Invirase

Generic Name: Saquinavir
Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: [3S-[2[1R*(R*),2S*],3α,4aβ,8aα]]-N1-[3-[3-[[(1,1-dimethyleth yl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy- 1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide
CAS Number: 127779-20-8

Introduction

Antiretroviral; HIV protease inhibitor (PI).1 3 6 10 28 51

Uses for Invirase

Treatment of HIV Infection

Treatment of HIV type 1 (HIV-1) infection in conjunction with other antiretrovirals.1 174 178 179 200 201

Used in conjunction with low-dose ritonavir (ritonavir-boosted saquinavir) or, alternatively, with fixed combination of lopinavir/ritonavir.1 200

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Usually used in PI-based regimens that include a PI and 2 nucleoside reverse transcriptase inhibitors (NRTIs).200

For initial treatment in HIV-infected adults and adolescents, some experts state that ritonavir-boosted saquinavir and 2 NRTIs is not recommended as an alternative or preferred PI-based regimen, but may be acceptable if used with caution in selected patients.200 (See Cardiovascular Effects under Cautions.)

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.199 Used in conjunction with other antiretrovirals.199

Postexposure prophylaxis of HIV infection in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Invirase Dosage and Administration

Administration

Oral Administration

Administer orally within 2 hours of a meal.1 15 51

Administer in conjunction with low-dose ritonavir (ritonavir-boosted saquinavir).1 200 Alternatively, administer in conjunction with fixed combination of lopinavir/ritonavir.1 200 Saquinavir dose should be taken at the same time as ritonavir dose.1

Dosage

Available as saquinavir mesylate; dosage expressed as saquinavir.1

Must be given in conjunction with other antiretrovirals.1

Pediatric Patients

Treatment of HIV Infection
Oral

Adolescents ≥16 years of age: 1 g twice daily boosted with low-dose ritonavir (100 mg twice daily).1 Alternatively, 1 g twice daily in conjunction with fixed combination of lopinavir 400 mg/ritonavir 100 mg twice daily.1

Adults

Treatment of HIV Infection
Oral

1 g twice daily boosted with low-dose ritonavir (100 mg twice daily).1 Alternatively, 1 g twice daily in conjunction with fixed combination of lopinavir 400 mg/ritonavir 100 mg twice daily.1

Postexposure Prophylaxis of HIV
Occupational Exposure
Oral

1 g twice daily boosted with low-dose ritonavir (100 mg twice daily).199

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.199

Nonoccupational Exposure
Oral

1 g twice daily boosted with low-dose ritonavir (100 mg twice daily) or, alternatively, 400 mg twice daily boosted with low-dose ritonavir (400 mg twice daily).198

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.198

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Dosage adjustment not necessary in mild to moderate hepatic impairment;1 some experts recommend caution.200 Contraindicated in severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Treatment of HIV Infection

No initial dosage adjustment needed.1 Use with caution in severe renal impairment or end-stage renal disease.1

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Cautions for Invirase

Contraindications

  • Hypersensitivity (anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, ritonavir, or any ingredient in the formulation.1

  • Complete AV block without implanted pacemakers and patients at high risk of complete AV block.1

  • Congenital long QT syndrome.1 (See Cardiovascular Effects under Cautions.)

  • Refractory hypokalemia or hypomagnesemia.1 (See Cardiovascular Effects under Cautions.)

  • Concomitant use with drugs that increase saquinavir plasma concentrations and prolong the QT interval.1 (See Cardiovascular Effects under Cautions.)

  • Severe hepatic impairment.1

  • Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, amiodarone, cisapride, dofetilide, ergot alkaloids, flecainide, systemic lidocaine, lovastatin, oral midazolam, pimozide, propafenone, quinidine, rifampin, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, trazodone, triazolam).1 (See Specific Drugs and Foods under Interactions.)

Warnings/Precautions

Interactions

Concomitant use with certain drugs is not recommended or requires particular caution.1 200 (See Specific Drugs and Foods under Interactions.)

When ritonavir-boosted saquinavir is used, the usual cautions, precautions, and contraindications associated with ritonavir should be considered.1

Cardiovascular Effects

Ritonavir-boosted saquinavir causes dose-dependent prolongation of PR interval; second- or third-degree AV block reported rarely.1 Patients with underlying structural heart disease, preexisting conduction system abnormalities, cardiomyopathies, and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities; ECG monitoring recommended in such patients.1 Concomitant use of ritonavir-boosted saquinavir and other drugs that prolong the PR interval (e.g., calcium-channel blocking agents, β-adrenergic blockers, digoxin, atazanavir) not evaluated.1 Use ritonavir-boosted saquinavir with caution in patients receiving other drugs that prolong the PR interval, particularly drugs metabolized by CYP3A; clinical monitoring recommended.1 (See Specific Drugs and Foods under Interactions.)

Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT interval; torsades de pointes reported rarely.1 Perform ECG prior to initiation of ritonavir-boosted saquinavir.1 Patients with QT interval >450 msec should not receive the drug.1 Ritonavir-boosted saquinavir may be initiated in those with baseline QT interval <450 msec; however, repeat ECG after 3–4 days of saquinavir and discontinue the antiretroviral if QT interval is >480 msec or is prolonged >20 msec over baseline.1 ECG monitoring recommended if ritonavir-boosted saquinavir is initiated in patients with CHF, bradyarrhythmias, hepatic impairment, and electrolyte abnormalities.1 Correct hypokalemia or hypomagnesemia prior to initiating ritonavir-boosted saquinavir; monitor these electrolytes periodically during therapy.1

Do not use ritonavir-boosted saquinavir in conjunction with drugs that increase saquinavir plasma concentrations and prolong QT interval.1 Manufacturer states that concomitant use of ritonavir-boosted saquinavir and drugs with the potential to increase QT interval should be considered only when no alternative therapy is available and potential benefits outweigh risks.1 Perform ECG prior to initiation of the drugs.1 Do not use such concomitant therapy in patients with QT interval >450 msec.1 If baseline QT interval is <450 msec, repeat ECG after 3–4 days of concomitant therapy.1 If QT interval is >480 msec or is prolonged >20 msec over baseline, clinician should use best clinical judgement regarding discontinuing ritonavir-boosted saquinavir and/or the other drug.1 Cardiology consult recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.1

Hyperglycemic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred.1 129 131

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.1

Hepatic Effects

Exacerbation of chronic liver dysfunction reported in patients with HBV or HCV, cirrhosis, or other underlying liver abnormalities.1 (See Hepatic Impairment under Cautions.)

Hemophilia A and B

Spontaneous bleeding noted with HIV PIs; causal relationship not established.1 80 127

Caution in patients with history of hemophilia type A or B.80 Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.1 80

Hyperlipidemia

Elevated cholesterol and/or triglycerides reported.1 Markedly elevated triglycerides are a risk factor for developing pancreatitis.1

Monitor cholesterol and triglycerides prior to and periodically during ritonavir-boosted saquinavir therapy.1 Manage lipid disorders as clinically appropriate.1 (See HMG-CoA Reductase Inhibitors under Interactions.)

Lactose Intolerance

Each 200-mg capsule contains 63.3 mg of anhydrous lactose; this quantity should not induce specific symptoms of lactose intolerance.1

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1 144 145 146 147 148 149 150 151

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]);1 this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; time to onset is variable and can occur many months after initiation of antiretroviral therapy.1

HIV Resistance

Possibility of HIV-1 resistant to saquinavir and possible cross-resistance to other HIV PIs.1 Continued saquinavir therapy following loss of viral suppression may increase likelihood of cross-resistance to other HIV PIs.1

Specific Populations

Pregnancy

Category B.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Experts state that pharmacokinetic data regarding use in pregnancy are limited and ritonavir-boosted saquinavir is considered an alternative (not preferred) PI for use in antiretroviral regimens in pregnant women.202

Lactation

Distributed into milk in rats;202 not known whether distributed into human milk.1 202

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Safety and efficacy not established in children <16 years of age.1

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Use caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Contraindicated in severe hepatic impairment.1 Although usual dosage can be used in mild or moderate hepatic impairment,1 some experts recommend caution.200

Renal Impairment

Use caution in severe renal impairment.1

Common Adverse Effects

Diarrhea, abdominal discomfort, nausea, vomiting, fatigue.1 51 75

Interactions for Invirase

Metabolized by CYP3A.1 83 94

Inhibits CYP3A.1 94

Substrate for P-glycoprotein.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A with possible alteration in metabolism of saquinavir and/or other drug.1 51 83 94

Drugs Affecting or Affected by P-glycoprotein Transport

Potential pharmacokinetic interaction with drugs that are inhibitors, inducers, or substrates of P-glycoprotein with possible alteration in pharmacokinetics of saquinavir and/or other drug.1

Drugs that Prolong the QT or PR Interval

Dose-dependent prolongation of QT and PR intervals has been reported in individuals receiving ritonavir-boosted saquinavir; additive effects on QT and/or PR interval prolongation may occur if ritonavir-boosted saquinavir is used concomitantly with other drugs known to have similar effects.1 Concomitant use with other drugs known to prolong QT and/or PR intervals (e.g., class IA and class III antiarrhythmic agents, neuroleptics, phosphodiesterase type 5 inhibitors if used for pulmonary arterial hypertension, some antidepressants, some anti-infectives, some antihistamines) not recommended.1 119 (See Cardiovascular Effects under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Alfuzosin

Possible increased alfuzosin concentrations; may result in hypotension1

Concomitant use contraindicated1 200

Antiarrhythmic agents (amiodarone, dofetilide, flecainide, ibutilide, systemic lidocaine, propafenone, quinidine, sotalol)

Amiodarone, dofetilide, flecainide, systemic lidocaine, propafenone, quinidine: Possible increased antiarrhythmic agent concentrations; potential for serious or life-threatening effects (e.g., cardiac arrhythmias)1

Ibutilide, sotalol: Possible additive QT and/or PR interval prolongation1

Amiodarone, dofetilide, flecainide, systemic lidocaine, propafenone, quinidine: Concomitant use contraindicated1

Ibutilide, sotalol: Use concomitantly with caution1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Carbamazepine, phenobarbital, phenytoin: Possible decreased saquinavir concentrations1

Carbamazepine: Possible increased carbamazepine concentrations with ritonavir-boosted saquinavir200

Phenytoin: Possible decreased phenytoin and saquinavir concentrations with ritonavir-boosted saquinavir200

Carbamazepine, phenobarbital, phenytoin: Use concomitantly with caution1

Carbamazepine, phenobarbital, phenytoin: Consider alternative anticonvulsant; if used concomitantly, monitor anticonvulsant and saquinavir concentrations and assess virologic response200

Antidepressants, tricyclic

Amitriptyline, desipramine, imipramine, nortriptyline: Increased antidepressant concentrations expected1 200

In patients receiving ritonavir-boosted saquinavir, titrate antidepressant dosage based on clinical assessment and/or plasma concentrations;1 200 use lowest possible antidepressant dosage200

Antifungals, azoles

Fluconazole: Possible increased saquinavir AUC;200 data not available regarding ritonavir-boosted saquinavir200

Itraconazole: If used with ritonavir-boosted saquinavir, possible pharmacokinetic interaction may affect both drugs200

Ketoconazole: If used with ritonavir-boosted saquinavir, increased ketoconazole concentrations and AUC;1 saquinavir pharmacokinetics not affected1

Voriconazole: If used with low-dose ritonavir, decreased voriconazole concentrations200

Fluconazole: Some experts state dosage adjustments not needed if fluconazole and saquinavir used concomitantly200

Itraconazole: Itraconazole dosage >200 mg daily not recommended with ritonavir-boosted saquinavir;1 some experts state appropriate dosages for concomitant use not established and decreased itraconazole dosage may be needed;200 consider monitoring itraconazole concentrations200

Ketoconazole: Ketoconazole dosage >200 mg daily not recommended with ritonavir-boosted saquinavir1

Voriconazole: Concomitant use with ritonavir-boosted saquinavir not recommended unless potential benefits outweigh risks;200 consider monitoring voriconazole concentrations and adjust dosage accordingly200

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: If used with ritonavir-boosted saquinavir, increased concentrations of rifabutin and its active metabolite;1 96 slightly decreased saquinavir concentrations;1 96 no change in ritonavir concentrations96

Rifampin: If used with ritonavir-boosted saquinavir, markedly decreased saquinavir AUC (80%)1 200 and increased incidence of hepatotoxicity (markedly increased serum transaminases)1 173 200

Rifapentine: Possible decreased saquinavir concentrations200

Rifabutin: If used concomitantly with ritonavir-boosted saquinavir, saquinavir manufacturer states use usual dosage of ritonavir-boosted saquinavir and decrease rifabutin dosage by at least 75% (i.e., maximum rifabutin dosage of 150 mg every other day or 150 mg 3 times weekly);1 some experts recommend rifabutin dosage of 150 mg once daily or 300 mg 3 times weekly;200 increase monitoring for antimycobacterial effects and adverse events1 96 200 and consider monitoring plasma rifabutin concentrations1 200

Rifampin: Concomitant use contraindicated1 173 200

Rifapentine: Concomitant use not recommended200

Antipsychotics (clozapine, haloperidol, phenothiazines such as thioridazine, ziprasidone)

Potential additive effects on QT and/or PR interval prolongation1

Use concomitantly with caution1

Atazanavir

Increased saquinavir concentrations and AUC;1 no change in atazanavir concentrations1

Prolonged PR interval reported with both drugs; potential additive effects on PR interval 1

In vitro evidence of synergistic antiretroviral effects;1 no in vitro evidence of antagonistic antiretroviral effects203

Appropriate dosages for concomitant use with respect to safety and efficacy not established200 203

Use concomitantly with caution and clinical monitoring1

Avanafil

Possible increased avanafil concentrations and AUC188

Do not use concomitantly188

Benzodiazepines

Alprazolam, clorazepate, diazepam, flurazepam: Increased benzodiazepine concentrations1 200

Midazolam or triazolam: Increased benzodiazepine concentrations;1 200 potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression);1 interaction expected to be more substantial with oral midazolam than with parenteral midazolam1

Lorazepam, oxazepam, temazepam: No data, but may have less potential for pharmacokinetic interaction with HIV PIs compared with other benzodiazepines200

Alprazolam, clorazepate, diazepam, flurazepam: Clinical importance of interaction unknown;1 decreased benzodiazepine dosage may be needed1

Alprazolam or diazepam: Consider using a benzodiazepine with less potential for pharmacokinetic interaction (lorazepam, oxazepam, temazepam)200

Oral midazolam or triazolam: Concomitant use contraindicated1 200

Parenteral midazolam: Some experts state that a single parenteral midazolam dose can be given with caution in a monitored situation for procedural sedation in patients receiving ritonavir-boosted saquinavir;200 manufacturer states patient should be monitored closely for respiratory depression and/or prolonged sedation and dosage adjustment considered1

Boceprevir

Concomitant use with ritonavir-boosted saquinavir not studied; concomitant use with other ritonavir-boosted PIs (ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) decreases concentrations and AUCs of boceprevir and the PIs17 185 and may reduce efficacy of HCV and HIV treatment17 18

Concomitant use with low-dose ritonavir alone results in decreased boceprevir concentrations and AUC185

Concomitant use with ritonavir-boosted PIs not recommended12

If boceprevir was initiated for treatment of chronic HCV in a patient coinfected with HIV receiving a suppressive antiretroviral regimen containing a ritonavir-boosted PI, inform patient of possible drug interaction and closely monitor for HCV treatment response and potential HCV and HIV virologic rebound12 17 18 200

Bosentan

Potential for substantially increased bosentan concentrations1

In patients already receiving ritonavir-boosted saquinavir for ≥10 days, initiate bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 200

In patients receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted saquinavir; after ≥10 days of ritonavir-boosted saquinavir, resume bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 200

Calcium-channel blocking agents

Possible increased concentrations of the calcium-channel blocking agent (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil)1 200

Use concomitantly with caution;1 200 monitor closely and adjust dosage of calcium-channel blocking agent based on clinical response and toxicities200

Cisapride

Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1 200

Colchicine

Possible increased colchicine concentrations and AUC1 200

Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir-boosted saquinavir1

Colchicine for treatment of gout flares: In those receiving ritonavir-boosted saquinavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 200

Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted saquinavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 200

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted saquinavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1 200

Corticosteroids (dexamethasone, fluticasone)

Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations and AUC with ritonavir-boosted saquinavir resulting in decreased cortisol concentrations;1 200 adrenal insufficiency, including Cushing’s syndrome, may occur200

Dexamethasone: Possible decreased saquinavir concentrations;1 200 concomitant use with ritonavir-boosted saquinavir not studied1

Fluticasone nasal spray/oral inhalation: Concomitant use not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 200

Dexamethasone: Use concomitantly with caution; saquinavir may be less effective;1 consider alternative corticosteroid for long-term therapy200

Darunavir

Decreased darunavir concentrations and AUC and no effect on saquinavir concentrations and AUC with darunavir 400 mg, ritonavir 100 mg, and saquinavir 1 g twice daily204

No in vitro evidence of antagonistic antiretroviral effects204

Appropriate dosages for concomitant use with respect to safety and efficacy not established;200 204 concomitant use of ritonavir-boosted darunavir and saquinavir not recommended200 204

Delavirdine

Increased saquinavir concentrations1

Concomitant use with ritonavir-boosted saquinavir not evaluated1

Appropriate dosages for concomitant use with ritonavir-boosted saquinavir with respect to safety and efficacy not established1

Didanosine

In vitro evidence of additive or synergistic antiretroviral effects1 2 14 29 30 47 69

Digoxin

Ritonavir-boosted saquinavir: Increased digoxin concentrations1

Use concomitantly with caution; monitor digoxin concentrations; may need to reduce digoxin dose1 200

Efavirenz

Decreased saquinavir plasma concentrations and AUC;1 200 213 decreased efavirenz concentrations1 213

In vitro evidence of additive antiretroviral effects213

Manufacturer of saquinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established1

Some clinicians recommend using usual dosage of ritonavir-boosted saquinavir (saquinavir 1 g and ritonavir 100 mg twice daily) with efavirenz200

Emtricitabine

In vitro evidence of additive or synergistic antiretroviral effects218

Enfuvirtide

No clinically important changes in enfuvirtide concentrations1 190 223

Dosage adjustments not necessary1

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

Possibility of pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., acute ergot toxicity)1

Concomitant use contraindicated1 200

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving saquinavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Estrogens/Progestins

Hormonal contraceptives: Possible decreased ethinyl estradiol concentrations1

Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptive is used concomitantly with ritonavir-boosted saquinavir1 200

Etravirine

Ritonavir-boosted saquinavir: Decreased etravirine concentrations and AUC; no change in saquinavir concentrations and AUC200 214

No in vitro evidence of antagonistic antiretroviral effects214

Dosage adjustment not needed200 214

Decrease in systemic exposure to etravirine similar to that in patients receiving etravirine in conjunction with ritonavir-boosted darunavir (a combination found to be safe and effective)200 214

Fosamprenavir

Ritonavir-boosted saquinavir: Decreased saquinavir AUC1

In vitro evidence of synergistic antiretroviral effects205

Appropriate dosages for concomitant use with respect to safety and efficacy not established200 205

Garlic

Garlic supplements: Decreased saquinavir plasma concentrations and AUC1 61

Data not available on concomitant use with ritonavir-boosted saquinavir1

Garlic supplements: Do not use in patients receiving ritonavir-boosted saquinavir1 61 200

Grapefruit juice

Oral bioavailability of saquinavir increased103

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, simvastatin: Decreased clearance and increased concentrations of statins with potential for increased risk of myopathy and/or rhabdomyolysis1 186 200

Pravastatin: If used with ritonavir-boosted saquinavir, decreased pravastatin AUC200

Atorvastatin: Carefully titrate atorvastatin dosage using lowest necessary dosage; do not exceed atorvastatin dosage of 20 mg daily186 200

Lovastatin: Concomitant use contraindicated1 200

Pravastatin: Some experts state dosage adjustments not needed 200

Rosuvastatin: Carefully titrate rosuvastatin dosage using lowest necessary dosage; monitor for toxicities200

Simvastatin: Concomitant use contraindicated1 200

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Increased immunosuppressive agent concentrations1 155

Monitor immunosuppressive agent concentrations1

Indinavir

Increased saquinavir concentrations1

Data not available on concomitant use with ritonavir-boosted saquinavir1

Appropriate dosages for concomitant use with respect to safety and efficacy not established 1

Lamivudine

In vitro evidence of additive or synergistic antiretroviral effects1 2 14 29 30 47 69

 

Lopinavir

Saquinavir concentrations achieved with a regimen of saquinavir 1 g twice daily with fixed combination of lopinavir 400 mg/ritonavir 100 mg twice daily are similar to those with ritonavir-boosted saquinavir (saquinavir 1 g and ritonavir 100 mg twice daily)1 189

Potential additive effects on QT and/or PR interval prolongation1

In vitro evidence of additive to synergistic antiretroviral effects1 207

Use concomitantly with caution1

If used concomitantly, recommended dosage is saquinavir 1 g twice daily with lopinavir 400 mg/ritonavir 100 mg twice daily1 200 207

Lopinavir/ritonavir once-daily regimen not studied in conjunction with saquinavir207

Macrolides (clarithromycin, erythromycin)

Clarithromycin: Increased saquinavir and clarithromycin AUC; decreased 14-hydroxyclarithromycin AUC1 200

Erythromycin: Potential additive prolongation of QT and/or PR intervals1

Clarithromycin: Some experts suggest using alternative macrolide (e.g., azithromycin);200 clarithromycin dosage adjustment not needed in patients with normal renal function receiving ritonavir-boosted saquinavir; reduce clarithromycin dosage by 50% in those with Clcr of 30–60 mL/minute and by 75% in those with Clcr <30 mL/minute;1 200 monitor for clarithromycin toxicities200

Erythromycin: Use concomitantly with caution1

Maraviroc

Ritonavir-boosted saquinavir: Increased maraviroc concentrations and AUC1 200 224

No in vitro evidence of antagonistic antiretroviral effects224

Ritonavir-boosted saquinavir: Recommended dosage of maraviroc is 150 mg twice daily1 200

Methadone

Decreased methadone concentrations with ritonavir-boosted saquinavir1 200

Potential for additive QT and/or PR interval prolongation1

Use concomitantly with caution;1 monitor closely for opiate withdrawal and increase methadone dosage as clinically indicated1 200

Nelfinavir

Increased saquinavir concentrations and increased nelfinavir concentrations208

In vitro evidence of additive antiretroviral effects208

Appropriate dosages for concomitant use with respect to safety and efficacy not established208

Nevirapine

Decreased saquinavir concentrations and AUC;1 200 nevirapine concentrations not affected200

Concomitant use with ritonavir-boosted saquinavir not evaluated1

In vitro evidence of additive or synergistic antiretroviral effects1

Appropriate dosages for concomitant use with respect to safety and efficacy not established 1

Pimozide

Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1 200

Proton-pump inhibitors

Omeprazole with ritonavir-boosted saquinavir: Increased saquinavir concentrations1

Caution advised if ritonavir-boosted saquinavir used with a proton-pump inhibitor;1 monitor for saquinavir toxicities (GI symptoms, increased triglycerides, deep-vein thrombosis, QT-interval prolongation)1 200

Raltegravir

Specific data regarding concomitant use not available200

In vitro evidence of additive to synergistic antiretroviral effects225

Some experts state dosage adjustments not needed if raltegravir used concomitantly with ritonavir-boosted saquinavir200

Rilpivirine

Ritonavir-boosted saquinavir: Possible increased rilpivirine concentrations; not expected to affect saquinavir concentrations226

No in vitro evidence of antagonistic antiretroviral effects226

Ritonavir-boosted saquinavir: Dosage adjustments not needed 200

Ritonavir

Possible increased saquinavir concentrations (increased 1124% with saquinavir 1 g twice daily and ritonavir 100 mg twice daily compared with saquinavir 600 mg 3 times daily)1

Concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted saquinavir)1 200

Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT and PR intervals; torsades de pointes and complete heart block reported1 119

Recommended dosage is saquinavir 1 g twice daily with ritonavir 100 mg twice daily1 200 209

Monitor ECG and electrolytes prior to and during therapy with ritonavir-boosted saquinavir1 (See Cardiovascular Effects under Cautions.)

Salmeterol

Possible increased salmeterol concentrations and increased risk of QT interval prolongation, palpitations, or sinus tachycardia1 200

Concomitant use not recommended1 200

St. John’s wort (Hypericum perforatum)

Possible decreased saquinavir concentrations;1 162 163 206 potential loss of virologic response and development of resistance1

Some experts state that St. John’s wort and ritonavir-boosted saquinavir should not be used concomitantly200

Sildenafil

Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)1 200

Sildenafil for treatment of erectile dysfunction: Use caution and reduce sildenafil dosage (do not exceed 25 mg every 48 hours); closely monitor for adverse effects1 200

Sildenafil for treatment of pulmonary arterial hypertension (PAH): Concomitant use contraindicated1 200

Stavudine

In vitro evidence of additive or synergistic antiretroviral effects1 2 14 29 30 47 69

Tadalafil

Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)1 200

Tadalafil for treatment of erectile dysfunction: Use initial tadalafil dosage of 5 mg; do not exceed a single dose of 10 mg in 72 hours; monitor closely for adverse effects1 200

Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily200

Tadalafil (Adcirca) for treatment of PAH: In patients already receiving ritonavir-boosted saquinavir for ≥1 week, use initial tadalafil dosage of 20 mg once daily and increase dosage to 40 mg once daily based on individual tolerability1 200

Avoid use of tadalafil (Adcirca) for treatment of PAH during initiation of ritonavir-boosted saquinavir therapy;1 200 in patients receiving tadalafil for treatment of PAH, discontinue tadalafil for at least 24 hours before starting ritonavir-boosted saquinavir; tadalafil can be restarted after ≥1 week of ritonavir-boosted saquinavir therapy using initial tadalafil dosage of 20 mg once daily and increasing dosage to 40 mg once daily based on individual tolerability1 200

If tadalafil is used for treatment of benign prostatic hyperplasia, do not exceed tadalafil dosage of 2.5 mg once daily200

Telaprevir

Concomitant use with low-dose ritonavir alone results in decreased telaprevir concentrations and AUC184

Concomitant use with ritonavir-boosted saquinavir not studied; concomitant use with other ritonavir-boosted PIs (ritonavir-boosted atazanavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) decreases concentrations and AUC of telaprevir and decreases concentrations of some of the PIs (darunavir, fosamprenavir)184

Concomitant use not recommended pending further accumulation of data200

Tenofovir

No clinically important change in saquinavir or tenofovir concentrations or AUC with saquinavir 1 g twice daily and ritonavir 100 mg twice daily with tenofovir 300 mg once daily1 221

In vitro evidence of additive or synergistic antiretroviral effects against HIV-1221

Dosage adjustments not needed with ritonavir-boosted saquinavir221

Tipranavir

Decreased saquinavir concentrations1

Concomitant use not recommended;1 200 appropriate dosages not established200

Trazodone

Possible increased trazodone concentrations; increased risk of potentially life-threatening cardiac arrhythmias1

Concomitant use contraindicated1 200

Vardenafil

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)1 200

Do not exceed a single vardenafil dose of 2.5 mg in 72 hours; monitor closely for adverse effects1 200

Warfarin

Possible altered warfarin concentrations1

Monitor INR, especially when initiating or discontinuing ritonavir-boosted saquinavir; adjust warfarin dosage as needed1 200

Zidovudine

In vitro evidence of additive or synergistic antiretroviral effects1 2 14 29 30 47 69

 

Invirase Pharmacokinetics

Absorption

Bioavailability

Saquinavir mesylate incompletely absorbed from GI tract;1 44 48 49 50 51 oral bioavailability is low (calculated bioavailability 4%).1 3 44 48 49 50 51

When used with low-dose ritonavir (ritonavir-boosted saquinavir), there is a 5-fold increase in mean saquinavir AUC, increases of a similar magnitude in trough and peak plasma concentrations, and less interindividual variability in saquinavir pharmacokinetics compared with saquinavir without ritonavir.174 192

In HIV-infected patients with moderate liver impairment (Child-Pugh score 7-9), AUC and peak plasma concentrations are approximately 30% lower compared with HIV-infected patients with normal hepatic function.1

Food

Presence of food in GI tract substantially increases absorption of saquinavir.1

Effect of food on ritonavir-boosted saquinavir not evaluated.1

Distribution

Extent

Not fully characterized.1

Only minimal amounts cross human placenta.202

Distributed into milk in rats;202 not known whether distributed into human milk.1 202

Negligible concentrations detected in CSF.1 64 157

Plasma Protein Binding

98%.1

Elimination

Metabolism

Metabolized by CYP3A.1 51

Elimination Route

Excreted principally in feces as unabsorbed drug and metabolites.1

Half-life

3–6.8 hours.40 174

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Tablets

25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Pharmacologically related to other HIV PIs (e.g., atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir); differs structurally from these drugs and also differs pharmacologically and structurally from other currently available antiretrovirals.1 2 6 8 10 30 58

  • Active against HIV-1 and HIV-2.1 6 13 14 21 25 26 27 28 29 30 31 32 48 51

  • Inhibits replication of HIV-1 and HIV-2 by interfering with HIV protease.1 2 3 4 5 6 8 9 10 11 13 14 19 21 22 25 26 27 28 48 51 65

  • HIV-1 with reduced susceptibility to saquinavir have been selected in vitro and have emerged during therapy with the drug.1 3 6 9 19 31 34 35 37 38 39 70 92

  • Varying degrees of cross-resistance occur among HIV PIs.1 9 32 33 51 58 65 66 68 70 209

Advice to Patients

  • Saquinavir medication guide must be provided to the patient each time the drug is dispensed;1 importance of patient reading the medication guide prior to initiating saquinavir therapy and each time prescription is refilled.1

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.203

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

  • Importance of taking within 2 hours of a meal, not on an empty stomach.1

  • Advise patients that ECG changes (PR and/or QT interval prolongation) have occurred;1 importance of consulting clinician if symptoms such as dizziness, lightheadedness, fainting, or sensation of abnormal heartbeats occur.1

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Saquinavir Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg (of saquinavir)

Invirase

Genentech

Tablets, film-coated

500 mg (of saquinavir)

Invirase

Genentech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 7, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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204. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Feb.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.

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