Saquinavir (Invirase; Fortovase): An Overview

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Saquinavir (Invirase; Fortovase): An Overview
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HIV and Hepatitis.com has posted overview articles on all FDA-approved antiretroviral drugs. As the indications for these drugs change and new research results are presented at research conferences or published in peer-reviewed journals, these overview articles on the web site are revised to reflect the new knowledge available.

Following is a new overview article that incorporates the latest updates on the HIV protease inhibitor (PI) saquinavir mesylate (Invirase), which in 1995 became the first PI approved by the US Food and Drug Administration (FDA). There have been significant changes in the way the drug is used since that early approval. In addition, as described above, the other formulation of saquinavir—saquinavir soft-gel (Fortovase)-- soon will be discontinued.

Generic Names:	saquinavir mesylate; saquinavir*
Brand Names:	Invirase (saquinavir mesylate); Fortovase* (saquinavir)
Other Names:	saquinavir hard-gel capsules and tablets (Invirase); saquinavir soft-gel capsules (Fortovase)
Drug Class:	HIV Protease Inhibitor
*Fortovase capsules, the soft-gel formulation of saquinavir, will be discontinued by February 15, 2006. Saquinavir mesylate, aka hard-gel saquinavir, (brand name Invirase) and saquinavir, aka soft-gel saquinavir (brand name Fortovase) belong to the class of antiretroviral drugs called protease inhibitors (PIs). PIs act against HIV by blocking the protease enzyme, a protein that HIV needs to replicate itself.

Table of Contents
HIV-related Uses of Invirase
Dosing
Storage
Contraindications
Toxicities and Adverse Events
Food Interactions
Drug Interactions
Manufacturer (Roche) Contact Information
Recommended Reading

HIV-related Uses of Invirase

Because of the decreased demand for Fortovase-brand saquinavir, Roche Pharmaceuticals, the manufacturer of saquinavir, will discontinue producing and distributing Fortovase soft-gel capsules by February 15, 2006. Invirase-brand saquinavir hard-gel capsules and tablets (saquinavir mesylate), will continue to be available as the preferred formulation. If you are currently taking Fortovase, talk to your doctor about alternative treatment options.

Although the two drugs are very similar, Invirase offers key advantages over Fortovase, including improved gastrointestinal (GI) tolerability, fewer pills to take each day, smaller pill size, and easier storage requirements.

Dosing

Invirase is currently available as tablets containing saquinavir 500 mg and hard gelatin capsules containing saquinavir 200 mg.

It is important to note that Invirase must be combined with another protease inhibitor, ritonavir (Norvir), to provide appropriate levels of saquinavir in the blood plasma.

Fortovase and Invirase are not bioequivalent and cannot be used interchangeably.

The recommended dose of Invirase is 1,000 mg (taken as either two 500 mg tablets or five 200 mg capsules) coadministered with 100 mg of ritonavir two times a day.

For those individuals who are currently using Fortovase, the recommended dose is 1,200 mg (taken as six 200 mg capsules) three times a day or 1,000 mg coadministered with 100 mg of ritonavir two times a day.

A few patients may benefit from different doses of Fortovase or Invirase than those outlined here. Patients should always take the dose recommended by their doctors.

Both Invirase and Fortovase should be taken within 2 hours after a full meal. Because Invirase is now the preferred formulation of saquinavir, the manufacturer encourages physicians to refrain from starting their patients with Fortovase soft gelatin capsules.

Storage

Store Fortovase soft-gel capsules at 2 to 8 C (36 to 46 F) until dispensed. Keep Fortovase capsules refrigerated until their expiration date. Once brought to room temperature (at or above 25 C [77 F]), capsules should be used within 3 months.

Store Invirase hard-gel capsules and tablets at 15 to 30 C (59 to 86 F) in a tightly closed bottle. The Invirase tablet and capsule formulations do not require refrigeration.

Contraindications

Saquinavir is in FDA Pregnancy Category B. It is not known whether saquinavir crosses the placenta in humans. There are no adequate and well-controlled studies in pregnant women. Saquinavir should be used during pregnancy only when clearly needed. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents, including saquinavir. Physicians may register patients by calling 800-258-4263. It is not known whether saquinavir is secreted in human milk; however, it is secreted in the milk of laboratory rats.

Because saquinavir is metabolized by the liver, the manufacturer recommends that it be used with caution in patients with hepatic insufficiency. Patients with baseline liver function test results higher than five times the upper limit of normal were not included in clinical studies

Cross-resistance among protease inhibitors has been recognized; saquinavir-resistant isolates from patients on long-term therapy showed resistance to at least one of four other protease inhibitors: indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), and amprenavir (Agenerase).

Laboratory studies indicate that the antiretroviral effects of HIV protease inhibitors and some NRTIs or NNRTIs may be additive or synergistic.

Fortovase and Invirase are contraindicated in patients with clinically significant hypersensitivity to the drugs or any components in the formulations. Caution should be used when administering Fortovase or Invirase to patients with impaired hepatic function or hemophilia.

Concomitant use of unboosted Fortovase or Invirase with rifampin results in reduced plasma concentrations of saquinavir and is contraindicated.

Recent data from a 28-day Phase I clinical trial of saquinavir/ritonavir 1000 mg/100 mg twice daily and rifampin 600 mg once daily showed significant hepatocellular toxicity in nearly 40% of patients. Transaminase elevations of up to 20 times the upper limit of normal were noted. Following drug discontinuation, clinical symptoms abated and liver function tests began returning to normal in all affected patients. Based on this data, the manufacturer recommends that rifampin should not be administered to patients taking ritonavir-boosted saquinavir as part of combination antiretroviral therapy.

Toxicities and Adverse Events

Fortovase and Invirase appear to be well tolerated. In clinical studies, the most frequently reported adverse effects included abdominal discomfort, diarrhea, and nausea. Other reactions include abdominal pain, anxiety, asthenia, buccal mucosa ulceration, constipation, depression, dizziness, dyspepsia, eczema, fatigue, flatulence, headache, insomnia, libido disorder, musculoskeletal pain, numbness in extremities, paresthesia, peripheral neuropathy, rash, taste alteration, verruca, and vomiting.

Body fat accumulation and redistribution, increased bleeding in hemophilia patients, hyperglycemia, exacerbation of existing diabetes mellitus, and new onset diabetes mellitus have been reported in patients receiving protease inhibitors, including saquinavir.

In clinical studies there have been rare reports of serious adverse effects that may be related to treatment with Fortovase or Invirase. These rare effects included confusion, ataxia, and weakness; seizures; headache; acute myeloblastic leukemia; hemolytic anemia; thrombocytopenia; thrombocytopenia and intracranial hemorrhage resulting in death; attempted suicide; Stevens-Johnson syndrome; bullous skin eruptions and polyarthritis; severe cutaneous reaction associated with increased liver function test results; isolated elevation of transaminase values; exacerbation of chronic liver disease with elevated liver function tests, jaundice, ascites, and upper left and right quadrant abdominal pain; fatal pancreatitis; intestinal obstruction; portal hypertension; thrombophlebitis; peripheral vasoconstriction; drug fever; nephrolithiasis; and acute renal insufficiency.

Food Interactions

Presence of food in the gastrointestinal tract can substantially increase the absorption of saquinavir and saquinavir mesylate. Administering saquinavir mesylate hard gelatin capsules with a meal increases absorption 5- to 10-fold compared with administration on an empty stomach.

Limited data indicate that the bioavailability of saquinavir is increased when the drug is administered with grapefruit juice.

Drug Interactions

Metabolism of saquinavir is mediated by the cytochrome P450 isoenzyme CYP3A4. Drugs that induce this isoenzyme may reduce saquinavir plasma concentrations. Conversely, drugs that inhibit this isoenzyme may increase plasma concentrations of saquinavir. Saquinavir may alter the pharmacokinetics of other drugs that are metabolized by this enzyme system, which may create the possibility of serious adverse effects.

Use of Fortovase or Invirase with lovastatin or simvastatin is not recommended. Caution should be used when any HIV protease inhibitors, including saquinavir, are used concurrently with other HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The resulting increased concentration of statins may increase the risk of myopathy or rhabdomyolysis.

Use of Fortovase or Invirase with St. John's wort (Hypericum perforatum) or products containing St. John's wort may substantially decrease saquinavir concentrations and may lead to loss of virologic response and possible resistance to saquinavir or other protease inhibitors.

Saquinavir should not be coadministered with astemizole, cisapride, or terfenadine (no longer available in the United States). Other drugs, including midazolam, triazolam, and ergot derivatives should not be coadministered with saquinavir. Competition for CYP3A4 by saquinavir may inhibit the metabolism of these drugs, which could potentially cause serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation.

Concomitant use of certain other antiretroviral agents with Fortovase or Invirase may significantly increase or decrease saquinavir plasma concentrations. These antiretrovirals include delavirdine (Rescriptor), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), and ritonavir (Norvir).

Coadministration of certain other drugs with Fortovase or Invirase may cause an increase or decrease in plasma concentrations of saquinavir or of the coadministered drug. The manufacturer recommends caution when the following drugs are used concomitantly with saquinavir: calcium channel blockers, carbamazepine, clarithromycin, clindamycin, dapsone, dexamethasone, ketoconazole, phenobarbital, phenytoin, quinidine, rifabutin, and sildenafil.

Manufacturer (Roche) Contact Information

Fortovase
    Roche Laboratories
    340 Kingsland Street
    Nutley, NJ, 07110
    (973) 235-5000

Invirase
    Roche Laboratories
    340 Kingsland Street
    Nutley, NJ, 07110
    (973) 235-5000

Recommended Reading

Complete Invirase Prescribing Information at www.Invirase.com

M Kurowski and others. Pharmacokinetic and tolerability of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med 4(2):94-100. 2003

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Panel on Clincial Practices for Treatment of HIV Infection, Unites States Department of Health and Human Services; October 29, 2004.

S Grub and others. Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection. Clin Pharmacol Ther 71(3):122-130. March 2002.

V Vithayasai and others. Safety and efficacy of saquinavir soft-gelatin capsules + zidovudine + optional lamivudine in pregnancy and prevention of vertical HIV transmission. J Acquir Immune Defic Syndr 30(4):410-412. August 1, 2002

U B Dragsted and others. MaxCmin1 Trial Group. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis 188(5): 635-42. September 1, 2003.

L F Lopez-Cortes and others. Once-daily saquinavir-hgc plus low-dose ritonavir (1200/100 mg) in HIV-infected pregnant women: pharmacokinetics and efficacy. HIV Clin Trials. 4(3):227-229. May-June 2003.

L F Lopez-Cortes and others. Once-daily saquinavir-sgc plus low-dose ritonavir (1200/100 mg) in combination with efavirenz: pharmacokinetics and efficacy in HIV-infected patients with prior antiretroviral therapy. J Acquir Immune Defic Syndr 32(2):240-242. February 1, 2003

Fortovase and Invirase Articles

Roche Distributes “Dear Healthcare Provider” Letter on Discontinuation of Fortovase-brand Saquinavir - 6/06/05

Saquinavir (Invirase; Fortovase): An Overview - 6/06/05

Roche Gains European Approval for More Potent Formulation of Saquinavir - 6/01/05

In Early 2006 Roche Will Voluntarily Discontinue Sale and Distribution of HIV Protease Inhibitor (PI) Fortovase - 5/20/05

Atazanavir Plus Ritonavir or Saquinavir Compared to Lopinavir/Ritonavir in Patients Experiencing Multiple Virological Failures - 4/11/05

Boosted Saquinavir Hard-gel (Invirase) Formulation Exposure in HIV Patients: Ritonavir 100 mg Once Daily Versus Twice Daily - 3/07/05

Roche Issues Drug Interaction Warning on Hepatocellular Toxicity in Healthy Volunteers Receiving TB Drug Rifampin and Saquinavir/Ritonavir - 2/09/05

Short-course Induction with Boosted Saquinavir Monotherapy for Naive Patients with Late-stage Infection - 1/28/05

Hepatotoxicity Associated with Protease inhibitor-based Regimens with or without Concurrent Ritonavir - 1/05/05

FDA Approves New 500 mg Tablet Formulation of PI Saquinavir (Invirase) - 1/03/05

Complementary and Alternative Medicine Use Is Common Among HIV Positive Women - 12/06/04

Intracellular Accumulation of PIs Occurs But Mechanism Is Unclear - 11/22/04

Simultaneous Administration of Saquinavir Hard Gel and Ritonavir Is Required for Optimal SQV Absorption - 11/01/04

Steady-State Pharmacokinetics of Saquinavir Hard-Gel/Ritonavir/Fosamprenavir in HIV Patients - 10/20/04

Analysis of Failure Rates in a Study of Resistance Profiles and Adherence in Three Different HAART Regimens - 09/24/04

Taking the Convenience of Once-daily Dosing into Consideration, Saquinavir/Ritonavir 2000/100 mg Once-daily May Be the Peferred Dosing Regimen - 09/08/04

Sex-related Differences in the Pharmacokinetics of Once Daily Saquinavir Boosted with Low-dose Ritonavir - 09/01/04

FDA Gives Priority Review Status to Roche's New Formulation of Invirase - 08/18/04

At 24 Weeks a Once-daily Regimen of Saquinavir/Ritonavir with Two NRTIs Is as Effective as a Twice-daily Regimen of Indinavir/Ritonavir with Two NRTIs - 08/16/04

Lopinavir/Ritonavir and Saquinavir Hard Gel Combination Is an Effective Alternative HAART Regimen - 07/21/04

New Data on Boosted Saquinavir Demonstrate Undetectable Viral Load in 91% of Patients - 07/14/04

Double PI Therapy with Lopinavir/Ritonavir + Saquinavir Is a Potent Option as Salvage therapy But Is Not Suitable for Patients with Heavy PI Resistance and Very Low CD4 Count - 07/14/04

Roche Submits New Invirase Application to FDA - 06/23/04

No Dosage Adjustments Necessary when Enfuvirtide Is Co-administered with Low-dose Ritonavir or Saquinavir Boosted with a Low Dose of Ritonavir - 06/21/04

Atazanavir Enhances Saquinavir Hard-gel Concentrations in a Ritonavir-boosted Once-daily Regimen - 05/28/04

Once Daily Dosing of Saquinavir Soft-gel Capsules and Ritonavir Combination - 05/21/04

Pharmacokinetics of Tenofovir DF in HIV Patients Receiving Saquinavir Hard Gel/Ritonavir 1000/100 mg Twice Daily 04/14/04

Sex-Based Differences in Saquinavir Pharmacology and Virologic Response in ACTG Study 359 - 3/29/04

Once-daily Saquinavir and Ritonavir in Treatment-experienced HIV-infected Individuals - 3/29/04

Double Protease Inhibitor Lopinavir/Ritonavir Does Not Impair Drug Exposure of Saquinavir 03/19/04

Pharmacokinetics of Saquinavir Plus Low-dose Ritonavir in HIV Positive Pregnant Women 03/10/04

The Effects of Once-daily Saquinavir/Low-dose Ritonavir on the Pharmacokinetics of Methadone 03/10/04

Once-daily Saquinavir/ Ritonavir Shows Considerable Short-term Virologic Activity in Treatment-experienced HIV Patients 03/10/04

Oral Contraception Does Not Alter Single Dose Saquinavir Pharmacokinetics in Women 03/10/04

Enhanced Saquinavir (Invirase) Exposure in HIV Patients with Diarrhea and/or Wasting Syndrome -3/10/04

Pharmacokinetics of Saquinavir Plus Low-dose Ritonavir in HIV Positive Pregnant Women 03/10/04

Saquinavir Useful in HIV Patients with Gastrointestinal Problems 3/04/04

Synergistic Activity of Lopinavir and Saquinavir on Protease Inhibitor-resistant HIV - 2/25/04

Reyataz Enhances Invirase Concentrations in a Norvir-boosted Once Daily Regimen 02/11/04

Steady State Pharmacokinetics of Invirase/Lexiva 1000/700 mg Plus 100 mg and 200 mg of Norvir Twice Daily 02/11/04

Lipid Profiles of Patients Enrolled in the MaxCmin 2 Trial: Safety and Efficacy of Lopinavir/Ritonavir 400/100 mg Twice Daily vs Saquinavir/Ritonavir 1000/100 mg Twice Daily 02/11/04

Efficacy and Safety of Reyataz (atazanavir) with Ritonavir or Saquinavir vs Lopinavir/Ritonavir in Patients Who Have Experienced Virologic Failure on Multiple HAART Regimens: 48-Week Results 02/09/04

Enhanced Saquinavir Exposure in HIV Patients with Diarrhea and/or Wasting Syndrome 02/04/04

Saquinavir-Ritonavir Dual PI Regimen at 800/100 mg B.I.D. Is a Reasonable Treatment Option for HIV Positive Pregnant Women 02/04/04

FDA Approves Roche Protease Inhibitor Invirase Boosted with Norvir 01/07/04

Therapeutic Dose of Protease Inhbitor Saquinavir Does Not Permanently Influence Early Insulin Signaling 01/14/04

A randomized clinical trial to compare the effectiveness of indinavir, ritonavir and saquinavir.
11/10/03

Pharmacokinetics (PK) of Saquinavir/Ritonavir (SQV/R) once daily (OD) in HIV Patients Compared with Standard Regimens 10/31/03

Final Analysis of Trial to Evaluate Safety and Efficacy of Lopinavir/Ritonavir Versus Saquinavir/Ritonavir: MaxCmin 2 10/27/03