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  • CLASSES

    Protease Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Protease inhibitor (PI)
    Indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents
    Only use when 'boosted' with ritonavir; PR and QT prolongation (including TdP) reported

    COMMON BRAND NAMES

    Invirase

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    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. Saquinavir boosted with ritonavir in combination with a preferred 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option is an alternative regimen that should be used with caution in treatment-naive patients.

    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. Saquinavir boosted with ritonavir in combination with a preferred 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option is an alternative regimen that should be used with caution in treatment-naive patients.

    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.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    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.

    ADMINISTRATION

    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.

    Oral Solid Formulations

    For patients unable to swallow capsules:
    Empty the contents of Invirase capsules into a container.
    Add either 15 ml of sugar syrup, 15 ml of sorbitol syrup, or 3 teaspoons of jam to the container holding the capsule contents.
    Stir for 30—60 seconds and then administer the full dose.
    Ensure the suspension is at room temperature prior to administering.

    STORAGE

    Fortovase:
    - Refrigerate (between 36 and 46 degrees F)
    Invirase:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Saquinavir is contraindicated in patients with clinically significant ritonavir hypersensitivity, saquinavir hypersensitivity, saquinavir mesylate hypersensitivity, or hypersensitivity to any of its ingredients. Clinically significant hypersensitivity includes reactions such as anaphylactic reaction and Stevens-Johnson syndrome.
     
    Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., < 1—2 days) is necessary, in general it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicities. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable concentrations of efavirenz and nevirapine range from < 1 week to > 3 weeks; simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

    Antimicrobial resistance

    Testing for HIV antimicrobial resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform antimicrobial resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In the US and Europe, recent studies suggest that 6—16% of transmitted virus will be resistant to at least one antiretroviral drug, with 3—5% exhibiting reduced susceptibility to more than one class of drugs; therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of saquinavir following loss of viral suppression may increase the likelihood of antimicrobial resistance to other protease inhibitors. Monotherapy with saquinavir is also not recommended due to the increased risk of resistance. In studies of indinavir with saquinavir, ritonavir, and amprenavir, the extent and spectrum of cross-resistance varied with the specific HIV mutational patterns observed; the degree of cross-resistance typically increased with the accumulation of resistance-associated amino acid substitutions. Within a panel of 29 viral isolates from indinavir-treated patients that exhibited measurable phenotypic resistance to indinavir, all were resistant to ritonavir and of the indinavir-resistant HIV isolates, 63% showed resistance to saquinavir and 81% to amprenavir.

    Hepatic disease, hepatitis, hepatitis B and HIV coinfection

    Elimination of saquinavir is largely hepatic, and saquinavir use has not been investigated in patients with baseline liver function tests greater than 5-times the upper limit of normal; therefore, administration of saquinavir with ritonavir is contraindicated in patients with severe hepatic disease. Although a causal relationship has not been established, exacerbation of chronic liver dysfunction, including portal hypertension, has been reported in patients with underlying hepatitis B or C, cirrhosis, or other underlying liver disease. All patients presenting with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts). HIV treatment guidelines recommend coinfected patients receive an ARV regimen that contains a dual NRTI backbone of emtricitabine; tenofovir alafenamide or tenofovir disoproxil fumarate with either lamivudine or emtricitabine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, pancreatitis

    Patients with advanced acquired immunodeficiency syndrome (AIDS) may be at increased risk for developing hypertriglyceridemia and pancreatitis. Patients who exhibit signs or symptoms of pancreatitis should discontinue treatment with saquinavir. Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of protease inhibitors. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during treatment with a protease inhibitor, possible interventions include dietary modification, use of lipid lowering agents, or discontinuation of the protease inhibitor. Clinicians should be aware of the potential drug interaction between certain cholesterol-lowering agents and saquinavir.

    Diabetes mellitus, diabetic ketoacidosis, hyperglycemia

    Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during saquinavir treatment. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

    Hemophilia

    Protease inhibitors such as saquinavir should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A casual relationship has not been established.

    Pregnancy

    Antiretroviral therapy should be provided to all women 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. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. Saquinavir is classified as FDA pregnancy risk category B. No adequate and well-controlled studies in pregnant women have been conducted, and data involving first trimester exposures (n = 184) 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 and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. 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 women 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 women with high-risk factors for glucose intolerance. All pregnant women 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 woman decides to discontinue therapy, a consultation with a HIV specialist is recommended. It is strongly recommended that health care providers report cases of antenatal antiretroviral drug exposure to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.

    Breast-feeding

    To reduce the risk of postnatal transmission, HIV-infected mothers within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy. 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.

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to saquinavir may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

    Alcoholism, AV block, bradycardia, cardiac arrhythmias, cardiac disease, cardiomyopathy, coronary artery disease, females, geriatric, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, malnutrition, myocardial infarction, QT prolongation, thyroid disease, torsade de pointes

    Saquinavir administered in combination with ritonavir has resulted in QT prolongation, PR prolongation, second and third degree atrioventricular (AV) block, and torsade de pointes (TdP); the use of this combination is contraindicated in patients with congenital long QT syndrome and those with refractory hypokalemia or hypomagnesemia. Patients with preexisting conduction system disease (cardiac arrhythmias, complete AV block without pacemaker, high risk for complete AV block), ischemic heart disease (myocardial infarction), cardiomyopathy, or underlying structural heart disease/cardiac disease should also avoid treatment with saquinavir and ritonavir. In addition, concurrent use of saquinavir and medications that both prolong the QT interval and increase saquinavir plasma concentrations is contraindicated. Use saquinavir with caution in patients with other conditions that may increase the risk of QT prolongation including heart failure, bradycardia, hypertension, coronary artery disease, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation. Perform baseline ECG and correct electrolyte abnormalities prior to initiating therapy. Patients with a baseline QT interval >= 450 msec should not start saquinavir with ritonavir therapy. Treatment-naive patients and patients switching from certain other antiretroviral regimens (delavirdine- or rilpivirine-containing regimens) should receive a reduced dose during the first 7 days of treatment due to the potential for an increased risk of PR and QT prolongation with the standard dose. For patients with a QT interval < 450 msecs, a repeat on-treatment ECG is recommended after approximately 10 days of treatment; patients with an on-treatment QT interval prolongation over baseline by > 20 msec should discontinue ritonavir-boosted saquinavir. Patients on saquinavir and ritonavir who require treatment with a QT prolonging medication should receive a baseline ECG prior to initiation of the concomitant therapy. If the QT interval is > 450 msec, do not start the concomitant therapy. If baseline QT interval < 450 msec, a repeat on-treatment ECG is recommended after 3 to 4 days of treatment; discontinue either ritonavir-boosted saquinavir, the concomitant therapy, or both in patients with on-treatment QT interval prolongation over baseline by > 20 msec after beginning concomitant therapy. Consider a cardiology consult if discontinuation is being considered based on ECG results.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    ADVERSE REACTIONS

    Severe

    eczema vaccinatum / Delayed / 2.0-2.0
    AV block / Early / 0-1.0
    torsade de pointes / Rapid / 0-1.0
    pancreatitis / Delayed / Incidence not known
    GI obstruction / 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 / 5.4-5.4
    hyperglycemia / Delayed / 2.7-2.7
    diabetes mellitus / Delayed / 2.7-2.7
    constipation / Delayed / 2.0-2.0
    hyperbilirubinemia / Delayed / 4.0
    dysphagia / Delayed / Incidence not known
    gastritis / 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
    hematoma / Early / Incidence not known
    bleeding / 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
    PR prolongation / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    edema / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known

    Mild

    nausea / Early / 10.8-10.8
    diarrhea / Early / 8.1-8.1
    vomiting / Early / 7.4-7.4
    abdominal pain / Early / 6.1-6.1
    fatigue / Early / 6.1-6.1
    infection / Delayed / 2.7-5.4
    rash (unspecified) / Early / 3.4-3.4
    pruritus / Rapid / 3.4-3.4
    fever / Early / 3.4-3.4
    influenza / Delayed / 2.7-2.7
    sinusitis / Delayed / 2.7-2.7
    xerosis / Delayed / 2.0-2.0
    back pain / Delayed / 2.0-2.0
    flatulence / Early / Incidence not known
    eructation / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    xerostomia / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    diaphoresis / Early / 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
    lethargy / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    tinnitus / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Severe) 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) A dose reduction of abemaciclib is required if coadministration with saquinavir is necessary due to increased plasma concentrations of abemaciclib. In patients at the recommended starting doses of either 200 mg or 150 mg twice daily, reduce the dose of abemaciclib to 100 mg twice daily. In patients who have already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg twice daily. If saquinavir is discontinued, resume the original dose of abemaciclib after 3 to 5 half-lives of saquinavir. Abemaciclib is a CYP3A4 substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor was predicted to increase exposure to unbound abemaciclib and its active metabolites by 1.7-fold to 2.2-fold.
    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; Butalbital; Caffeine; Codeine: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Acetaminophen; Codeine: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Acetaminophen; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with saquinavir may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of saquinavir could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If saquinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and saquinavir is a CYP3A4 inhibitor.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP3A4. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP3A4 inhibitor, such as saquinavir. A reduced dosage of propoxyphene may be needed. Monitor patients for central nervous system (CNS) and respiratory depression.
    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 concomitant use of ado-trastuzumab emtansine with saquinavir, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until saquinavir is cleared from the circulation (approximately 3 elimination half-lives), or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Saquinavir is a strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Afatinib: (Major) If the concomitant use of saquinavir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of saquinavir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and saquinavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir 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 ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. 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.
    Albuterol: (Minor) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Albuterol; Ipratropium: (Minor) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    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) Alfentanil is metabolized by the hepatic isoenzyme CYP3A4. Drugs that inhibit this enzyme, such as protease inhibitors, may alter responses to alfentanil. A dose reduction of one or both drugs may be warranted. Monitor closely for oversedation and respiratory depression.
    Alfuzosin: (Severe) Alfuzosin is contraindicated for use with anti-retroviral protease inhibitors due to the potential for serious/life-threatening reactions, including hypotension. Alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes; potent inhibitors of CYP3A4, such as anti-retroviral protease inhibitors, block the metabolism of alfuzosin and increase systemic exposure to alfuzosin. Additionally, ritonavir, saquinavir boosted with ritonavir and lopinavir; ritonavir cause dose-dependent QT and PR prolongation; the risk of QT interval prolongation may be increased if these drugs are used with alfuzosin.
    Aliskiren; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Almotriptan: (Major) Saquinavir boosted with ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate. Saquinavir is an inhibitor of CYP3A4; when boosted with ritonavir, CYP3A4 inhibition is potent. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    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: (Major) Coadministration of alprazolam and saquinavir boosted with ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Saquinavir boosted with ritonavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Amiodarone: (Severe) 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.
    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.
    Amitriptyline; 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. (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) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with saquinavir in combination with ritonavir. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with saquinavir plus ritonavir. Patients should be monitoried for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 3.9-fold with the concomitant administration of saquinavir in combination with ritonavir in a pharmacokinetic study; however, the dose of saquinavir plus ritonavir used in the study was lower than doses used in clinical practice. The increase in atorvastatin AUC due to coadministration with clinically appropriate doses of saquinavir plus ritonavir are likely to be even higher. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and saquinavir plus ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Benazepril: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Telmisartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amlodipine; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) 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.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) 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.
    Apixaban: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as saquinavir coadministered with ritonavir. Concomitant administration of saquinavir plus ritonavir and apixaban results in increased exposure to apixaban which increases the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and saquinavir plus ritonavir.
    Apomorphine: (Major) Concurrent use of saquinavir and apomorphine 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 indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    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.
    Arformoterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Aripiprazole: (Major) Because both saquinavir and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as saquinavir. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    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: (Severe) 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).
    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; Butalbital; Caffeine; Codeine: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    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) Concomitant use of oxycodone with saquinavir may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of saquinavir could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If saquinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and saquinavir is a CYP3A4 inhibitor.
    Atazanavir: (Severe) 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: (Severe) 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). (Severe) 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 daruanavir are CYP3A4 substrates.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include saquinavir.
    Atorvastatin: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with saquinavir in combination with ritonavir. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with saquinavir plus ritonavir. Patients should be monitoried for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 3.9-fold with the concomitant administration of saquinavir in combination with ritonavir in a pharmacokinetic study; however, the dose of saquinavir plus ritonavir used in the study was lower than doses used in clinical practice. The increase in atorvastatin AUC due to coadministration with clinically appropriate doses of saquinavir plus ritonavir are likely to be even higher. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and saquinavir plus ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg atorvastatin daily in adults when coadministered with saquinavir in combination with ritonavir. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with saquinavir plus ritonavir. Patients should be monitoried for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The atorvastatin AUC was increased 3.9-fold with the concomitant administration of saquinavir in combination with ritonavir in a pharmacokinetic study; however, the dose of saquinavir plus ritonavir used in the study was lower than doses used in clinical practice. The increase in atorvastatin AUC due to coadministration with clinically appropriate doses of saquinavir plus ritonavir are likely to be even higher. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and saquinavir plus ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    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.
    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 50%; 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 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine; Fluticasone: (Major) Saquinavir may inhibit CYP3A4 metabolism of fluticasone, resulting in increased plasma fluticasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to fluticasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
    Azithromycin: (Severe) The concurrent use of azithromycin and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). Both saquinavir and azithromycin are P-glycoprotein (P-gp) substrates and inhibitors, which may lead to increased serum concentrations of either drug when given concomitantly, 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 azithromycin. There have been case reports of QT prolongation and TdP with the use of azithromycin in post-marketing reports.
    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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) 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.
    Benzonatate: (Major) The FDA recommends that saquinavir boosted with ritonavir should not be used in combination with other drugs that may prolong the QT interval. Benzonatate has a low, but possible risk for QT prolongation and torsades de pointes.
    Bepridil: (Major) Saquinavir can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of bepridil. The concurrent use of bepridil and saquinavir should be done cautiously used due to the potential for serious toxicity.
    Bexarotene: (Moderate) Bexarotene is metabolized by cytochrome P450 3A4. Protease Inhibitors inhibit CYP3A4 and may increase bexarotene plasma concentrations following oral administration.
    Bicalutamide: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as protease inhibitors, decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include saquinavir.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include saquinavir.
    Boceprevir: (Major) Close clinical monitoring is advised when administering saquinavir with boceprevir due to an increased potential for adverse events. If saquinavir dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of saquinavir and boceprevir. Both saquinavir and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (PGP). When used in combination, the plasma concentrations of both medications may be elevated.
    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.
    Bretylium: (Major) The FDA recommends that saquinavir boosted with ritonavir should not be used in combination with other drugs that may prolong the QT interval, including bretylium.
    Brigatinib: (Major) Avoid coadministration of brigatinib with saquinavir if possible due to increased plasma exposure of brigatinib and decreased exposure to saquinavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy of the antiretroviral regimen and 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 inducer; saquinavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A 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.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Budesonide: (Minor) Plasma concentrations of orally administered budesonide may increase during coadministration with CYP3A4 inhibitors like saquinavir; a budesonide dose reduction should be considered. Toxicity may occur, particularly excessive HPA-axis suppression. Theoretically, inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Budesonide; Formoterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors. (Minor) Plasma concentrations of orally administered budesonide may increase during coadministration with CYP3A4 inhibitors like saquinavir; a budesonide dose reduction should be considered. Toxicity may occur, particularly excessive HPA-axis suppression. Theoretically, inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Bupivacaine; Lidocaine: (Severe) 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.
    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%.
    Cabozantinib: (Major) Avoid concomitant use of cabozantinib with saquinavir due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if saquinavir is discontinued. Additionally, monitor for a possible increase in saquinavir-related adverse events. Cabozantinib is primarily metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; saquinavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of saquinavir may be increased and concentrations of cabozantinib further increased.
    Caffeine; Ergotamine: (Severe) 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.
    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.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Saquinavir is a PGP inhibitor/substrate.Theoretically, concentrations of either drug may be increased. In addition, 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) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Saquinavir is a PGP inhibitor/substrate.Theoretically, concentrations of either drug may be increased. In addition, 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.
    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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    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: (Severe) 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 inhibitor that causes concentration-dependent prolongation of the QT interval. Saquinavir is also a 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).
    Cevimeline: (Major) Cevimeline is metabolized by CYP3A4 and CYP2D6. Anti-retroviral protease inhibitors inhibit one or both of these isoenzymes and are expected to lead to an increase in cevimeline plasma concentrations.
    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; 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) Concurrent use of chloroquine 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. Chloroquine is also associated with an increased risk of QT prolongation and TdP.
    Chlorpheniramine; Codeine: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpromazine: (Severe) 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.
    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) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    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.
    Ciprofloxacin: (Major) Concurrent use of saquinavir and ciprofloxacin 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. Ciprofloxacin has been associated with a possible risk for QT prolongation and TdP.
    Cisapride: (Severe) Concurrent use of cisapride with anti-retroviral protease inhibitors (PI) is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Cisapride is metabolized by CYP3A4, and all PIs inhibit this enzyme; thus, coadministration may increases cisapride plasma concentrations and increase the risk of adverse events. Cases of QT prolongation and ventricular arrhythmias, including TdP and death, have been observed during post-marketing surveillance when cisapride is administered with potent CYP3A4 inhibitors. Additionally, saquinavir boosted with ritonavir and lopinavir; ritonavir causes QT prolongation, which could further increase the risk for TdP if coadministered with cisapride.
    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: (Severe) 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.
    Clindamycin: (Moderate) Concomitant use of clindamycin and saquinavir may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; boosted saquinavir is a strong inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    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: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity. A decrease in the clonazepam dose may be needed.
    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: (Severe) 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: (Severe) 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 daruanavir are CYP3A4 substrates.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) 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 daruanavir are CYP3A4 substrates. (Major) Avoid coadministration of saquinavir with elvitegravir. No data are available regarding use of these drugs concurrently.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) 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 daruanavir 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.
    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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Guaifenesin: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    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: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like saquinavir boosted with ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and saquinavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; saquinavir is a substrate of both CYP3A4 and P-gp. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    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: (Severe) Concomitant use of saquinavir with crizotinib is contraindicated due to the risk of QT prolongation; plasma concentrations of both drugs may also significantly increase. Crizotinib is a CYP3A4 substrate and moderate inhibitor that has been associated with concentration-dependent QT prolongation. Saquinavir is a CYP3A4 substrate and strong inhibitor, that is also associated with concentration-dependent QT prolongation, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
    Cyclobenzaprine: (Major) Concurrent use of saquinavir boosted with ritonavir and cyclobenzaprine should be avoided if possible due to the potential for cyclobenzaprine-related side effects, such as CNS depression and 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). Cyclobenzaprine is also associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose. If coadministration is required, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Also, the CYP3A4 enzyme and CYP1A2 enzyme are primarily responsible for the hepatic metabolism of cyclobenzaprine via N-demethylation in humans in vitro. Theoretically, levels of cyclobenzaprine could rise if used in combination with CYP3A4 inhibitors such as saquinavir/ritonavir; however, the clinical significance of potential interactions has not been established. Observe the patient for enhanced side effects, such as CNS depression, if these drugs are coadministered.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with saquinavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Saquinavir is a strong CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Cyclosporine: (Major) An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug.
    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: (Severe) According to the manufacturer, concurrent administration of dapsone 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). In addition, 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. Due to elevated plasma dapsone concentrations, there is a potential for excessive dapsone-related side effects, including hemolytic anemia, methemoglobinemia, or peripheral neuropathy.
    Darifenacin: (Moderate) Antiretroviral protease inhibitors may decrease the metabolism of darifenacin leading to a possible increase in adverse anticholinergic effects.
    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: (Severe) 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 daruanavir 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
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of saquinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of saquinavir, dasabuvir, ombitasvir, paritaprevir, and ritonavir and subsequent adverse effects such as QT prolongation. Both saquinavir and ritonavir are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. In addition, saquinavir inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Saquinavir and ritonavir have both been associated with QT prolongation; caution and close monitoring are advised if these drugs are administered together. (Minor) Although often administered together, ritonavir increases saquinavir plasma concentrations by two mechanisms: 1) the inhibition of GI cytochrome P450 during absorption and 2) metabolic inhibition of hepatic CYP450. Clinically, the interaction is used to therapeutic benefit. The combination allows for less frequent saquinavir dosing, while reducing the likelihood of developing saquinavir-resistant HIV strains. Saquinavir (Invirase) should only be used in combination with ritonavir. The use of saquinavir 'boosted' with ritonavir is contraindicated in patients with severe hepatic impairment. Saquinavir boosted with ritonavir has been found to increase the risk of QT prolongation and PR prolongation in a dose-dependent fashion. The manufacturer of saquinavir recommends that saquinavir boosted with ritonavir not be used in combination with other drugs that may prolong the QT or PR interval. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, older age (i.e., elderly), significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia).
    Dasatinib: (Severe) 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). Both saquinavir boosted with ritonavir and dasatinib are inhibitors and substrates of CYP3A4. These drugs used together may result in large increases in dasatinib and saquinavir serum concentrations. 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 dasatinib.
    Daunorubicin: (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. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
    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) 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. Drugs with a possible risk for QT prolongation and TdP that should avoided in combination with saquinavir include degarelix.
    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.
    Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with saquinavir. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QT prolongation may occur with deutetrabenazine. 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).
    Dexamethasone: (Major) Avoid concurrent administration of dexamethasone and saquinavir boosted with ritonavir. Dexamethasone is may induce the CYP3A4 metabolism of saquinavir, resulting in reduced saquinavir plasma concentrations. Decreased saquinavir plasma concentrations could lead to HIV treatment failures or the development of viral-resistance. If used concomitantly, the patient should be observed for changes in the clinical efficacy and concentrations of the antiretroviral regimen.
    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.
    Dextromethorphan; 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.
    Dextromethorphan; Quinidine: (Severe) 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: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity. Prolonged sedation and respiratory depression can occur. A decrease in the diazepam dose may be needed
    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: (Severe) 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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Disopyramide: (Severe) 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: (Minor) Saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes, such as docetaxel.
    Dofetilide: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP); therefore, use with drugs having a possible risk of QT prolongation and TdP, such as lopinavir; ritonavir, is contraindicated. In addition, lopinavir; ritonavir, a CYP3A4 inhibitor, may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation.
    Dolasetron: (Severe) 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: (Major) Concurrent use of saquinavir and rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    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.
    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: (Major) Avoid coadministration of saquinavir and doxorubicin if possible. If avoidance is not possible, perform a baseline ECG prior to initiation of concomitant therapy and carefully monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Saquinavir is a potent CYP3A4 inhibitor and a moderate inhibitor of P-glycoprotein (P-gp); doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. 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). Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronabinol, THC: (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: (Severe) 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; 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.
    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: (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.
    Elbasvir; Grazoprevir: (Severe) 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: (Severe) 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.
    Eliglustat: (Severe) 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).
    Elvitegravir: (Major) Avoid coadministration of saquinavir with elvitegravir. No data are available regarding use of these drugs concurrently.
    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; 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: (Major) Concurrent use of saquinavir and rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Concurrent use of saquinavir and rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (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.
    Enalapril; Felodipine: (Moderate) Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir 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.
    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.
    Epirubicin: (Major) Concurrent use of saquinavir boosted with ritonavir and epirubicin 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. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eplerenone: (Severe) 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.
    Ergoloid Mesylates: (Severe) 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.
    Ergonovine: (Severe) 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: (Severe) 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: (Severe) 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: (Severe) 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 eribulin. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with saquinavir due to the risk of increased erlotinib-related adverse reactions; if concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Saquinavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with saquinavir may also increase erlotinib exposure.
    Erythromycin: (Severe) 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). Both saquinavir boosted with ritonavir and erythromycin are inhibitors and substrates of the hepatic isoenzyme CYP3A4 as well as the drug efflux pump, P-glycoprotein (P-gp). This complex interaction may ultimately result in altered plasma concentrations of both erythromycin 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 erythromycin.
    Erythromycin; Sulfisoxazole: (Severe) 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). Both saquinavir boosted with ritonavir and erythromycin are inhibitors and substrates of the hepatic isoenzyme CYP3A4 as well as the drug efflux pump, P-glycoprotein (P-gp). This complex interaction may ultimately result in altered plasma concentrations of both erythromycin 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 erythromycin.
    Escitalopram: (Major) Although not studied, anti-retroviral protease inhibitors might theoretically impair the metabolism of escitalopram when administered concomitantly. In addition, escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as saquinavir and lopinavir; ritonavir, should be done with caution and close monitoring. Escitalopram is metabolized by CYP3A4 and CYP2C19. Several drugs can inhibit the metabolism of CYP 450 isoenzymes, including those that are responsible for the metabolism of escitalopram. Although clinical studies have not been done to determine the clinical significance of such an interaction, the potential for increased adverse effects and toxicity associated with elevated plasma levels of escitalopram theoretically exists. In clinical trial subjects, combined administration of cimetidine and citalopram for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical relevance of these findings is unknown as the combination was not associated with significant adverse effects. Because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease drug clearance.
    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.
    Esomeprazole; Naproxen: (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 Cypionate; 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.
    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.
    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: (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; Desogestrel: (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.
    Ethinyl Estradiol; Ethynodiol Diacetate: (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; Etonogestrel: (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.
    Ethinyl Estradiol; Levonorgestrel: (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.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; 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) 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.
    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; Norethindrone Acetate; 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.
    Ethinyl Estradiol; Norethindrone: (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; 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.
    Ethinyl Estradiol; Norgestimate: (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.
    Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as saquinavir may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with saquinavir. Saquinavir is a strong inhibitor of CYP3A4 as well as a P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    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 saquinavir with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of saquinavir with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); saquinavir is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Ezetimibe; Simvastatin: (Severe) 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.
    Ezogabine: (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. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Drugs with a possible risk for QT prolongation and TdP that should avoided in combination with saquinavir include ezogabine.
    Felodipine: (Moderate) Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir 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.
    Fentanyl: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as saquinavir, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4 and 2D6. In theory, the CYP3A4 inhibitory effects of anti-retroviral protease inhibitors may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. Anti-retroviral protease inhibitors which also inhibit 2D6, such as ritonavir, may impair both CYP metabolic pathways of 5-hydroxymethyltolterodine. Fesoterodine doses greater than 4 mg/day are not recommended during concurrent use of potent 3A4 inhibitors.
    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: (Severe) 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: (Severe) 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: (Severe) 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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including saquinavir. Saquinavir boosted with ritonavir and fluoxetine used together may result in increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including saquinavir. Saquinavir boosted with ritonavir and fluoxetine used together may result in increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias. (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.
    Fluphenazine: (Severe) 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: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. A decrease in the flurazepam dose may be needed.
    Fluticasone: (Major) Saquinavir may inhibit CYP3A4 metabolism of fluticasone, resulting in increased plasma fluticasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to fluticasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
    Fluticasone; Salmeterol: (Major) Saquinavir may inhibit CYP3A4 metabolism of fluticasone, resulting in increased plasma fluticasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to fluticasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal. (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Saquinavir may inhibit CYP3A4 metabolism of fluticasone, resulting in increased plasma fluticasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to fluticasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal. (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Fluticasone; Vilanterol: (Major) Saquinavir may inhibit CYP3A4 metabolism of fluticasone, resulting in increased plasma fluticasone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Similar results are expected with saquinavir. Consider using an alternative treatment to fluticasone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone). If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal. (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    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: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Formoterol; Mometasone: (Moderate) Concomitant administration of saquinavir and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with saquinavir long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    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.
    Galantamine: (Moderate) The plasma concentrations of galantamine, a partial CYP3A4 substrate, may be elevated when administered with protease inhibitors, which are strong CYP3A4 inhibitors. If this combination is required, monitor for galantamine-related adverse effects such as nausea, vomiting, diarrhea, increased urination, decreased appetite, confusion, dizziness, bradycardia, and excessive sweating.
    Garlic, Allium sativum: (Severe) Coadministration of garlic supplementation with saquinavir may result in significantly reduced saquinavir plasma concentrations, which may cause treatment failures and/or development of viral resistance. 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). While no information is available regarding the use of garlic capsules with saquinavir that is enhanced or 'boosted' with ritonavir, the manufacturer of saquinavir recommends that they not be coadministered.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and saquinavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib 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.
    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.
    Glycopyrrolate; Formoterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Goserelin: (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 goserelin. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of 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.
    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.
    Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    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.
    Halofantrine: (Moderate) Protease Inhibitors significantly inhibit cytochrome CYP3A4,and may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity.
    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: (Severe) 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.
    Homatropine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    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.
    Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Ibuprofen: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and saquinavir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as saquinavir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydroxychloroquine: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may 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 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. Ventricular arrhythmias and TdP have been reported with the use of hydroxychloroquine.
    Hydroxyprogesterone: (Minor) Coadministration of hydroxyprogesterone, a primary 3A4 substrate and saquinavir, a strong CYP3A4 inhibitor may increase the serum concentration of hydroxyprogesterone.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include saquinavir.
    Ibrutinib: (Major) Avoid the 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; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with saquinavir may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of saquinavir could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If saquinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and saquinavir is a CYP3A4 inhibitor.
    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.
    Idarubicin: (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. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, and idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
    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: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Iloperidone: (Severe) The concurrent use of iloperidone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). Iloperidone is a P-glycoprotein (P-gp) inhibitor, which may lead to increased serum concentrations of saquinavir when given concomitantly, 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 iloperidone.
    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.
    Indacaterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Indacaterol; Glycopyrrolate: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    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.
    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.
    Interferon Alfa-2b; 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.
    Interferons: (Major) The concomitant use of interferons 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.
    Irinotecan Liposomal: (Major) If possible, avoid concomitant use of irinotecan liposomal with saquinavir, a strong CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. Discontinue saquinavir at least 1 week prior to initiation of liposomal irinotecan therapy. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Major) Saquinavir is a strong CYP3A4 and moderate P-glycoprotein (P-gp) inhibitor; irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer saquinavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue saquinavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Severe) 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: (Moderate) Both saquinavir boosted with ritonavir and isoniazid, INH are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with isoniazid 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]).
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) 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). (Moderate) Both saquinavir boosted with ritonavir and isoniazid, INH are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with isoniazid 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]).
    Isoniazid, INH; Rifampin: (Severe) 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). (Moderate) Both saquinavir boosted with ritonavir and isoniazid, INH are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. The use of saquinavir/ritonavir with isoniazid 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]).
    Isradipine: (Moderate) Concurrent administration of isradipine with protease inhibitors may result in elevated isradipine plasma concentrations and increased hypotensive effects. Isradipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir 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.
    Itraconazole: (Major) If itraconazole is administered with saquinavir boosted with ritonavir, do not exceed itraconazole doses of 200 mg/day. Use caution when unboosted itraconazole is coadministered with itraconazole due to the potential for increased itraconazole exposure. Saquinavir concentrations may also be increased. Both itraconazole and saquinavir are substrates and inhibitors of CYP3A4.
    Ivabradine: (Severe) 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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, and saquinavir is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); saquinavir is metabolized by CYP3A4 and is a substrate of P-gp. Coadministration may increase saquinavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as saquinavir should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider reducing the ixabepilone dose to 20 mg/m2 given every 3 weeks; clinical data for this dose adjustment are lacking. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Ketoconazole: (Major) Plasma concentrations of saquinavir are significantly increased if coadministered with ketoconazole; steady state saquinavir AUC and Cmax values may be three times those of saquinavir alone. However, no saquinavir dosage adjustments are recommended when saquinavir and ketoconazole are coadministered for a short period of time. When saquinavir boosted with ritonavir is coadministered with ketoconazole, ketoconazole plasma concentrations increase; therefore, doses of more than 200 mg/day of ketoconazole are not recommended. Although the manufacturer of saquinavir recommends a dosage maximum when coadministered with ketoconazole, saquinavir is contraindicated for use with drugs that prolong the QT interval and can increase the plasma concentration of saquinavir. Ketoconazole has been associated with QT prolongation and is a potent inhibitor of CYP3A4.
    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; Naproxen: (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.
    Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like protease inhibitors, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Lapatinib: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as saquinavir boosted with ritonavir, should generally be avoided. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider a lapatinib dose reduction. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Administer lapatinib with extreme caution in patients taking CYP3A4 inhibitors that also have potential to induce QT prolongation, as lapatinib 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). Further, saquinavir is a P-glycoprotein inhibitor; concurrent administration of lapatinib with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Lenvatinib: (Major) Saquinavir should be used cautiously and with close monitoring with lenvatinib. 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. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include saquinavir.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include saquinavir.
    Levalbuterol: (Minor) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Levobupivacaine: (Moderate) Levobupivacaine is metabolized by CYP3A4; use caution when administering levobupivacaine concurrently with the potent CYP3A4 inhibitor saquinavir boosted with ritonavir. Inhibitors of CYP3A4, including saquinavir/ritonavir, may increase the systemic exposure of levobupivacaine by decreasing the metabolism of the drug. Monitor patients for adverse effects related to the levobupivacaine.
    Levofloxacin: (Major) Concurrent use of saquinavir and levofloxacin 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. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
    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.
    Lidocaine: (Severe) 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.
    Lomitapide: (Severe) 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.
    Long-acting beta-agonists: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Loperamide: (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 loperamide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, use of these drugs together may result in elevated loperamide concentrations and a 54 percent decrease in saquinavir exposure. Predictions about this interaction can be made based on the drugs metabolic pathways. Loperamide is a substrate for CYP3A4 and P-glycoprotein (P-gp), while saquinavir is a potent inhibitor of CYP3A4 and P-gp. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (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 loperamide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, use of these drugs together may result in elevated loperamide concentrations and a 54 percent decrease in saquinavir exposure. Predictions about this interaction can be made based on the drugs metabolic pathways. Loperamide is a substrate for CYP3A4 and P-glycoprotein (P-gp), while saquinavir is a potent inhibitor of CYP3A4 and P-gp. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Lopinavir; ritonavir should only be used in combination with saquinavir when there are no acceptable alternative therapies because additive QT and/or PR interval prolongation may occur, increasing the risk for serious cardiac arrhythmias such as such as 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 in combination with ritonavir causes dose-dependent QT and PR prolongation; lopinavir; ritonavir has also been associated with QT and PR interval prolongation. If lopinavir; ritonavir is used in combination with saquinavir, the recommended dosage is lopinavir/ritonavir 400 mg/100mg PO twice daily plus saquinavir 1000 mg PO twice daily. (Minor) Although often administered together, ritonavir increases saquinavir plasma concentrations by two mechanisms: 1) the inhibition of GI cytochrome P450 during absorption and 2) metabolic inhibition of hepatic CYP450. Clinically, the interaction is used to therapeutic benefit. The combination allows for less frequent saquinavir dosing, while reducing the likelihood of developing saquinavir-resistant HIV strains. Saquinavir (Invirase) should only be used in combination with ritonavir. The use of saquinavir 'boosted' with ritonavir is contraindicated in patients with severe hepatic impairment. Saquinavir boosted with ritonavir has been found to increase the risk of QT prolongation and PR prolongation in a dose-dependent fashion. The manufacturer of saquinavir recommends that saquinavir boosted with ritonavir not be used in combination with other drugs that may prolong the QT or PR interval. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, older age (i.e., elderly), significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia).
    Loratadine: (Minor) Theoretically, anti-retroviral protease inhibitors could lead to elevated loratadine concentrations due to inhibition of CYP3A4, CYP2D6 and/or P-glycoprotein (P-gp). Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events. Although significant drug interactions have not been confirmed between loratadine and other agents that inhibit cytochrome P-450, like protease inhibitors, caution should be used during coadministration due to the serious nature of interactions between these drugs and certain other H1-antagonists.
    Loratadine; Pseudoephedrine: (Minor) Theoretically, anti-retroviral protease inhibitors could lead to elevated loratadine concentrations due to inhibition of CYP3A4, CYP2D6 and/or P-glycoprotein (P-gp). Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events. Although significant drug interactions have not been confirmed between loratadine and other agents that inhibit cytochrome P-450, like protease inhibitors, caution should be used during coadministration due to the serious nature of interactions between these drugs and certain other H1-antagonists.
    Lovastatin: (Severe) 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.
    Lovastatin; Niacin: (Severe) 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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, and saquinavir is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); saquinavir is metabolized by CYP3A4 and is a substrate of P-gp. Coadministration may increase saquinavir exposure leading to increased or prolonged therapeutic effects and adverse events. (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 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, itraconazole, 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 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, itraconazole, 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.
    Lurasidone: (Severe) 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.
    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.
    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: (Severe) 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.
    Meperidine; 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.
    Mesoridazine: (Severe) 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 mesoridazine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Mestranol; Norethindrone: (Major) Saquinavir may increase the metabolism of estrogen-based oral contraceptives, such as mestranol. Women receiving hormonal contraceptives and saquinavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with saquinavir to use an additional method of contraception to protect against unwanted pregnancy.
    Metaproterenol: (Minor) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    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; 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. 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) 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. (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. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1), protease inhibitors inhibit CYP3A4 and OATP.
    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: (Severe) 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.
    Methysergide: (Severe) 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.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include saquinavir.
    Midazolam: (Major) The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated. Midazolam is metabolized by hepatic isozyme CYP3A4; inhibitors of this pathway can potentiate the clinical effects of midazolam. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. Parenteral midazolam can be used with protease inhibitors in a setting that allows for close clinical monitoring with the ability to manage respiratory depression or sedation should they occur; a reduction in the dose of parenteral midazolam may be warranted.
    Midostaurin: (Severe) Concomitant use of midostaurin and saquinavir boosted with ritonavir is contraindicated, as significantly increased exposure of midostaurin and its active metabolites may occur resulting in serious adverse effects, including QT prolongation. Both midostaurin and saquinavir boosted with ritonavir have been associated with QT prolongation. Additionally, midostaurin is a CYP3A4 substrate; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Mifepristone, RU-486: (Severe) The concurrent use of mifepristone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and mifepristone are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Mifepristone also is an inhibitor of the drug efflux pump, P-glycoprotein (P-gp), and saquinavir is a substrate for P-gp. This complex interaction may ultimately result in altered plasma concentrations of both mifepristone 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 mifepristone.
    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.
    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.
    Mometasone: (Moderate) Concomitant administration of saquinavir and mometasone may increase systemic exposure to mometasone, increasing the risk of corticosteroid-related adverse events. Exercise caution when administering mometasone with saquinavir long-term and monitor closely for hypercorticism and adrenal suppression. Mometasone is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor.
    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.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with protease inhibitors may result in increased paclitaxel plasma concentrations and risk for toxicity. Caution and close monitoring are advised if these drugs are administered together. Paclitaxel is metabolized by the hepatic isoenzymes CYP2C8 and CYP3A4; protease inhibits are potent CYP3A4 inhibitors. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp); some protease inhibitors also inhibit P-gp. Several case reports describe potential interactions between anti-retroviral protease inhibitors and paclitaxel. In one report, two patients on combined therapy with delavirdine, didanosine, and saquinavir developed unexpectedly severe paclitaxel toxicity, including mucositis and neutropenia, but a causal relationship was not established. These patients were previously treated with paclitaxel with only mild toxicity (i.e., nausea and alopecia). In another case, paclitaxel was given concomitantly with antiretroviral agents and no dosage adjustments of paclitaxel, indinavir, ritonavir, saquinavir or nevirapine were required.
    Nateglinide: (Moderate) Concurrent administration of nateglinide with protease inhibitors may result in elevated nateglinide plasma concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia could occur. Nateglinide is partially metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitor of this enzyme. However, 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.[28839
    Neratinib: (Major) Avoid concomitant use of saquinavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant; 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 and nevirapine results in decreased saquinavir AUC and Cmax, 38% and 32%, respectively. No significant changes in nevirapine pharmacokinetics were noted. Appropriate doses for this combination are not established, but an increase in the dosage of saquinavir may be required. The interaction between nevirapine and saquinavir boosted with ritonavir has not been evaluated.
    Niacin; Simvastatin: (Severe) 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: (Severe) 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. Further, nilotinib is an inhibitor of P-glycoprotein, for which saquinavir is a substrate. 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. 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 nilotinib.
    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) Saquinavir is a moderate inhibitor of P-glycoprotein (P-gp) and a potent CYP3A4 inhibitor; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of saquinavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nisoldipine: (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. In addition, 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.
    Norfloxacin: (Major) Concurrent use of saquinavir boosted with ritonavir and norfloxacin 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. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    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.
    Octreotide: (Severe) 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 octreotide. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Ofloxacin: (Major) Concurrent use of saquinavir boosted with ritonavir and ofloxacin 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. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    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.
    Olaparib: (Major) Avoid coadministration of olaparib with saquinavir and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and saquinavir is a strong CYP3A4 inhibitor.
    Olodaterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of saquinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of saquinavir, dasabuvir, ombitasvir, paritaprevir, and ritonavir and subsequent adverse effects such as QT prolongation. Both saquinavir and ritonavir are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. In addition, saquinavir inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Saquinavir and ritonavir have both been associated with QT prolongation; caution and close monitoring are advised if these drugs are administered together. (Minor) Although often administered together, ritonavir increases saquinavir plasma concentrations by two mechanisms: 1) the inhibition of GI cytochrome P450 during absorption and 2) metabolic inhibition of hepatic CYP450. Clinically, the interaction is used to therapeutic benefit. The combination allows for less frequent saquinavir dosing, while reducing the likelihood of developing saquinavir-resistant HIV strains. Saquinavir (Invirase) should only be used in combination with ritonavir. The use of saquinavir 'boosted' with ritonavir is contraindicated in patients with severe hepatic impairment. Saquinavir boosted with ritonavir has been found to increase the risk of QT prolongation and PR prolongation in a dose-dependent fashion. The manufacturer of saquinavir recommends that saquinavir boosted with ritonavir not be used in combination with other drugs that may prolong the QT or PR interval. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, older age (i.e., elderly), significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia).
    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; 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.
    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 electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Saquinavir 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.
    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) Oxybutynin is metabolized by CYP3A4. Caution should be used when oxybutynin is given in combination with inhibitors of CYP3A4, such as protease inhibitors. Monitor for adverse effects if these drugs are administered together.
    Oxycodone: (Moderate) Concomitant use of oxycodone with saquinavir may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of saquinavir could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If saquinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and saquinavir is a CYP3A4 inhibitor.
    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.
    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) 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 paliperidone. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    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: (Severe) 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.
    Pentamidine: (Severe) 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.
    Pergolide: (Severe) 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.
    Perindopril; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. 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.
    Perphenazine: (Severe) 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: (Severe) 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.
    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.
    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.
    Pimozide: (Severe) 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 CYP3A4 inhibitors, such as the protease inhibitors. Similarly, concurrent use of pimozide and potent CYP2D6 inhibitors, such as tipranavir, may elevated pimozide concentrations. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP. Saquinavir boosted with ritonavir and lopinavir; ritonavir may also cause QT prolongation, which could further increase the risk for TdP if coadministered with pimozide.
    Pirbuterol: (Minor) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Pitavastatin: (Major) Pitavastatin should not be used in combination with ritonavir-boosted anti-retroviral protease inhibitors, such as saquinavir, due to the potential increase in pitavastatin concentrations and the increased risk of rhabdomyolitis.
    Ponatinib: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, saquinavir.
    Posaconazole: (Severe) 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.
    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.
    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.
    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: (Severe) 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.
    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.
    Propafenone: (Severe) 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.
    Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP3A4. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP3A4 inhibitor, such as saquinavir. A reduced dosage of propoxyphene may be needed. Monitor patients for central nervous system (CNS) and respiratory depression.
    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: (Severe) 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: (Severe) 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.
    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: (Severe) 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 raolazine 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: (Severe) 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.
    Regadenoson: (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. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Drugs with a possible risk for QT prolongation and TdP that should avoided in combination with saquinavir include regadenoson.
    Regorafenib: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Repaglinide: (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. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1), protease inhibitors inhibit CYP3A4 and OATP.
    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: (Severe) 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. Ribociclib is also extensively metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a moderate CYP3A4 inhibitor and saquinavir is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Severe) 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. Ribociclib is also extensively metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a moderate CYP3A4 inhibitor and saquinavir is a CYP3A4 substrate.
    Rifabutin: (Major) Systemic exposure (AUC) of rifabutin is increased by 60% when administered concurrently with saquinavir boosted with ritonavir. To compensate, the manufacturer recommends reducing the adult rifabutin dose by at least 75% (i.e., 150 mg every other day or three times weekly) during times of coadministration. The CDC guidelines suggest decreasing the adult dose of rifabutin to 150 mg daily or 300 mg three times per week when coadministered with ritonavir boosted protease inhibitors, such as saquinavir. No dosage adjustment is necessary for saquinavir/ritonavir. Monitor patients carefully when this combination is used.
    Rifampin: (Severe) 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) Rifapentine is an inducer of CYP3A4 and CYP2C8/9, and should not be coadministered with protease inhibitors as complex interactions may lead to decreased plasma concentrations of the anti-retroviral agents. In one study, indinavir Cmax and AUC were reduced by 55% and 70%, respectively. The clearance of indinavir was increased 3-fold in the presence of rifapentine while half-life did not change. 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) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and saquinavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Major) Concurrent use of saquinavir and rilpivirine 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    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.
    Ritonavir: (Minor) Although often administered together, ritonavir increases saquinavir plasma concentrations by two mechanisms: 1) the inhibition of GI cytochrome P450 during absorption and 2) metabolic inhibition of hepatic CYP450. Clinically, the interaction is used to therapeutic benefit. The combination allows for less frequent saquinavir dosing, while reducing the likelihood of developing saquinavir-resistant HIV strains. Saquinavir (Invirase) should only be used in combination with ritonavir. The use of saquinavir 'boosted' with ritonavir is contraindicated in patients with severe hepatic impairment. Saquinavir boosted with ritonavir has been found to increase the risk of QT prolongation and PR prolongation in a dose-dependent fashion. The manufacturer of saquinavir recommends that saquinavir boosted with ritonavir not be used in combination with other drugs that may prolong the QT or PR interval. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, older age (i.e., elderly), significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia).
    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,
    Ruxolitinib: (Major) Modify the ruxolitinib dosage when coadministered with saquinavir. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with saquinavir. Ruxolitinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of saquinavir use.
    Salmeterol: (Moderate) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. The coadministration of salmeterol with CYP3A4 inhibitors, such as the anti-retroviral protease inhibitors, can result in elevated salmeterol plasma concentrations. Avoid coadministration of salmeterol with the anti-retroviral protease inhibitors.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and saquinavir as coadministration may result in increased systemic exposure of saquinavir. Saquinavir is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of saquinavir.
    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.
    Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include saquinavir.
    Short-acting beta-agonists: (Minor) 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 with other drugs that may prolong the QT interval, such as beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Sibutramine: (Moderate) Saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes, such as sibutramine. Patients should be monitored for toxicities associated with sibutramine.
    Sildenafil: (Major) Coadministration of saquinavir with sildenafil is expected to substantially increase the plasma concentrations of sildenafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Coadministration is contraindicated when sildenafil is used for the treatment of pulmonary arterial hypertension (PAH). If coadministered when sildenafil is used for erectile dysfunction, use sildenafil at reduced doses of 25 mg every 48 hours with increased monitoring for adverse reactions. One death has been reported in a patient who received sildenafil in combination with ritonavir and saquinavir (Fortovase).
    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.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and saquinavir. Inhibition of CYP3A4 by saquinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Simvastatin: (Severe) 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.
    Simvastatin; Sitagliptin: (Severe) 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. (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.
    Sirolimus: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    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.
    Sofosbuvir; Velpatasvir: (Mo