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Saquinavir (Invirase)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of saquinavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for saquinavir treatment
References
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Drug Labeling (Package Inserts)
Saquinavir hgc and tablet (Invirase)
Class

Protease inhibitor

Background
U.S. Manufacturer

Roche

Approval

The hard-gel capsule form of saquinavir (Invirase, SQV hgc) was approved by the FDA in 1995 for adult use in combination with nucleoside analogues. Approval was based on trials that found greater (although modest) increases in CD4 T-lymphocyte counts in patients receiving the 3-drug combination saquinavir + zidovudine + zalcitabine compared with zidovudine + zalcitabine, as well as on studies showing improved CD4 cell counts with saquinavir + zidovudine or saquinavir + zalcitabine compared with zidovudine or zalcitabine alone. A reduction in both mortality and AIDS-defining clinical events was also demonstrated for the 2-drug combination saquinavir + zalcitabine compared with monotherapy with either drug.

The soft-gel capsule form of saquinavir (Fortovase, SQV sgc) was approved in 1997 for adult use. Approval was based on a trial showing that antiretroviral-naive patients randomized to receive 2 nucleoside analogues (of choice) and saquinavir soft-gel capsules were more likely to have undetectable HIV viral load (<400 RNA copies/mL plasma) after 16 weeks than were subjects randomized to receive 2 nucleoside analogues and saquinavir hard-gel capsules.(1)

In 2004 a tablet formulation was approved by the FDA for use in combination with low-dose ritonavir plus nucleoside analogues.

Because ritonavir-boosted tablet and hard gel formulations provide high serum levels of saquinavir and offer lower pill burden and improved tolerability compared with the soft-gel formulation, production of the soft-gel formulation (Fortovase) was discontinued in 2006.

Formulation and Dosing

Saquinavir is available in hard-gel capsules and tablets. The soft-gel capsule formulation (Fortovase) has been discontinued.

Saquinavir should be used in combination with low-dose ritonavir. In the hard-gel capsule and the tablet formulations, saquinavir is poorly absorbed, and resulting drug levels are generally too low to achieve potent antiviral activity. However, fully active levels of saquinavir may be attained by combining either formulation with ritonavir. The combination of saquinavir hard-gel capsule or tablet boosted with ritonavir has been approved by the FDA for twice-daily dosing.

Dosing of Saquinavir
AdultBoostedSaquinavir (tablet or hgc) 1,000 mg BID + ritonavir 100 mg BID
PediatricAge <16 yearsNot FDA approved; should not be used as a single protease inhibitor
Age >=16 yearsAdult dose

Key to abbreviations: BID, twice daily; hgc, hard-gel capsule.

Saquinavir should be taken with or after a meal.
No dosage adjustment is necessary in renal insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.
Clinical Use
Combinations

Regimens consisting of 2 nucleoside analogues and saquinavir soft-gel capsule (Fortovase) were found to provide potent suppression of viral load in previously untreated patients.(2) The soft-gel capsule formulation is no longer available, and the currently available tablet and hard-gel formulations (Invirase) require boosting with low-dose ritonavir in order to achieve long-term virologic suppression and avoid selection of resistance mutations. The efficacy of regimens containing ritonavir-boosted saquinavir with nucleoside analogues compares favorably to that of other potent combination regimens.(3,4,5)

Saquinavir is metabolized by the cytochrome P450 3A4 isoenzyme, and may alter the concentrations of other drugs metabolized by this pathway, including, certain benzodiazepines, antiarrhythmics, lipid-lowering agents, erectile dysfunction treatments, and others. Similarly, drugs that induce or inhibit the action of this isoenzyme may cause therapeutically significant alterations in saquinavir levels. For example, ritonavir, nelfinavir, and ketoconazole each inhibit CYP3A4 activity and increase saquinavir levels, whereas efavirenz and rifampin induce CYP3A4, thereby decreasing saquinavir levels. The addition of ritonavir may boost saquinavir to therapeutic levels in combination with efavirenz, but ritonavir-boosted saquinavir should not be used in combination with rifampin because hepatotoxicity may occur.(6,7) Certain protease inhibitors, including atazanavir, darunavir, fosamprenavir, and tipranavir may alter saquinavir levels; coadministration with darunavir or tipranavir is contraindicated and other combinations may require dosage adjustment.

Information on drug interactions should be consulted, as dosage adjustments are frequently required, and certain combinations are contraindicated.

Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate ritonavir-boosted saquinavir, in combination with specified nucleoside analogue backbones, as "regimens that may be acceptable but should be used with caution" in initial treatment, based on convenience and toxicity considerations. The guidelines classify unboosted saquinavir as "not recommended." Because of poor efficacy, saquinavir tablets and hard-gel capsules should not be used as a sole protease inhibitor at any time.

Failure of a regimen containing saquinavir may decrease the likelihood that subsequent protease inhibitor-containing regimens will succeed (see "Resistance," below).

Regimens combining saquinavir with ritonavir may be effective following virologic recurrence on an initial regimen containing nelfinavir (8) or other protease inhibitors.(9) In patients without prior protease inhibitor experience, combinations including saquinavir + nelfinavir compare favorably with combinations containing one protease inhibitor.(10)

Factors Affecting Adherence

Although symptomatic side effects may include diarrhea, abdominal discomfort, and nausea, saquinavir is relatively well tolerated. Protease inhibitors, including saquinavir, have been associated with metabolic abnormalities including dyslipidemia and abnormalities of body fat distribution. Saquinavir may prolong PR and QT cardiac intervals. An EKG should be obtained before treatment with ritonavir-boosted saquinavir; persons with prolongation of these intervals or those with other risk factors for arrhythmias should not be given saquinavir, or should be monitored closely during treatment with saquinavir. Other medications that prolong these cardiac intervals should be coadministered only if necessary with close monitoring.(11)

It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with protease inhibitors is initiated.

Resistance

Resistance to saquinavir is associated with the selection of 1 or more of several resistance mutations.

Implications of saquinavir resistance for treatment with other antiretrovirals

Resistance mutations (G48V, L90M) selected by saquinavir frequently confer or contribute to resistance against other protease inhibitors. In one study,(12) participants with protease resistance mutations after treatment with saquinavir hard-gel capsules were less likely to respond to treatment with indinavir than were patients without such mutations. Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of regimens containing saquinavir.

Implications of resistance to other antiretrovirals for saquinavir treatment

Following failure of a nelfinavir-containing regimen, patients may still respond to regimens containing saquinavir boosted with ritonavir.(8)

Following failure of an indinavir-containing regimen, sustained response to regimens containing saquinavir was observed in only a minority of patients.(13)

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to saquinavir following failure of regimens containing other antiretrovirals.(9)

References
1.   Mitsuyasu RT, Skolnik PR, Cohen SR, Conway B, Gill MJ, Jensen PC, Pulvirenti JJ, Slater LN, Schooley RT, Thompson MA, Torres RA, Tsoukas CM. Activity of the soft gelatin formulation of saquinavir in combination therapy in antiretroviral-naive patients. NV15355 Study Team. AIDS 1998;12:F103-9.
2.   Cohen Stuart JW, Schuurman R, Burger DM, Koopmans PP, Sprenger HG, Juttmann JR, Richter C, Meenhorst PL, Hoetelmans RM, Kroon FP, Bravenboer B, Hamann D, Boucher CA, Borleffs JC. Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study). AIDS 1999;13:F53-8.
3.   Kirk O, Katzenstein TL, Gerstoft J, Mathiesen L, Nielsen H, Pedersen C, Lundgren JD. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999;13:F9-16.
4.   Dragsted UB, Gerstoft J, Youle M, Fox Z, Losso M, Benetucci J, Jayaweera DT, Rieger A, Bruun JN, Castagna A, Gazzard B, Walmsley S, Hill A, Lundgren JD; MaxCmin2 Trial Group. A randomized trial to evaluate lopinavir/ritonavir versus saquinavir/ritonavir in HIV-1-infected patients: the MaxCmin2 trial. Antivir Ther. 2005;10(6):735-43.
5.   Dragsted UB, Gerstoft J, Pedersen C, Peters B, Duran A, Obel N, Castagna A, Cahn P, Clumeck N, Bruun JN, Benetucci J, Hill A, Cassetti I, Vernazza P, Youle M, Fox Z, Lundgren JD; 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. 2003 Sep 1;188(5):635-42.
6.  Hendrix CW, Fiske WD, Fuchs EJ, Redpath EC, Stevenson DL, Benedek IH, Kornhauser DM. Pharmacokinetics of the Triple Combination of Saquinavir, Ritonavir, and Efavirenz in HIV-Positive Patients. Abstract 79. 7th Conference on Retroviruses and Opportunistic Infections. January 30 - February 2, 2000; San Francisco.
7.  Dear Health Care Provider from Roche Laboratories Inc. "Important Drug Interaction Warning: Drug-Induced Hepatitis with Marked Transaminase Elevations Has Been Observed in Healthy Volunteers Receiving Rifampin 600 Mg Once Daily in Combination with Ritonavir 100 mg/Saquinavir 1000 mg Twice Daily (Ritonavir Boosted Saquinavir)." February 2005.
8.   Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K. Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999;13:F23-8.
9.   Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan TC, Efron B. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 1999;131:813-21.
10.   Moyle G, Pozniak A, Opravil M, Clumeck N, DelFraissy JF, Johnson M, Pelgrom J, Reynes J, Vittecoq D, DeLora P, Salgo M, Duff F. The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues. Study of Protease Inhibitor Combinations in Europe. J Acquir Immune Defic Syndr 2000;23:128-37.
11.  Invirase [package insert]. South San Francisco, CA; Genentech; October 2010.
12.   Para MF, Glidden DV, Coombs RW, Collier AC, Condra JH, Craig C, Bassett R, Leavitt R, Snyder S, McAuliffe V, Boucher C. Baseline human immunodeficiency virus type 1 phenotype, genotype, and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel-capsule saquinavir in AIDS Clinical Trials Group protocol 333. J Infect Dis 2000;182:733-43.
13.   Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H, Acosta E, Lagakos SW, Swanstrom R, Freimuth W, Snyder S, Mills C, Fischl M, Pettinelli C, Katzenstein D. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis 2000;182:1375-84.