily) alone. There are limited safety and efficacy data available regarding the use of this combination, although, if coadministered, the dose of saquinavir-SGC should be decreased to 800 mg three times daily.
Desipramine: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Desogestrel; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) Coadministration of desogestrel and strong CYP3A4 inhibitors such as saquinavir may increase the serum concentration of desogestrel.
Deutetrabenazine: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions and a decrease in saquinavir efficacy if concomitant use of dexamethasone and saquinavir is necessary. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may increase dexamethasone concentrations and decrease saquinavir exposure. Dexamethasone is a CYP3A substrate and CYP3A inducer; saquinavir is a CYP3A substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexlansoprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Contraindicated) Concurrent use of quinidine or quinidine-containing products (e.g., dextromethorphan; quinidine) and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of quinidine. Concurrent administration may result in large increases in quinidine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such quinidine.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Dienogest; Estradiol valerate: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. (Minor) Coadministration of dienogest, a primary 3A4 substrate and saquinavir, a strong CYP3A4 inhibitor may increase the serum concentration of dienogest.
Digoxin: (Major) The concurrent use of saquinavir boosted with ritonavir and digoxin should be used very cautiously due to the potential for increased serum digoxin concentrations and possible cardiac arrhythmias. The increase in serum concentrations may be greater in females, as compared to males. Additionally, saquinavir boosted with ritonavir causes dose-dependent PR prolongation; if possible, avoid use with other drugs that may prolong the PR interval, such as digoxin. If concomitant therapy cannot be avoided, measure serum digoxin concentrations before initiating saquinavir boosted with ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Dihydroergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Diltiazem: (Moderate) Saquinavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4. Although drug interaction studies have not been conducted, the serum concentration of diltiazem may be increased with concomitant administration of saquinavir.
Disopyramide: (Contraindicated) The concurrent use of disopyramide and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of disopyramide. Coadministration may result in large increases in disopyramide serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as all Class 1A antiarrhythmics.
Docetaxel: (Major) Avoid coadministration of docetaxel with saquinavir if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Contraindicated) Coadministration of saquinavir boosted with ritonavir with dofetilide is contraindicated as concurrent use may increase dofetilide exposure and risk of QT prolongation. Saquinavir boosted with ritonavir is strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is a CYP3A4 substrate that is associated with a well-established risk of QT prolongation and TdP.
Dolasetron: (Contraindicated) Concurrent use of saquinavir boosted with ritonavir and dolasetron should be avoided if possible due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as dolasetron. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
Donepezil: (Moderate) Saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes, such as donepezil. Patients should be monitored for toxicities associated with donepezil.
Donepezil; Memantine: (Moderate) Saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes, such as donepezil. Patients should be monitored for toxicities associated with donepezil.
Doravirine: (Minor) Coadministration of doravirine and saquinavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; saquinavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.Coadministration may increase doravirine exposure. Concurrent use of strong inhibitors like saquinavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Coadministration of doravirine and saquinavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; saquinavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.Coadministration may increase doravirine exposure. Concurrent use of strong inhibitors like saquinavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with saquinavir. Saquinavir is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxepin: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Doxercalciferol: (Moderate) Protease inhibitors may decrease efficacy of doxercalciferol. Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including protease inhibitors, 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 these drugs are administered together.
Doxorubicin Liposomal: (Major) Avoid coadministration of saquinavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Saquinavir is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of saquinavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Saquinavir is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Major) Avoid the use of dronabinol with saquinavir due to the risk of increased dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; saquinavir is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) The concurrent use of dronedarone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Both saquinavir boosted with ritonavir and dronedarone are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Further, dronedarone is an inhibitor of the drug efflux pump, P-glycoprotein, for which saquinavir is a substrate. 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 saquinavir have not been described, although an increase in saquinavir serum concentrations is possible.
Droperidol: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as droperidol. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Drospirenone: (Minor) In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as saquinavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects, including the potential for hyperkalemia in high-risk patients.
Drospirenone; Estetrol: (Minor) In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as saquinavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects, including the potential for hyperkalemia in high-risk patients.
Drospirenone; Estradiol: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. (Minor) In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as saquinavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects, including the potential for hyperkalemia in high-risk patients.
Drospirenone; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as saquinavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects, including the potential for hyperkalemia in high-risk patients.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as saquinavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects, including the potential for hyperkalemia in high-risk patients.
Dutasteride: (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity of both drugs when coadministered with saquinavir. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; saquinavir is a sensitive substrate and strong inhibitor of CYP3A. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as saquinavir.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Edoxaban: (Moderate) Coadministration of edoxaban and saquinavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and saquinavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of saquinavir; 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: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as efavirenz. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Also, appropriate dosing recommendations for concomitant efavirenz and saquinavir, coadministered with or without ritonavir, have not been established. The concurrent administration of saquinavir soft gel capsule and efavirenz has resulted in decrease in saquinavir AUC and Cmax by 62% and 50%, respectively. A case report of 2 patients who had efavirenz (600 mg once daily) added to their ritonavir/saquinavir-SGC regimen (400/600 mg twice daily), showed modest increases in saquinavir AUC after the addition of efavirenz. The AUC of ritonavir increased in one patient and decreased in the other. Increasing the dose of saquinavir to 800 mg every 12 hours decreased the AUC of ritonavir and increased the AUC of efavirenz in both patients after 14 days. However, the increased dose of saquinavir produced a less than proportional increase in the saquinavir AUC.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as efavirenz. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Also, appropriate dosing recommendations for concomitant efavirenz and saquinavir, coadministered with or without ritonavir, have not been established. The concurrent administration of saquinavir soft gel capsule and efavirenz has resulted in decrease in saquinavir AUC and Cmax by 62% and 50%, respectively. A case report of 2 patients who had efavirenz (600 mg once daily) added to their ritonavir/saquinavir-SGC regimen (400/600 mg twice daily), showed modest increases in saquinavir AUC after the addition of efavirenz. The AUC of ritonavir increased in one patient and decreased in the other. Increasing the dose of saquinavir to 800 mg every 12 hours decreased the AUC of ritonavir and increased the AUC of efavirenz in both patients after 14 days. However, the increased dose of saquinavir produced a less than proportional increase in the saquinavir AUC. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as efavirenz. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Also, appropriate dosing recommendations for concomitant efavirenz and saquinavir, coadministered with or without ritonavir, have not been established. The concurrent administration of saquinavir soft gel capsule and efavirenz has resulted in decrease in saquinavir AUC and Cmax by 62% and 50%, respectively. A case report of 2 patients who had efavirenz (600 mg once daily) added to their ritonavir/saquinavir-SGC regimen (400/600 mg twice daily), showed modest increases in saquinavir AUC after the addition of efavirenz. The AUC of ritonavir increased in one patient and decreased in the other. Increasing the dose of saquinavir to 800 mg every 12 hours decreased the AUC of ritonavir and increased the AUC of efavirenz in both patients after 14 days. However, the increased dose of saquinavir produced a less than proportional increase in the saquinavir AUC. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Elacestrant: (Major) Avoid concomitant use of elacestrant and saquinavir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. The exposure of saquinavir may also be increased. Elacestrant is a CYP3A substrate and P-gp inhibitor and saquinavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and saquinavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and saquinavir to 6 months. Monitor for elagolix-related side effects and reduced response to saquinavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; saquinavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease saquinavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and saquinavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and saquinavir to 6 months. Monitor for elagolix-related side effects and reduced response to saquinavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; saquinavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease saquinavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with saquinavir 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). Saquinavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
Eletriptan: (Contraindicated) Eletriptan is contraindicated for use within 72 hours of using any drug that is a potent CYP3A4 inhibitor as described in the prescribing information of the interacting drug including protease inhibitors. Eletriptan is metabolized via CYP3A4, and coadministration with protease inhibitors may cause increased eletriptan concentrations and thus toxicity.
Elexacaftor; tezacaftor; ivacaftor: (Major) If saquinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in saquinavir-related adverse reactions if coadministration with ivacaftor is necessary as concomitant use may increase saquinavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and saquinavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with saquinavir; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; saquinavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with saquinavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); saquinavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Contraindicated) Coadministration of saquinavir and eliglustat is contraindicated. Saquinavir is a P-glycoprotein (P-gp) substrate and strong CYP3A inhibitor that, when boosted with ritonavir, prolongs the QT and PR interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP); its use is contraindicated with other drugs that prolong the QT interval and CYP3A substrates for which increased plasma concentrations may result in serious reactions. Eliglustat is a CYP3A substrate and P-gp inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of saquinavir and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Eluxadoline: (Major) When administered concurrently with saquinavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); saquinavir is an OATP1B1 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Major) Avoid coadministration of saquinavir with elvitegravir. No data are available regarding use of these drugs concurrently.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Major) Avoid coadministration of saquinavir with elvitegravir. No data are available regarding use of these drugs concurrently. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Empagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Enasidenib: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with enasidenib is necessary. Saquinavir is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of encorafenib and saquinavir due to increased encorafenib exposure and QT prolongation. Increased or decreased saquinavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of saquinavir. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If saquinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of saquinavir. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Saquinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with saquinavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; saquinavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with saquinavir boosted with ritonavir due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If saquinavir/ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of saquinavir/ritonavir. Additionally, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; saquinavir/ritonavir is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
Enzalutamide: (Major) Coadministration of saquinavir with enzalutamide is not recommended as there is a potential for decreased saquinavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Saquinavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Contraindicated) Coadministration of saquinavir boosted with ritonavir and eplerenone is contraindicated. Saquinavir boosted with ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and saquinavir due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If saquinavir is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
Ergoloid Mesylates: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergot alkaloids: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergotamine; Caffeine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Eribulin: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with eribulin. If no acceptable alternative therapy is available, perform an ECG at baseline and during concomitant therapy. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Eribulin has also been associated with QT prolongation.
Erlotinib: (Major) Avoid coadministration of erlotinib with saquinavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Ertugliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Ertugliflozin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Erythromycin: (Contraindicated) Concurrent use of erythromycin and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. Saquinavir boosted with ritonavir is a substrate of CYP3A4. Erythromycin is a CYP3A4. Elevated concentrations of saquinavir may further increase the risk of QT prolongation.
Escitalopram: (Major) Avoid concomitant use of saquinavir boosted with ritonavir with escitalopram. If use together is necessary, obtain a baseline ECG and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
Esomeprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Estazolam: (Moderate) In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity (i.e., prolonged sedation and respiratory depression).
Esterified Estrogens: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Esterified Estrogens; Methyltestosterone: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Levonorgestrel: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. (Minor) Coadministration of levonorgestrel with a strong CYP3A4 inhibitor such as saquinavir may increase the serum concentration of levonorgestrel. The oxidative metabolism of levonorgestrel is catalyzed by hepatic cytochrome P450 isoenzymes, especially CYP3A4.
Estradiol; Norethindrone: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Norgestimate: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol; Progesterone: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers. (Moderate) Use caution if coadministration of saquinavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Saquinavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estropipate: (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethinyl Estradiol; Norelgestromin: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Ethinyl Estradiol; Norethindrone Acetate: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Ethinyl Estradiol; Norgestrel: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Ethosuximide: (Moderate) Saquinavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
Ethotoin: (Major) Complex interactions may occur when phenytoin or fosphenytoin are administered to patients receiving treatment for HIV infection. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. An alternative anticonvulsant should be considered when possible. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Phenytoin will likely increase the metabolism of anti-retroviral protease inhibitors (PIs), leading to decreased antiretroviral efficacy. In addition, PIs may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as saquinavir may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as saquinavir may increase the serum concentration of etonogestrel.
Etravirine: (Minor) The coadministration of etravirine and saquinavir (boosted with ritonavir) resulted in a 33% decrease in etravirine exposure (AUC). This reduction is similar to that seen in etravirine phase 3 clinical trials (when administered with daruanvir boosted with ritonavir), therefore, no dosage adjustments are necessary.
Everolimus: (Major) Avoid coadministration of everolimus with saquinavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Saquinavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Fedratinib: (Major) Avoid coadministration of fedratinib with saquinavir as concurrent use may increase fedratinib exposure; saquinavir exposure may also increase. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If saquinavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; saquinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Moderate) Concurrent use of felodipine and protease inhibitors should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concurrent use of a strong CYP3A inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. Concurrent use of a moderate CYP3A inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with anti-retroviral protease inhibitors. Avoid use of fesoterodine and protease inhibitors in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Finasteride; Tadalafil: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of saquinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of saquinavir therapy. Stop tadalafil at least 24 hours prior to starting saquinavir. After at least 1 week of saquinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and saquinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Finerenone: (Contraindicated) Concomitant use of finerenone and saquinavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Fingolimod: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If no acceptable alternative therapy is available, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Contraindicated) The concurrent use of flecainide and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as flecainide.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as saquinavir boosted with ritonavir, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Contraindicated) Although the manufacturer of fluconazole provides dose adjustment recommendations for saquinavir when the two drugs are coadministered, the manufacturer of saquinavir contraindicates this drug combination. According to the manufacturer of saquinavir, saquinavir is contraindicated with drugs that prolong the QT interval and increase saquinavir concentrations. Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50%.
Fluoxetine: (Major) Avoid coadministration of fluoxetine with saquinavir boosted with ritonavir due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. QT prolongation and TdP have been reported in patients treated with fluoxetine. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Fluphenazine: (Contraindicated) Concurrent use of fluphenazine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and saquinavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with saquinavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and saquinavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministra tion with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and saquinavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and saquinavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluvastatin: (Moderate) Concurrent use of saquinavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Saquinavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, saquinavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated saquinair concentrations during concurrent use of fluvoxamine and saquinavir boosted with ritonavir. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, both saquinavir boosted with ritonavir and fluvoxamine are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. These drugs used together may result in large increases in saquinavir serum concentrations, which could cause adverse events such as life threatening cardiac arrhythmias.
Food: (Major) Advise patients to avoid cannabis use during protease inhibitor treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and protease inhibitors are strong CYP3A inhibitors. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Major) Saquinavir may inhibit CYP3A4 metabolism of mometasone, resulting in increased plasma mometasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to mometasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Fosamprenavir: (Minor) Use caution when administering saquinavir concurrently with amprenavir or fosamprenavir. Coadministration of fosamprenavir and saquinavir boosted with ritonavir resulted in a 15% decrease in the AUC of saquinavir. Further, concurrent administration of saquinavir and amprenavir results in a 32% decrease in the AUC of amprenavir. There are insufficient data to support any dosing recommendations. Patients should be closely monitored.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as saquinavir. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Also, abnormal renal function has been observed in clinical practice during the use of foscarnet in combination with saquinavir. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Major) Complex interactions may occur when phenytoin or fosphenytoin are administered to patients receiving treatment for HIV infection. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. An alternative anticonvulsant should be considered when possible. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Phenytoin will likely increase the metabolism of anti-retroviral protease inhibitors (PIs), leading to decreased antiretroviral efficacy. In addition, PIs may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; saquinavir is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Fostemsavir: (Contraindicated) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Futibatinib: (Major) Avoid concurrent use of futibatinib and saquinavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Concomitant use may also increase saquinavir exposure. Futibatinib is a substrate of CYP3A and P-gp and a P-gp inhibitor; saquinavir is a P-gp substrate and dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Garlic, Allium sativum: (Contraindicated) Patients taking saquinavir or saquinavir "boosted" with ritonavir, should avoid dietary supplements of Garlic, Allium sativum, due to the potential for antiretroviral treatment failure and/or development of viral resistance. Coadministration may result in significantly reduced saquinavir plasma concentrations. In one study, mean saquinavir concentrations dropped by 51% in the presence of garlic supplementation equivalent to roughly 2 cloves/day (4.64 mg allicin and 11.2 mg allin per capsule given twice daily).
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with saquinavir is necessary. Gefitinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemifloxacin: (Major) Concurrent use of saquinavir boosted with ritonavir and gemifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with saquinavir due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Gilteritinib: (Contraindicated) Coadministration of gilteritinib and saquinavir is contraindicated due to the risk of additive QT prolongation and other gilteritinib-related toxicities. Gilteritinib is a CYP3A4 substrate and a P-gp inhibitor; saquinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Gilteritinib has been associated with QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias.
Glasdegib: (Contraindicated) Coadministration of glasdegib and saquinavir is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP); glasdegib exposure may be increased further increasing the risk of QT prolongation. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Saquinavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and saquinavir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and saquinavir are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and saquinavir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Pibrentasvir and saquinavir are both substrates and inhibitors of P-glycoprotein (P-gp).
Glipizide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glyburide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Goserelin: (Major) Avoid coadministration of saquinavir with goserelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, perform a baseline QCT prior to initiation of therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), concurrent use of granisetron and saquinavir should be avoided if possible. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron with drugs known to prolong the QT interval or are arrhythmogenic, may result in clinical consequences. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Grapefruit juice: (Moderate) Saquinavir is metabolized via the cytochrome CYP3A4 isozyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. Saquinavir levels may increase; it is possible that saquinavir-induced side effects could be increased in some individuals. Individuals should not drastically alter their intake of grapefruit juice or should avoid concurrent use unless advised differently by their healthcare professional.
Guanfacine: (Major) Saquinavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If saquinavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and saquinavir is a strong CYP3A4 inhibitor.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with saquinavir. Halogenated anesthetics can prolong the QT interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Haloperidol: (Contraindicated) Concurrent use of haloperidol and saquinavir boosted with ritonavir is contraindicated due to the risk for cardiac arrhythmias. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. In addition, saquinavir is an inhibitor of CYP3A4. Elevated haloperidol concentrations occurring through inhibition of CYP3A4 may increase the risk of adverse effects, including QT prolongation.
Histrelin: (Major) Concomitant use of saquinavir and androgen deprivation therapy (i.e., histrelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydantoins: (Major) Complex interactions may occur when phenytoin or fosphenytoin are administered to patients receiving treatment for HIV infection. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. An alternative anticonvulsant should be considered when possible. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Phenytoin will likely increase the metabolism of anti-retroviral protease inhibitors (PIs), leading to decreased antiretroviral efficacy. In addition, PIs may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
Hydroxychloroquine: (Major) Avoid coadministration of saquinavir and hydroxychloroquine due to an increased risk of QT prolongation. If no acceptable alternative therapy is available, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Hydroxychloroquine prolongs the QT interval.
Hydroxyzine: (Major) Avoid coadministration of saquinavir boosted with ritonavir and hydroxyzine due to the risk of QT prolongation or torsade de pointes (TdP). Monitor ECG at baseline and during therapy if coadministration cannot be avoided. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with saquinavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and saquinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of saquinavir is necessary. If saquinavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like saquinavir 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 saquinavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) The concurrent use of saquinavir boosted with ritonavir and ibutilide should be avoided if possible due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Idelalisib: (Major) Concomitant use of idelalisib, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may increase the exposure of idelalisib. Additionally, idelalisib is a strong CYP3A inhibitor while saquinavir is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and saquinavir.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with saquinavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Saquinavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of iloperidone and saquinavir boosted with ritonavir due to the potential for QT prolongation and increased iloperidone exposure. If coadministration cannot be avoided, reduce the dose of iloperidone by one-half and closely monitor for evidence of QT prolongation. If saquinavir boosted with ritonavir is withdrawn from combination therapy, increase the iloperidone dose to where it was before. Iloperidone is a CYP3A4 substrate that prolongs the QT interval. Saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor that also prolongs the QT interval.
Imatinib: (Major) Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended.
Imipramine: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Incretin Mimetics: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Indinavir: (Major) There are insufficient data to support any dosing recommendations for indinavir and saquinavir boosted with ritonavir. If prescribed together, closely monitor for adverse events. Both indinavir and saquinavir boosted with ritonavir are substrates and inhibitors of CYP3A4. When indinavir and saquinavir are administered concurrently, a greater than 350% increase in saquinavir AUC is noted; the AUC of indinavir may also increase.
Infigratinib: (Major) Avoid concomitant use of infigratinib and saquinavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with saquinavir due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Interferons: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Irinotecan Liposomal: (Major) Avoid administration of saquinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Saquinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of saquinavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Saquinavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with saquinavir is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; saquinavir is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated saquinavir concentrations may also be seen with coadministration, as saquinavir is a substrate and isavuconazole is an inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp).
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Coadministration of rifampin and saquinavir is contraindicated. Coadministration results in markedly decreased saquinavir concentrations; HIV treatment failure and virologic resistance would be expected. Coadministration of rifampin with saquinavir reduced the steady-state AUC and Cmax of saquinavir by about 80%. In addition, saquinavir, alone or 'boosted' with ritonavir, is contraindicated in combination with rifampin due to inceased risk of severe hepatocellular toxicity. In a 28 day phase I, randomized, open-label, multiple-dose study, significant drug-induced hepatitis with marked transaminase levels occurred in 11 of 17 healthy volunteers receiving saquinavir (1000 mg twice daily) with ritonavir (100 mg twice daily) and rifampin (600 mg once daily).
Isoniazid, INH; Rifampin: (Contraindicated) Coadministration of rifampin and saquinavir is contraindicated. Coadministration results in markedly decreased saquinavir concentrations; HIV treatment failure and virologic resistance would be expected. Coadministration of rifampin with saquinavir reduced the steady-state AUC and Cmax of saquinavir by about 80%. In addition, saquinavir, alone or 'boosted' with ritonavir, is contraindicated in combination with rifampin due to inceased risk of severe hepatocellular toxicity. In a 28 day phase I, randomized, open-label, multiple-dose study, significant drug-induced hepatitis with marked transaminase levels occurred in 11 of 17 healthy volunteers receiving saquinavir (1000 mg twice daily) with ritonavir (100 mg twice daily) and rifampin (600 mg once daily).
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with protease inhibitors is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with saquinavir/ritonavir as istradefylline exposure and adverse effects may increase. Saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Major) Monitor for adverse effects (i.e.,cardiac arrhythmias, hepatotoxicity) with administering itraconazole with saquinavir boosted with ritonavir. Serum concentrations of both itraconazole and saquinavir are expected to increase if these drugs are given together, as both itraconazole and saquinavir are substrates and inhibitors of CYP3A4.
Ivabradine: (Contraindicated) Coadministration of ivabradine and saquinavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; saquinavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If saquinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in saquinavir-related adverse reactions if coadministration with ivacaftor is necessary as concomitant use may increase saquinavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and saquinavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with saquinavir due to increased plasma concentrations of ivosidenib and additive QT prolongation; exposure to saquinavir may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of saquinavir. If saquinavir is discontinued, wait at least 5 half-lives of saquinavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Saquinavir boosted with ritonavir is a strong CYP3A4 and increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and saquinavir due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and saquinavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. Both saquinavir and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole 200 mg/day increased saquinavir exposure by 168%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lansoprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and clarithromycin is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as clarithromycin. In addition to the potential for arrhythmias, because saquinavir and clarithromycin are both CYP3A4 inhibitors and substrates, clinically significant increases in the plasma concentrations of both drugs are seen with concurrent use. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (Fortovase and Invirase; 1200mg three times daily) resulted in a 177% increase in saquinavir AUC, a 45% increase in clarithromycin AUC, and a 24% decrease in the clarithromycin 14-OH metabolite AUC. (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Lapatinib: (Contraindicated) Coadministration of saquinavir with lapatinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP); exposure to lapatinib may also increase. Saquinavir, boosted with ritonavir, is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Lapatinib is a CYP3A4 substrate that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with saquinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If saquinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of saquinavir. Larotrectinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lasmiditan: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with lasmiditan is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; lasmiditan is a P-gp inhibitor.
Lefamulin: (Major) Coadministration of lefamulin tablets is contraindicated with saquinavir due to increased saquinavir exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with saquinavir. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Saquinavir is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor that is associated with concentration-dependent QT prolongation, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Lefamulin is a CYP3A4 substrate and CYP3A4 inhibitor that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
Lemborexant: (Major) Avoid coadministration of lemborexant and saquinavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with lenacapavir is necessary. Concomitant use may increase the plasma concentrations of saquinavir. Saquinavir is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor.
Leniolisib: (Major) Avoid concomitant use of leniolisib and saquinavir due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with saquinavir due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
Letermovir: (Moderate) An increase in the plasma concentration of saquinavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Saquinavir is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Avoid coadministration of saquinavir with leuprolide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, perform a baseline ECG prior to initiation of therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of saquinavir with leuprolide if possible due to the risk of QT prolongation. If concomitant use is unavoidable, perform a baseline ECG prior to initiation of therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levofloxacin: (Major) Concomitant use of levofloxacin and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and saquinavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. Both saquinavir and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole 200 mg/day increased saquinavir exposure by 168%.
Levonorgestrel: (Minor) Coadministration of levonorgestrel with a strong CYP3A4 inhibitor such as saquinavir may increase the serum concentration of levonorgestrel. The oxidative metabolism of levonorgestrel is catalyzed by hepatic cytochrome P450 isoenzymes, especially CYP3A4.
Levonorgestrel; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) Coadministration of levonorgestrel with a strong CYP3A4 inhibitor such as saquinavir may increase the serum concentration of levonorgestrel. The oxidative metabolism of levonorgestrel is catalyzed by hepatic cytochrome P450 isoenzymes, especially CYP3A4.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) Coadministration of levonorgestrel with a strong CYP3A4 inhibitor such as saquinavir may increase the serum concentration of levonorgestrel. The oxidative metabolism of levonorgestrel is catalyzed by hepatic cytochrome P450 isoenzymes, especially CYP3A4.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) Coadministration of levonorgestrel with a strong CYP3A4 inhibitor such as saquinavir may increase the serum concentration of levonorgestrel. The oxidative metabolism of levonorgestrel is catalyzed by hepatic cytochrome P450 isoenzymes, especially CYP3A4.
Lidocaine: (Contraindicated) The concurrent use of systemic lidocaine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. These drugs used together may result in large increases in lidocaine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as lidocaine.
Lidocaine; Epinephrine: (Contraindicated) The concurrent use of systemic lidocaine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. These drugs used together may result in large increases in lidocaine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as lidocaine.
Lidocaine; Prilocaine: (Contraindicated) The concurrent use of systemic lidocaine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. These drugs used together may result in large increases in lidocaine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as lidocaine.
Linagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Linagliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Lithium: (Major) Lithium should avoided in combination with saquinavir. Lithium has been associated with QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Lofexidine: (Major) Avoid coadministration of lofexidine and saquinavir boosted with ritonavir due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG at baseline and during therapy if coadministration cannot be avoided. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Lomitapide: (Contraindicated) Concomitant use of saquinavir and lomitapide is contraindicated. If treatment with saquinavir is unavoidable, lomitapide should be stopped during the course of treatment. Saquianvir is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and saquinavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, a P-gp inhibitor, and a strong CYP3A4 inhibitor. Saquinavir is a sensitive CYP3A4 substrate, a P-gp substrate, and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Major) Concomitant use of loperamide and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A4 and P-gp substrate and saquinavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A4 and P-gp substrate and saquinavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir; ritonavir with saquinavir due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. When coadministered with lopinavir; ritonavir 400/100 mg twice daily, the saquinavir dose is 1,000 mg twice daily. Lopinavir; ritonavir is associated with QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
Lorlatinib: (Major) Avoid coadministration of lorlatinib with saquinavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of saquinavir may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If saquinavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of saquinavir. Lorlatinib is a CYP3A substrate and moderate inducer. Saquinavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Lovastatin: (Contraindicated) Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
Lumacaftor; Ivacaftor: (Major) If saquinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in saquinavir-related adverse reactions if coadministration with ivacaftor is necessary as concomitant use may increase saquinavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and saquinavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of saquinavir; avoid concurrent use if possible. If concomitant use of saquinavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when saquinavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking saquinavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking saquinavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Saquinavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of saquinavir and decrease its therapeutic efficacy. Although saquinavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, saquinavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of saquinavir; avoid concurrent use if possible. If concomitant use of saquinavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when saquinavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking saquinavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking saquinavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Saquinavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of saquinavir and decrease its therapeutic efficacy. Although saquinavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, saquinavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of saquinavir is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; saquinavir must be administered with ritonavir, which is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with saquinavir is contraindicated. Lurasidone is primarily metabolized by CYP3A4; saquinavir is a CYP3A4 inhibitor. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and saquinavir due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as saquinavir. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
Maprotiline: (Major) Concurrent use of maprotiline and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Maprotiline is related to the tricyclic antidepressants and has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Maraviroc: (Major) Coadministration of maraviroc, a CYP3A/P-gp substrate, with saquinavir, a strong CYP3A4 inhibitor and P-gp inhibitor, has been reported to increase maraviroc concentrations by 9.8-fold. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with saquinavir (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
Maribavir: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with maribavir is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; maribavir is a P-gp inhibitor.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with saquinavir due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease plasma concentrations of saquinavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and saquinavir is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Medroxyprogesterone: (Minor) Coadministration of medroxyprogesterone, a CYP3A substrate with saquinavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Mefloquine: (Contraindicated) Concurrent use of saquinavir boosted with ritonavir and mefloquine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of mefloquine. Further, both saquinavir and mefloquine are substrates and inhibitors of the drug efflux protein, P-glycoprotein. This complex interaction may ultimately result in altered plasma concentrations of both mefloquine and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as mefloquine.
Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Rosiglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. Limit the saxagliptin dose to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as saquinavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Methadone: (Major) Concurrent use of methadone and saquinavir boosted with ritonavir should be avoided if possible due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring. Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. Methadone may also prolong the QT interval. Additionally, administering methadone (60 to 120 mg daily) in combination with saquinavir/ritonavir (1000/100 mg twice daily) has resulted in a decrease in both methadone and saquinavir serum concentrations. Monitor patients carefully and adjust the methadone dose if necessary.
Methylergonovine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Methylprednisolone: (Moderate) Saquinavir may inhibit CYP3A4 metabolism of methylprednisolone, resulting in increased plasma methylprednisolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to methylprednisolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Metronidazole: (Major) Concomitant use of metronidazole and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Major) Protease inhibitors may increase midazolam concentrations; the risk for midazolam-related adverse effects varies by midazolam dosage form and route of administration. Oral midazolam use is contraindicated. Intranasal midazolam should be avoided when possible. Additional monitoring and a dosage reduction may be necessary with parenteral midazolam. Midazolam is a CYP3A substrate and protease inhibitors are CYP3A inhibitors. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation.
Midostaurin: (Contraindicated) Avoid concomitant use of midostaurin and saquinavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase midostaurin exposure and the risk for other midostaurin-related adverse effects; midostaurin is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor.
Mifepristone: (Contraindicated) Coadministration of saquinavir and mifepristone is contraindicated due to the risk of additive QT prolongation and life-threatening arrhythmias such as torsade de pointes (TdP); the exposure of both drugs may also be increased. If concomitant use of mifepristone is necessary for the treatment of Cushing's syndrome in a patient already receiving saquinavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg daily if clinically indicated. If therapy with saquinavir is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with saquinavir is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with saquinavir is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with saquinavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg/day. Both mifepristone and saquinavir are substrates and strong inhibitors of CYP3A4 that are associated with QT prolongation.
Miglitol: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Mirtazapine: (Moderate) Concurrent administration of mirtazapine and saquinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of saquinavir is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with saquinavir due to increased risk of adverse reactions. Coadministration increases mitapivat and saquinavir concentrations. Mitapivat is a CYP3A substrate and P-gp inhibitor and saquinavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Major) Concomitant use of mitotane with saquinavir should be undertaken with caution due to potential decreased saquinavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and saquinavir is a CYP3A4 substrate.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and saquinavir. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Mometasone: (Major) Saquinavir may inhibit CYP3A4 metabolism of mometasone, resulting in increased plasma mometasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to mometasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Moxifloxacin: (Major) Concurrent use of saquinavir boosted with ritonavir and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with saquinavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; saquinavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with saquinavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as saquinavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with saquinavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Naproxen; Esomeprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Nateglinide: (Moderate) Concurrent administration of nateglinide with some protease inhibitors may result in elevated nateglinide plasma concentrations via inhibition of CYP2C9. Ritonavir may induce CYP2C9 leading to a reduction of nateglinide concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia or hyperglycemia could occur. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Monitor blood glucose concentrations during coadministration. Caution and close monitoring are advised if these drugs are administered together.
Nefazodone: (Major) The concurrent use of saquinavir boosted with ritonavir and nefazodone should be avoided if possible due to the potential for elevated saquinavir plasma concentrations and associated adverse effects. Both saquinavir boosted with ritonavir and nefazodone are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. The use of saquinavir/ritonavir with nefazodone may result in large increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsade de pointes [TdP]).
Nelfinavir: (Major) Concomitant administration of nelfinavir and saquinavir boosted with ritonavir is not recommended. Both nelfinavir and saquinavir boosted with ritonavir are inhibitors of CYP3A4; the concurrent use of nelfinavir and saquinavir results in elevated AUC and Cmax of both drugs. In a pharmacokinetic study, administration of nelfinavir (750 mg PO three times daily) with a single 1200 mg oral dose of saquinavir resulted in a 392% increase in the AUC and a 179% increase in the Cmax of saquinavir. Similarly, administering saquinavir (1200 mg PO three times daily) with a single 750 mg oral dose of nelfinavir caused an increase in the nelfinavir AUC by 18%. Further, when ritonavir (500 mg PO twice daily) was coadministered with nelfinavir (750 mg single PO dose) the AUC and Cmax for nelfinavir were increased by 152% and 44%, respectively.
Neratinib: (Major) Avoid concomitant use of saquinavir with neratinib due to an increased risk of neratinib-related toxicity; saquinavir exposure may also increase. Neratinib is a CYP3A4 substrate and a P-gycoprotein (P-gp) inhibitor. Saquinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4 such as saquinavir since the plasma concentrations can increase; the inhibitory effect on CYP3A4 can last for multiple days. Increased saquinavir concentrations may lead to an increased risk for side effects, including possible QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as saquinavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Nevirapine: (Major) Coadministration of saquinavir with nevirapine is not recommended as there is a potential for decreased saquinavir concentrations, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Additionally, the exposure of nevirapine may also be increased, leading to increased toxicity. Saquinavir is a CYP3A4 substrate and strong CYP3A inhibitor; nevirapine is a CYP3A substrate and weak CYP3A4 inducer.
Niacin; Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Nicardipine: (Moderate) Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Nifedipine: (Moderate) According to the manufacturer of nifedipine, coadministration with saquinavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. If coadministration is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Nilotinib: (Contraindicated) The concurrent use of nilotinib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and nilotinib are inhibitors and substrates of the hepatic isoenzyme CYP3A4. This complex interaction may ultimately result in elevated plasma concentrations of both nilotinib and saquinavir, thus increasing the risk of drug toxicity and proarrhythmic effects.
Nimodipine: (Moderate) Anti-retroviral protease inhibitors are CYP3A4 inhibitors and may decrease the hepatic metabolism of nimodipine, leading to increased plasma concentrations of nimodipine. In addition, ritonavir and calcium channel blockers both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. Monitor therapeutic response and for adverse effects, such as hypotension. Decreased calcium-channel blocker doses may be warranted.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as saquinavir (when administered with ritonavir), 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. Saquinavir is a potent CYP3A4 inhibitor and when combined with ritonavir also inhibits P-gp; 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%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with protease inhibitors due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Norethindrone; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Norgestimate; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects.
Nortriptyline: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Ofloxacin: (Major) Concomitant use of ofloxacin and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Concurrent use of olanzapine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of fluoxetine with saquinavir boosted with ritonavir due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. QT prolongation and TdP have been reported in patients treated with fluoxetine. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. (Major) Concurrent use of olanzapine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Olanzapine; Samidorphan: (Major) Concurrent use of olanzapine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Olaparib: (Major) Avoid coadministration of olaparib with saquinavir due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after saquinavir is discontinued. Olaparib is a CYP3A substrate and saquinavir is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Olopatadine; Mometasone: (Major) Saquinavir may inhibit CYP3A4 metabolism of mometasone, resulting in increased plasma mometasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to mometasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and saquinavir. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Omeprazole; Amoxicillin; Rifabutin: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with saquinavir/ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with saquinavir/ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and saquinavir/ritonavir is a strong CYP3A inhibitor. Coadministration with saquinavir/ritonavir increased the AUC of rifabutin by approximately 50%.
Omeprazole; Sodium Bicarbonate: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Ondansetron: (Major) Concurrent use of saquinavir boosted with ritonavir and ondansetron should be avoided if possible due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ondansetron. Further, both saquinavir and ondansetron are substrates of P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in altered plasma concentrations of both ondansetron and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as ondansetron. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Oritavancin: (Major) Saquinavir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of saquinavir may be reduced if these drugs are administered concurrently.
Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral protease inhibitors. Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osilodrostat: (Major) Avoid coadministration of osilodrostat and saquinavir boosted with ritonavir due to the potential for additive QT prolongation. Monitor ECG at baseline and during therapy if coadministration cannot be avoided. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as osimertinib. If concomitant use is unavoidable, monitor for an increase in saquinavir-related adverse reactions, monitor electrolytes, and monitor ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Saquinavir is a P-glycoprotein (P-gp) substrate that, when boosted with ritonavir, increases the QT interval in a dose-dependent fashion which may increase the risk for serious arrhythmias such as TdP. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
Oxaliplatin: (Major) Avoid coadministration of saquinavir with oxaliplatin due to the risk of additive QT prolongation. If concomitant use is unavoidable, perform a baseline ECG, and monitor ECGs and electrolytes during treatment; correct electrolyte abnormalities prior to administration of oxaliplatin. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with protease inhibitors is necessary. Oxybutynin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of saquinavir is necessary. If saquinavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like saquinavir 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 saquinavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) Avoid coadministration of saquinavir boosted with ritonavir with ozanimod due to the risk of additive QT prolongation. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Paclitaxel: (Minor) Although saquinavir does not inhibit cytochrome-based metabolism to the same degree as ritonavir, saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes including paclitaxel. Patients should be monitored for toxicities associated with paclitaxel.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with saquinavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor.
Palbociclib: (Major) Avoid coadministration of saquinavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. Concentrations of saquinavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If saquinavir is discontinued, increase the palbociclib (after 3 to 5 half-lives of saquinavir) to the dose used before initiation of saquinavir. Palbociclib is primarily metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while saquinavir is a sensitive CYP3A4 substrate that may increase the QT interval in a dose-dependent fashion.
Paliperidone: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, including paliperidone. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Palovarotene: (Major) Avoid concomitant use of palovarotene and saquinavir due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) The co-administration of panobinostat with saquinavir is not recommended; QT prolongation has been reported with both of these agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Saquinavir is a strong CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Pantoprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as protease inhibitors. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pasireotide: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as pasireotide. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Pazopanib: (Contraindicated) Concurrent use of pazopanib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Pazopanib is a weak inhibitor of CYP3A4, which may lead to increased serum concentrations of saquinavir when given concomitantly, thus increasing the risk of drug toxicity and proarrhythmic effects. Pazopanib is also substrate for CYP3A4 and P-glycoprotein (P-gp). Saquinavir is a strong inhibitor of CYP3A4 and P-gp. Concurrent administration of saquinavir and pazopanib may also result in increased pazopanib concentrations. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation, which could further increase the risk for TdP if coadministered with pazopanib.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and saquinavir 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 saquinavir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of saquinavir. Pemigatinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Pentamidine: (Contraindicated) The concurrent use of systemic pentamidine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as pentamidine.
Perampanel: (Moderate) Concurrent use of perampanel with saquinavir, may increase exposure to perampanel and lead to elevated plasma concentrations. Saquinavir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Perphenazine: (Contraindicated) Concurrent use of perphenazine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Contraindicated) Concurrent use of perphenazine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation. (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and saquinavir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease saquinavir plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If saquinavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of saquinavir. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; saquinavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenytoin: (Major) Complex interactions may occur when phenytoin or fosphenytoin are administered to patients receiving treatment for HIV infection. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. An alternative anticonvulsant should be considered when possible. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Phenytoin will likely increase the metabolism of anti-retroviral protease inhibitors (PIs), leading to decreased antiretroviral efficacy. In addition, PIs may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as saquinavir. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Pim ozide: (Contraindicated) Coadministration of pimozide with protease inhibitors is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Pimozide is thought to be metabolized through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide plasma levels are probable when coadministered with CYP450 inhibitors, such as the protease inhibitors. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP.
Pioglitazone; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and saquinavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of saquinavir may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of saquinavir use. Resume the previous dose of pirtobrutinib after saquinavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and P-gp inhibitor and saquinavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitolisant: (Major) Avoid coadministration of pitolisant with saquinavir/ritonavir as concurrent use may increase the risk of QT prolongation. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Pitolisant prolongs the QT interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of saquinavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; saquinavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Ponatinib: (Major) Avoid coadministration of ponatinib and saquinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of saquinavir and consider alternative therapy. After saquinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting saquinavir. Ponatinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Ponesimod: (Major) Avoid coadministration of saquinavir boosted with ritonavir with ponesimod due to the risk of additive QT prolongation. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Posaconazole: (Contraindicated) Concurrent use of posaconazole and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both saquinavir boosted with ritonavir and posaconazole are potent inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of saquinavir. Further, both posaconazole and saquinavir are inhibitors and substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as posaconazole.
Pralsetinib: (Major) Avoid concomitant use of saquinavir and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and saquinavir is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Pramlintide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Prednisone: (Major) Saquinavir may inhibit CYP3A4 metabolism of prednisone, resulting in increased plasma prednisone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving ritonavir with other corticosteroids, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to prednisone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Pretomanid: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with pretomanid is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; pretomanid is a P-gp inhibitor.
Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include saquinavir.
Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and saquinavir 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. Saquinavir 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 saquinavir 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.
Procainamide: (Major) Concurrent use of procainamide and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Procainamide is also associated with a well-established risk of QT prolongation and TdP.
Prochlorperazine: (Contraindicated) Concurrent use of prochlorperazine and saquinavir is contraindicated due to an increased risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Phenothiazines, such as prochlorperazine, have also been reported to prolong the QT interval.
Progesterone: (Moderate) Use caution if coadministration of saquinavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Saquinavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval including promethazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Promethazine; Dextromethorphan: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval including promethazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Promethazine; Phenylephrine: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval including promethazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Propafenone: (Contraindicated) Concurrent use of propafenone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is an inhibitor of CYP3A4 and CYP2D6, two enzymes responsible for the metabolism of propafenone. These drugs used together may result in large increases in propafenone serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as propafenone.
Proton pump inhibitors: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Protriptyline: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Quazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. A decrease in the quazepam dose may be needed.
Quetiapine: (Major) Avoid concurrent use of quetiapine and saquinavir due to the potential for additive effects on the QT interval and torsade de pointes. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir may be associated with QT prolongation. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances. Saquinavir may also inhibit the CYP3A4 metabolism of quetiapine, resulting in elevated quetiapine plasma concentrations. If administration of saquinavir is required in a patient taking quetiapine, reduce the quetiapine dose to one sixth of the current dose. If saquinavir is discontinued, increase the quetiapine dose by 6-fold.
Quinidine: (Contraindicated) Concurrent use of quinidine or quinidine-containing products (e.g., dextromethorphan; quinidine) and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of quinidine. Concurrent administration may result in large increases in quinidine serum concentrations, which could cause fatal cardiac arrhythmias. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such quinidine.
Quinine: (Contraindicated) Concurrent use of saquinavir boosted with ritonavir and quinine is contraindicated due to the potential for life threatening arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir is an inhibitor of CYP3A4 and of the drug efflux protein, P-glycoprotein (P-gp). Quinine is a substrate for P-gp, as well as a substrate and inhibitor of CYP3A4. These drugs used together may result in altered serum concentrations of both saquinavir and quinine, which could cause drug related adverse events. In addition, saquinavir boosted with ritonavir causes dose-depnedent QT prolongation; avoid use in combination with other drugs that may prolong the QT interval such as quinine.
Quizartinib: (Major) Avoid concomitant use of saquinavir with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. Concomitant use may also increase the risk for torsade de pointes (TdP) and QT/QTc prolongation. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quizartinib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Rabeprazole: (Major) Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
Ramelteon: (Moderate) The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
Ranitidine: (Minor) The coadministration of saquinavir and ranitidine increases saquinavir plasma concentrations. However, the increase is not thought to be clinically relevant. No dose adjustment of saquinavir is recommended; no dosage information regarding the use of saquinavir enhanced or 'boosted' with ritonavir is available.
Ranolazine: (Contraindicated) Concurrent use of ranolazine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both saquinavir boosted with ritonavir and ranolazine are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Further, both ranolazine and saquinavir are substrates for P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in elevated plasma concentrations of both ranolazine and saquinavir, thus increasing the risk of drug toxicity and proarrhythmic effects. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as ranolazine.
Red Yeast Rice: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when anti-retroviral protease inhibitors are given in combination with most HMG-CoA reductase inhibitors. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, coadministration of red yeast rice with anti-retroviral protease inhibitors is not recommended.
Regorafenib: (Major) Avoid coadministration of regorafenib with saquinavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Relugolix: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval such as relugolix. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Administer saquinavir at least six hours after relugolix and monitor for adverse reactions. Saquinavir is a P-gp inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Relugolix is a P-gp substrate that may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval such as relugolix. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Administer saquinavir at least six hours after relugolix and monitor for adverse reactions. Saquinavir is a P-gp inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Relugolix is a P-gp substrate that may also prolong the QT/QTc interval. (Moderate) Saquinavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as saquinavir boosted with ritonavir, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Ribociclib: (Contraindicated) Coadministration of ribociclib with saquinavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to saquinavir may also increase. Both ribociclib and saquinavir prolong the QT interval in a concentration-dependent manner. Both drugs are also CYP3A4 substrates and strong CYP3A4 inhibitors.
Ribociclib; Letrozole: (Contraindicated) Coadministration of ribociclib with saquinavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to saquinavir may also increase. Both ribociclib and saquinavir prolong the QT interval in a concentration-dependent manner. Both drugs are also CYP3A4 substrates and strong CYP3A4 inhibitors.
Rifabutin: (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with saquinavir/ritonavir is necessary. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with saquinavir/ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and saquinavir/ritonavir is a strong CYP3A inhibitor. Coadministration with saquinavir/ritonavir increased the AUC of rifabutin by approximately 50%.
Rifampin: (Contraindicated) Coadministration of rifampin and saquinavir is contraindicated. Coadministration results in markedly decreased saquinavir concentrations; HIV treatment failure and virologic resistance would be expected. Coadministration of rifampin with saquinavir reduced the steady-state AUC and Cmax of saquinavir by about 80%. In addition, saquinavir, alone or 'boosted' with ritonavir, is contraindicated in combination with rifampin due to inceased risk of severe hepatocellular toxicity. In a 28 day phase I, randomized, open-label, multiple-dose study, significant drug-induced hepatitis with marked transaminase levels occurred in 11 of 17 healthy volunteers receiving saquinavir (1000 mg twice daily) with ritonavir (100 mg twice daily) and rifampin (600 mg once daily).
Rifapentine: (Major) Avoid coadministration of protease inhibitors and rifapentine as concurrent use may result in significant decreases in the plasma concentrations of the antiretroviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with saquinavir 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 saquinavir is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
Rimegepant: (Major) Avoid coadministration of rimegepant with saquinavir; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; saquinavir is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with saquinavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risperidone: (Major) Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid coadministration. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Ritlecitinib: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with ritlecitinib is necessary. Concomitant use may increase the plasma concentrations of saquinavir. Saquinavir is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Rivaroxaban: (Major) Avoid concomitant administration of rivaroxaban and saquinavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Saquinavir, a combined P-gp inhibitor and strong CYP3A4 inhibitor, is given with ritonavir, a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 150% and to an increase in Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as romidepsin. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Rosuvastatin: (Major) The concurrent use of saquinavir boosted with ritonavir and rosuvastatin should be avoided if possible due to the potential for myopathies, including rhabdomyolysis. Coadministration of saquinavir boosted with ritonavir and rosuvastatin results in an increased plasma concentration of rosuvastatin. The combination saquinavir/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. If coadministered, use the lowest possible dose of rosuvastatin with careful clinical monitoring,
Rosuvastatin; Ezetimibe: (Major) The concurrent use of saquinavir boosted with ritonavir and rosuvastatin should be avoided if possible due to the potential for myopathies, including rhabdomyolysis. Coadministration of saquinavir boosted with ritonavir and rosuvastatin results in an increased plasma concentration of rosuvastatin. The combination saquinavir/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. If coadministered, use the lowest possible dose of rosuvastatin with careful clinical monitoring,
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with saquinavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of saquinavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with saquinavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. Limit the saxagliptin dose to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as saquinavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Segesterone Acetate; Ethinyl Estradiol: (Major) The concurrent use of saquinavir boosted with ritonavir and oral contraceptives should be avoided if possible due to the potential for decreased contraceptive effectiveness. Saquinavir may increase the metabolism of oral contraceptives and non-oral combination contraceptives. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as saquinavir/ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Women who receive hormonal contraceptives concurrently with PIs should use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Furthermore, the oral contraceptive, ethinyl estradiol, may inhibit CYP3A4 mediated metabolism of saquinavir, potentially resulting in elevated saquinavir plasma concentrations and the development of saquinavir-related adverse effects. (Minor) Coadministration of segesterone, a CYP3A4 substrate and saquinavir, a strong CYP3A4 inhibitor may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and saquinavir due to the risk of additive QT prolongation and increased exposure to both drugs resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If saquinavir is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of saquinavir. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%. Additionally, saquinavir is a P-gp substrate and selpercatinib is a P-gp inhibitor.
Sertraline: (Major) Concomitant use of sertraline and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sildenafil: (Major) Sildenafil is contraindicated for use with saquinavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of saquinavir increased the sildenafil AUC by about 3-fold in a drug interaction study.
Silodosin: (Major) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as anti-retroviral protease inhibitors may cause significant increases in silodosin plasma concentrations.
Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Siponimod: (Contraindicated) Coadministration of saquinavir with siponimod is contraindicated due to the risk of QT prolongation; increased exposure to siponimod is also possible. Siponimod is a CYP2C9 and CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sodium Oxybate: (Minor) One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with taurursodiol is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; taurursodiol is a P-gp inhibitor.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with saquinavir. 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). In addition, saquinavir is a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of saquinavir, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with saquinavir. 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). In addition, saquinavir is a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Solifenacin: (Major) Solifenacin is a substrate for CYP3A4. Saquinavir boosted with ritonavir is a strong inhibitor of CYP3A4. Concurrent administration of solifenacin with a strong CYP3A4 inhibitor may cause an increase in systemic solifenacin concentrations. Additionally, saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as solifenacin. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Sonidegib: (Major) Avoid coadministration of sonidegib with saquinavir due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
Sorafenib: (Contraindicated) Concurrent use of sorafenib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. Sorafenib is also associated with prolongation of the QT interval. Additionlly, sorafenib inhibits P-glycoprotein (P-gp) in vitro. Concurrent use of sorafenib with a P-gp substrate, such as saquinavir, could increase the concentrations of saquinavir thus increasing the risk of drug toxicity and proarrhythmic effects.
Sotalol: (Major) Concomitant use of sotalol and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Moderate) Monitor for decreased efficacy or increased toxicity of saquinavir if concurrent use of sotorasib is necessary. Concurrent use may alter saquinavir plasma concentrations. Saquinavir is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Sparsentan: (Major) Avoid concomitant use of sparsentan and saquinavir. Concomitant use may increase the exposure of both drugs and the risk for adverse effects. Sparsentan is a CYP3A substrate and P-gp inhibitor and saquinavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Stiripentol: (Moderate) Consider a dose adjustment of saquinavir when coadministered with stiripentol. Coadministration may alter plasma concentrations of saquinavir resulting in an increased risk of adverse reactions and/or decreased efficacy. Saquinavir is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if protease inhibitors must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If protease inhibitors is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a CYP3A inhibitor like protease inhibitors 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 protease inhibitors 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.
Sulfonylureas: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sunitinib: (Contraindicated) The concomitant use of saquinavir with sunitinib is contraindicated due to the risk of QT prolongation. Sunitinib is a CYP3A4 substrate that can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Saquinavir is a strong CYP3A4 inhibitor that also increases the QT interval in a dose-dependent fashion. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and saquinavir is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Saquinavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Contraindicated) Concurrent administration of tacrolimus and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as tacrolimus. In addition to the potential for arrhythmias, inhibition of CYP3A4 by saquinavir boosted with ritonavir may increase the whole blood concentrations of tacrolimus and lead to other tacrolimus-related side effects such as nephrotoxicity.
Tadalafil: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of saquinavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of saquinavir therapy. Stop tadalafil at least 24 hours prior to starting saquinavir. After at least 1 week of saquinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and saquinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with saquinavir is necessary. Talazoparib is a P-gp substrate and saquinavir is a P-gp inhibitor.
Tamoxifen: (Major) Concomitant use of tamoxifen and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and saquinavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as saquinavir, may increase exposure to tasimelteon with the potential for adverse reactions.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with saquinavir as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as telavancin. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Temsirolimus: (Major) Avoid coadministration of saquinavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to saquinavir may also increase. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of saquinavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Saquinavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of saquinavir.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Tepotinib: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with tepotinib is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; tepotinib is a P-gp inhibitor.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering saquinavir. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; saquinavir is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as tetrabenazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Tezacaftor; Ivacaftor: (Major) If saquinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in saquinavir-related adverse reactions if coadministration with ivacaftor is necessary as concomitant use may increase saquinavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and saquinavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with saquinavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); saquinavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thiazolidinediones: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with saquinavir which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and saquinavir if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; saquinavir is a strong CYP3A4 inhibitor.
Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as saquinavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with saquinavir substantially increases ticagrelor exposure which may increase the bleeding risk.
Tipranavir: (Contraindicated) Concurrent administration of tipranavir (in the FDA approved dosage regimen) with saquinavir results in decreased saquinavir concentrations (76% reduction in AUC). It is recommended that these drugs not be coadministered.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with saquinavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with saquinavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with saquinavir. Saquinavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval such as tolterodine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and reduce tolterodine doses. Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with saquinavir. Concurrent use may increase tolterodine exposure. Saquinavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and saquinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; saquinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Topotecan: (Major) Avoid coadministration of saquinavir with oral topotecan due to increased topotecan exposure; saquinavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and saquinavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Contraindicated) Coadministration of saquinavir and toremifene is contraindicated due to the risk of QT prolongation. Saquinavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with saquinavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Trazodone: (Contraindicated) The concurrent use of trazodone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrythmias. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of trazodone. These drugs used together may result in large increases in trazodone serum concentrations, which could cause adverse events such as nausea, dizziness, hypotension, syncope, and cardiac arrhythmias.
Triamcinolone: (Moderate) Saquinavir may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as protease inhibitors, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects.
Triclabendazole: (Major) Concomitant use of triclabendazole and saquinavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tricyclic antidepressants: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Trifluoperazine: (Minor) Coadministration may increase the risk of QT prolongation. If concurrent use is necessary, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Trifluoperazine is associated with a possible risk for QT prolongation; saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
Trimipramine: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Triptorelin: (Major) Avoid coadministration of saquinavir with triptorelin if possible due to the risk of QT prolongation. If concomitant use is unavoidable, perform a baseline ECG prior to initiation of therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Tucatinib: (Moderate) Monitor for increased toxicity of saquinavir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of saquinavir. Saquinavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with saquinavir. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; saquinavir is a P-gp inhibitor.
Ulipristal: (Minor) Concomitant use of ulipristal and saquinavir may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Upadacitinib: (Major) During concomitant use of upadacitinib and saquinavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Vandetanib: (Major) Avoid coadministration of vandetanib with saquinavir due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Saquinavir boosted with ritonavir also increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Vardenafil: (Contraindicated) Coadministration of saquinavir boosted with ritonavir is contraindicated with other drugs that may prolong the QT interval and which are primary CYP3A4 substrates, such as vardenafil. Saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
Vemurafenib: (Contraindicated) Concurrent use of vemurafenib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Saquinavir boosted with ritonavir also increases the QT interval in a dose-dependent fashion. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of saquinavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of saquinavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; saquinavir is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Concurrent use of venlafaxine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Venlafaxine is also associated with a possible risk of QT prolongation; TdP has been reported with post-marketing use.
Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as saquinavir boosted with ritonavir. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with saquinavir is necessary. Vinblastine is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vincristine: (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a 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 saquinavir is necessary. Vinorelbine is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and saquinavir is contraindicated as use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Concomitant use may also increase the risk for saquinavir-related adverse effects and result in additive QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and P-gp inhibitor and saquinavir is a strong CYP3A4 inhibitor and P-gp substrate that has been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Concurrent administration of saquinavir boosted with ritonavir and clarithromycin is contraindicated due to the risk of life threatening cardiac arrhythmias. Saquinavir prolongs the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious cardiac arrhythmias such as torsades de pointes (TdP). The potential for saquinavir induced cardiac arrhythmias could increase if administered with other drugs that prolong the QT interval, such as clarithromycin. In addition to the potential for arrhythmias, because saquinavir and clarithromycin are both CYP3A4 inhibitors and substrates, clinically significant increases in the plasma concentrations of both drugs are seen with concurrent use. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (Fortovase and Invirase; 1200mg three times daily) resulted in a 177% increase in saquinavir AUC, a 45% increase in clarithromycin AUC, and a 24% decrease in the clarithromycin 14-OH metabolite AUC.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and saquinavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with saquinavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Contraindicated) Concurrent use of voriconazole and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both saquinavir boosted with ritonavir and voriconazole are inhibitors and substrates of the hepatic isoenzyme CYP3A4. This complex interaction may ultimately result in altered plasma concentrations of both voriconazole and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT interval, such as voriconazole.
Vorinostat: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as vorinostat. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
Voxelotor: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with voxelotor is necessary. Concomitant use may increase the plasma concentrations of saquinavir. Saquinavir is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with saquinavir. Concurrent use may increase the INR and the risk of bleeding. Saquinavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zafirlukast: (Contraindicated) The concurrent use of saquinavir boosted with ritonavir and zafirlukast should be used cautiously due to the potential for life threatening arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and zafirlukast are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. The use of saquinavir/ritonavir with zafirlukast may result in increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as saquinavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with saquinavir. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of saquinavir, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
Ziprasidone: (Major) Concomitant use of ziprasidone and saquinavir should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Additionally, because saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4 and may reduce the metabolism of ziprasidone, monitor for ziprasidone-induced adverse effects such as extrapyramidal symptoms, drowsiness, dizziness, nausea, and vomiting, if coadministration is necessary.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and saquinavir 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.

Invirase Oral Cap: 200mg
Invirase Oral Tab: 500mg

NOTE: The following maximum dosage limits apply for typical saquinavir use; maximum dosage limits may be altered based on certain individual patient circumstances, such as in the case of specific drug interactions.

Adults

2,000 mg/day PO.

Geriatric

2,000 mg/day PO.

Adolescents

17 years: 2,000 mg/day PO.
13 to 16 years: Safety and efficacy have not been established; however, doses up to 100 mg/kg/day PO or 1,500 mg/m2/day (Max: 1,600 mg) have been studied.

Children

7 years and older: Safety and efficacy have not been established; however, doses up to 100 mg/kg/day PO or 1,500 mg/m2/day (Max: 1,600 mg) have been studied.
2 years to 6 years: Safety and efficacy have not been established; however, doses up to 100 mg/kg/day PO have been studied.
Younger than 2 years: Safety and efficacy have not been established.
 

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Saquinavir is a competitive inhibitor of HIV protease, an enzyme involved in the replication of HIV. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core, and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Saquinavir demonstrates activity against both HIV-1 and HIV-2 and is effective in acutely and chronically infected cells. Replication of HIV is also inhibited in macrophages, a major reservoir of HIV.
 
Resistance to saquinavir is associated with primary protease gene mutations at G48V and L90M. Variable cross-resistance to other protease inhibitors (PIs) has been observed. In 1 study, 22 HIV-1 isolates with reduced susceptibility (greater than 4-fold increase in the IC50 value) to saquinavir were evaluated for cross-resistance to amprenavir, indinavir, nelfinavir, and ritonavir. Six of the 22 isolates (27%) remained susceptible to all 4 PIs, 12 of the isolates (55%) retained susceptibility to at least 1 of the PIs, and 4 of the isolates (18%) displayed broad cross-resistance to all PIs. Combining saquinavir therapy with reverse transcriptase inhibitors enhances the suppression of viral replication, and limits the emergence of viral resistance. Because different enzyme targets are involved, there is no cross-resistance between saquinavir and reverse transcriptase inhibitors.

Saquinavir is administered orally. Plasma protein binding is high (98%) but not saturable. After intravenous infusion, saquinavir exhibited hepatic and extra-hepatic elimination, and a large volume of distribution, suggesting extensive tissue binding. Saquinavir undergoes extensive first-pass metabolism. Metabolism occurs via the hepatic P450 enzyme system, with CYP3A4 being responsible for about 90% of the initial biotransformation. Saquinavir is also a substrate of the drug transporter P-glycoprotein (P-gp). It is rapidly metabolized to several mono- and di-hydroxylated inactive compounds. Renal elimination is negligible. Of an oral dose of 600 mg, 88% was recovered in feces and only 1% in urine. The systemic clearance in adults is rapid (1.14 L/h/kg) after intravenous doses and the calculated mean residence time (MRT) is only 7 hours. This differential can be explained by redistribution of saquinavir from tissues.[28995] [39864]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
Saquinavir is a substrate and inhibitor of CYP3A4 and P-gp.[28995] [34557] [34558] [39864]

Oral Route

The absolute bioavailability of saquinavir HGC and tablets is only about 4%. The low bioavailability is thought to be due to a combination of incomplete absorption and extensive first-pass metabolism. Food increases the extent of absorption. A high caloric and high fat meal can significantly increase the absorption of saquinavir.

Pregnancy

Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. HIV guidelines recommend against the use of saquinavir-containing regimens during pregnancy. According to the guidelines, patients who become pregnant while taking saquinavir should be switched to an alternative treatment regimen. According to data from the Antiretroviral Pregnancy Registry (APR), there have been 7 birth defects reported in 183 first trimester exposures to saquinavir-containing regimens and 9 birth defects reported in 221 second and third trimester exposures; however, these data are insufficient to draw conclusions regarding the potential for birth defects. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to saquinavir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.

HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission; thus, replacement feeding is recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). There are limited data regarding the use of saquinavir during breast-feeding and excretion into breast milk is unknown. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.