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
Brands: Invirase

REMS:

FDA approved a REMS for saquinavir to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antiretroviral; HIV protease inhibitor (PI).^{1 6 8 10 28 32 51}

Uses for Saquinavir

Treatment of HIV Infection

Treatment of HIV infection in conjunction with other antiretrovirals.^{1 3 6 17 20 21 48 51}

Used in conjunction with low-dose ritonavir (ritonavir-boosted saquinavir) or with the fixed combination of lopinavir/ritonavir.^{1 130 178 179 185 186}

Used in PI-based regimens that include a PI and 2 nucleoside reverse transcriptase inhibitors (NRTIs).¹³⁰

For initial treatment in HIV-infected adults and adolescents, some experts state that ritonavir-boosted saquinavir is an alternative PI (not a preferred PI) for use in PI-based regimens in conjunction with 2 NRTIs.¹³⁰

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.¹¹⁷ Used in conjunction with other antiretrovirals.¹¹⁷

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.¹⁷⁴ Used in conjunction with other antiretrovirals.¹⁷⁴

Saquinavir Dosage and Administration

Administration

Oral Administration

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

Must be used in conjunction with low-dose ritonavir (either as ritonavir-boosted saquinavir or in conjunction with fixed combination of lopinavir/ritonavir).^{1 130} Saquinavir should be taken at the same time as ritonavir.¹

Dosage

Available as saquinavir mesylate; dosage expressed as saquinavir.¹

Must be given in conjunction with other antiretrovirals.¹ If used with nelfinavir, dosage adjustment recommended.^{1 130} (See Specific Drugs and Foods under Interactions.)

Pediatric Patients

Treatment of HIV Infection

Oral

Adolescents ≥16 years of age: 1 g twice daily in conjunction with low-dose ritonavir (100 mg twice daily).^{1 130} Alternatively, 1 g twice daily in conjunction with usual dosage of lopinavir/ritonavir twice daily.^{1 130}

Adults

Treatment of HIV Infection

Oral

1 g twice daily in conjunction with low-dose ritonavir (100 mg twice daily).^{1 130} Alternatively, 1 g twice daily in conjunction with usual dosage of lopinavir/ritonavir twice daily.^{1 130}

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

1 g twice daily with low-dose ritonavir (100 mg twice daily).¹¹⁷

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.¹¹⁷

Nonoccupational Exposure†

Oral

1 g twice daily in conjunction with low-dose ritonavir (100 mg twice daily) or, alternatively, 400 mg twice daily in conjunction with low-dose ritonavir (400 mg twice daily).¹⁷⁴

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.¹⁷⁴

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Dosage recommendations not available; use with caution in mild to moderate hepatic impairment.¹ Contraindicated in severe hepatic impairment.¹

Renal Impairment

Treatment of HIV Infection

No initial dosage adjustment needed.¹ Use with caution in severe renal impairment.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 Saquinavir

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.¹⁹⁹

  
  


• 
  

  Congenital long QT syndrome.¹⁹⁹

  
  


• 
  

  Refractory hypokalemia or hypomagnesemia.¹⁹⁹ (See Cardiovascular Effects under Cautions.)

  
  


• 
  

  Concomitant use with drugs that increase saquinavir plasma concentrations and prolong the QT interval.¹⁹⁹ (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., amiodarone, cisapride, ergot alkaloids, flecainide, midazolam, propafenone, quinidine, rifampin, pimozide, triazolam).¹ (See Specific Drugs and Foods under Interactions.)

  
  

Warnings/Precautions

Warnings

Cardiovascular Effects

Ritonavir-boosted saquinavir prolongs PR interval in a dose-dependent fashion; cases of second or third degree AV block reported rarely.¹⁹⁹ 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.¹⁹⁹ 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.¹⁹⁹ Use ritonavir-boosted saquinavir with caution in patients receiving other drugs that prolong the PR interval, particularly drugs metabolized by CYP3A; clinical monitoring recommended.¹⁹⁹

Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT interval; torsades de pointes reported rarely.¹⁹⁹ Perform an ECG prior to initiation of ritonavir-boosted saquinavir.¹⁹⁹ Patients with QT interval >450 msec should not receive the drug.¹⁹⁹ Ritonavir-boosted saquinavir may be initiated in those with baseline QT interval <450 msec; however, preform a repeat ECG after 3–4 days of therapy and discontinue the antiretroviral if QT interval is >480 msec or is prolonged >20 msecs over baseline.¹⁹⁹ ECG monitoring recommended if ritonavir-boosted saquinavir is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment, and electrolyte abnormalities.¹⁹⁹ Correct hypokalemia or hypomagnesemia prior to initiating ritonavir-boosted saquinavir; monitor these electrolytes periodically during therapy.¹⁹⁹

Ritonavir-boosted saquinavir should not be used in conjunction with drugs that increase saquinavir plasma concentrations and prolong the QT interval.¹⁹⁹ Manufacturer states that concomitant use of ritonavir-boosted saquinavir and drugs with the potential to increase the QT interval should be considered only when no alternative therapy is available and potential benefits outweigh risks.¹⁹⁹ Perform an ECG prior to initiation of the drugs.¹⁹⁹ Do not use such concomitant therapy in patients with QT interval >450 msec.¹⁹⁹ If baseline QT interval is <450 msec, perform a repeat ECG after 3–4 days of concomitant therapy.¹⁹⁹ If QT interval is >480 msec or is prolonged >20 msecs over baseline, clinician should use best clinical judgement regarding discontinuing ritonavir-boosted saquinavir and/or the other drug.¹⁹⁹ Cardiology consult recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.¹⁹⁹

Interactions

Concomitant use with certain drugs not recommended (e.g., lovastatin, simvastatin, St. John’s wort, fluticasone) or require particular caution (e.g., digoxin, sildenafil, tadalafil, vardenafil).^{1 130} (See Specific Drugs and Foods under Interactions.)

Hyperglycemic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.^{1 57 129 131}

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

General Precautions

HIV Resistance

Possibility of HIV resistant to saquinavir and possible cross-resistance to other PIs.¹ Effect of saquinavir therapy on subsequent therapy with other PIs under investigation.¹

Hepatic Effects

Exacerbation of chronic liver dysfunction, including portal hypertension, reported in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV), cirrhosis, or other underlying liver abnormalities.¹

Hemophilia A and B

Spontaneous bleeding noted with PIs; causal relationship not established.^{1 57 80 127}

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

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

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 57 123 144 145 146 147 148 149 150 151}

Hyperlipidemia

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

Monitor cholesterol and triglyceride concentrations 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

Specific Populations

Pregnancy

Category B.¹ Antiretroviral Pregnancy Registry at 800-258-4263.¹

Some experts state that based on limited pharmacokinetic data and experience with use in pregnancy, ritonavir-boosted saquinavir can be considered an alternative (not a preferred) PI for antiretroviral regimens in pregnant women.¹⁶⁰

Lactation

Not known whether distributed into human milk.¹

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

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

Hepatic Impairment

Ritonavir-boosted saquinavir not evaluated in patients with hepatic impairment; caution advised because increased saquinavir concentrations or increased hepatic enzymes may occur.¹ Contraindicated in severe hepatic impairment.¹

Renal Impairment

Use with caution in severe renal impairment.¹

Common Adverse Effects

Diarrhea, abdominal discomfort, nausea, vomiting, fatigue.^{1 51 75}

Interactions for Saquinavir

Metabolized by CYP3A.^{1 83 94}

Substrate for p-glycoprotein.¹

Inhibits CYP3A.⁹⁴

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}

Inducers or Inhibitors of the p-Glycoprotein Transport System

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

Drugs that Prolong the QT or PR Interval

Because 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.¹⁹⁹ 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.^{198 199} (See Cardiovascular Effects under Cautions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antiarrhythmic agents (amiodarone, flecainide, systemic lidocaine, propafenone, quinidine)	Possible increased antiarrhythmic agent concentrations; potential for serious or life-threatening effects (e.g., cardiac arrhythmias)1	Concomitant use with amiodarone, flecainide, propafenone, or quinidine contraindicated1 Cautious use with systemic lidocaine; monitor for toxicity and lidocaine concentrations1
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased saquinavir concentrations1 Carbamazepine: Possible increased carbamazepine concentrations with ritonavir-boosted saquinavir130 Phenytoin: Possible decreased concentrations of phenytoin and saquinavir with ritonavir-boosted saquinavir130	Use concomitantly with caution1 Carbamazepine or phenytoin: Monitor concentrations of anticonvulsant and saquinavir and assess virologic response or consider alternative anticonvulsant130
Antidepressants, tricyclic	Increased amitriptyline or imipramine concentrations1	Cautious use; monitor antidepressant concentrations1
Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)	Fluconazole: Possible increased saquinavir AUC;130 data not available regarding ritonavir-boosted saquinavir130 Itraconazole: Possible pharmacokinetic interaction may affect both drugs with ritonavir-boosted saquinavir 130 Ketoconazole: Increased saquinavir concentrations and AUC; no change in ketoconazole pharmacokinetics;1 possible pharmacokinetic interaction may affect both drugs with ritonavir-boosted saquinavir130 Voriconazole: Concomitant use with ritonavir-boosted saquinavir not evaluated;1 decreased voriconazole concentrations reported with low-dose ritonavir130	Itraconazole: Appropriate dosages for concomitant use not established;1 130 decreased itraconazole dosage may be needed;130 consider monitoring itraconazole concentrations130 Ketoconazole: Appropriate dosages for concomitant use not established;1 ketoconazole dosage >200 mg daily not recommended with ritonavir-boosted saquinavir130 Voriconazole: Concomitant use of ritonavir-boosted saquinavir not recommended unless potential benefits outweigh risks;130 consider monitoring voriconazole concentrations130
Antimycobacterials (rifabutin, rifampin, rifapentine)	Rifabutin: Decreased saquinavir AUC (40%) with rifabutin;1 94 96 no clinically important change in saquinavir concentrations with a regimen of rifabutin 150 mg every 3 days or 300 mg every 7 days with saquinavir 400 mg twice daily and ritonavir 400 mg twice daily1 Rifampin: Decreased saquinavir AUC (80%);1 130 increased incidence of hepatotoxicity (marked increases in transaminase concentrations) with ritonavir-boosted saquinavir and rifampin1 130 173	Rifabutin: Some clinicians recommend ritonavir-boosted saquinavir with a rifabutin dosage of 150 mg once every other day or 3 times weekly130 Rifampin: Concomitant use contraindicated1 130 173 Rifapentine: Concomitant use not recommended130
Atazanavir	Increased plasma concentrations of saquinavir and no change in atazanavir concentrations with saquinavir 1.6 g once daily, ritonavir 100 mg once daily, and atazanavir 300 mg once daily1 Data not available on saquinavir 1 g twice daily and ritonavir 100 mg twice daily with atazanavir 300 mg once daily1 In vitro evidence of additive antiretroviral effects175	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 130 175
Benzodiazepines	Alprazolam, clorazepate, diazepam, or flurazepam: Increased benzodiazepine concentrations1 130 Midazolam or triazolam: Increased benzodiazepine concentrations;1 130 potential for prolonged or increased sedation or respiratory depression1 Lorazepam, oxazepam, temazepam: No data, but may have less potential for pharmacokinetic interaction with PIs compared with other benzodiazepines130	Clinical importance of interaction with alprazolam, clorazepate, diazepam, or flurazepam unknown;1 decreased benzodiazepine dosage may be needed;1 consider using a benzodiazepine with less potential for pharmacokinetic interaction (lorazepam, oxazepam, temazepam)130 Manufacturer of saquinavir states that concomitant use with midazolam or triazolam contraindicated;1 however, some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation130
Calcium-channel blocking agents	Possible increased concentrations of the calcium-channel blocking agent (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, verapamil, nisoldipine)1 130	Use concomitantly with caution;1 130 monitor for toxicity;1 130 adjust dosage of calcium-channel blocking agent based on clinical response and toxicities130
Cisapride	Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1 130
Corticosteroids (dexamethasone, fluticasone)	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations with ritonavir-boosted saquinavir resulting in decreased cortisol concentrations1 Dexamethasone: Possible decreased saquinavir concentrations;1 130 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 130 Dexamethasone: Use concomitantly with caution; saquinavir may be less effective1
Dapsone	Possible increased dapsone concentrations1	Use with caution1
Darunavir	Decreased concentrations of darunavir and no effect on saquinavir concentrations with darunavir 400 mg, ritonavir 100 mg, and saquinavir 1 g twice daily193	Concomitant use of ritonavir-boosted darunavir and saquinavir not recommended130 193
Delavirdine	Increased saquinavir AUC;1 140 130 no effect on delavirdine concentrations130 Concomitant use with ritonavir-boosted saquinavir not evaluated1	Manufacturer of saquinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established1 Some clinicians recommend using saquinavir 1 g twice daily and ritonavir 100 mg twice daily with usual dosage of delavirdine130
Didanosine	In vitro evidence of additive or synergistic antiretroviral effects1 2 14 29 30 47 69
Digoxin	Ritonavir-boosted saquinavir: Increased digoxin concentrations1	Caution advised; monitor digoxin concentrations; may need to reduce the digoxin dose1
Efavirenz	Decreased peak plasma concentrations and AUC of saquinavir;130 153 decreased efavirenz concentrations130 Concomitant use with ritonavir-boosted saquinavir not evaluated1 In vitro evidence of synergistic antiretroviral effects1	Manufacturer of saquinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established1 Some clinicians recommend using saquinavir 1 g twice daily and ritonavir 100 mg twice daily with usual dosage of efavirenz130
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsa
Enfuvirtide	Pharmacokinetic interaction unlikely1
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 130 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 possible160
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
Etravirine	Ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily): Decrease in AUC (33%) of etravirine; no change in plasma concentrations of saquinavir130 196 No in vitro evidence of antagonistic antiretroviral effects196	Dosage adjustment not needed130 196 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)130 196
Fosamprenavir		Appropriate dosages for concomitant use with respect to safety and efficacy not established130
Garlic	Decreased saquinavir plasma concentrations and AUC with garlic supplements.1 61 Data not available on concomitant use with ritonavir-boosted saquinavir1	Avoid garlic supplements1 61 130
Grapefruit juice	Oral bioavailability of saquinavir increased103
Histamine H2-receptor antagonists (ranitidine)	Ranitidine: Increased concentrations of saquinavir1 Data not available on concomitant use with ritonavir-boosted saquinavir1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1
HMG-CoA reductase inhibitors	Decreased clearance and increased concentrations of some HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin) with potential for increased risk of myopathy (including rhabdomyolysis)1 130 Decreased concentrations of pravastatin with ritonavir-boosted saquinavir130	Concomitant use with lovastatin or simvastatin not recommended1 95 130 Caution if used with other HMG-CoA reductase inhibitors metabolized by the CYP3A4 pathway (e.g., atorvastatin)1 95 130 If used with atorvastatin or rosuvastatin, use lowest possible dosage of the HMG-CoA reductase inhibitor1 130 Consider using HMG-CoA reductase inhibitors with a low potential for interaction (e.g., fluvastatin)1 130
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Increased immunosuppressant 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 1 130
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 400 mg of lopinavir and 100 mg of ritonavir twice daily similar to those with saquinavir 1 g twice daily and ritonavir 100 mg twice daily1 189	Recommended dosage is saquinavir 1 g twice daily with 400 mg of lopinavir and 100 mg of ritonavir twice daily1 130 169
Macrolides (clarithromycin)	Increased saquinavir and clarithromycin AUC; decreased 14-hydroxyclarithromycin AUC1 130	Manufacturer of saquinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established;1 monitor for clarithromycin toxicities;130 in patients receiving ritonavir-boosted saquinavir, consider reducing clarithromycin dosage by 50% in those with Clcr 30–60 mL/minute and by 75% in those with Clcr <30 mL/minute; dosage adjustment not needed in those with normal renal function 1 130
Maraviroc	Ritonavir-boosted saquinavir: Substantially increased maraviroc concentrations130 195	Ritonavir-boosted saquinavir: Recommended dosage of maraviroc is 150 mg twice daily130 195
Methadone	Decreased methadone concentrations with ritonavir-boosted saquinavir1 130	Monitor closely and consider that increased methadone dosage may be needed1 130
Nelfinavir	Increased saquinavir concentrations and increased nelfinavir concentrations1 123 Data not available on concomitant use with ritonavir-boosted saquinavir1 123	Manufacturer of nelfinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established123 Saquinavir 1.2 g twice daily with nelfinavir 1.25 g twice daily results in adequate plasma concentrations of both PIs1
Nevirapine	Decreased saquinavir concentrations; no change in nevirapine pharmacokinetics1 102 130 Concomitant use with ritonavir-boosted saquinavir not evaluated1 In vitro evidence of additive or synergistic antiretroviral effects1	Manufacturer of saquinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established 1 Consider saquinavir 1 g twice daily with ritonavir 100 mg twice daily with usual nevirapine dosage130
Pimozide	Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1 130
Proton-pump inhibitors	Omeprazole with ritonavir-boosted saquinavir: Increased concentrations of saquinavir1	Caution advised if ritonavir-boosted saquinavir used with a proton-pump inhibitor;1 monitor for saquinavir toxicities (GI symptoms, increased triglycerides, deep vein thrombosis)1 130
Ritonavir	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);1 130 no change in ritonavir concentrations130 Concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted saquinavir)1 130 Ritonavir-boosted saquinavir has produced dose-dependent prolongation of QT and PR intervals198 199	Recommended dosage is saquinavir 1 g twice daily with ritonavir 100 mg twice daily1 130
St. John’s wort (Hypericum perforatum)	Possible decreased saquinavir concentrations1 59 162 163	Concomitant use contraindicated1 130
Sildenafil	Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1 130 154	Sildenafil for treatment of erectile dysfunction: Use caution and reduced initial sildenafil dosage of 25 mg dose and do not exceed 25 mg every 48 hours); closely monitor for adverse effects1 130 154 Sildenafil for treatment of pulmonary arterial hypertension (PAH): Concomitant use contraindicated130
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 changes, prolonged erection)1 130	Use initial tadalafil dosage of 5 mg; do not exceed a single dose of 10 mg in 72 hours; monitor closely for adverse effects1 130
Tenofovir	No clinically important change in saquinavir concentrations with saquinavir 1 g twice daily and ritonavir 100 mg twice daily with tenofovir 300 mg once daily1 192	Dosage adjustment not needed with ritonavir-boosted saquinavir192
Tipranavir	Decreased saquinavir concentrations1	Concomitant use not recommended;1 130 appropriate dosage not established130
Trazodone	Possible increased trazodone concentrations; increased risk of trazodone-associated adverse effects1	Caution; decreased trazodone dosage may be needed1
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1 130	Do not exceed a single vardenafil dose of 2.5 mg in 72 hours; monitor closely for adverse effects1 130
Warfarin	Possible altered warfarin concentrations1	Monitor INR1
Zidovudine	In vitro evidence of additive or synergistic antiretroviral effects1 2 14 29 30 47 69

Saquinavir 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 saquinavir used with low-dose ritonavir, there is a 5-fold increase in mean AUC of saquinavir, increases of a similar magnitude in trough and peak plasma concentrations, and less interindividual variability in saquinavir pharmacokinetics compared with saquinavir without ritonavir.^{185 186}

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

Not known whether saquinavir crosses the placenta or is distributed into milk.^{1 64}

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.^{184 185}

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

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  Pharmacologically related to other PIs (e.g., atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir); differs structurally from these drugs and also differs pharmacologically and structurally from other currently available antiretrovirals.^{1 2 6 8 10}