Saquinavir

Pronunciation

(sa KWIN a veer)

U.S. Brand Names

Fortovase®; Invirase®

Synonyms

Saquinavir Mesylate

Generic Available

Canadian Brand Names

Fortovase®; Invirase®

Use

Treatment of HIV infection; used in combination with at least two other antiretroviral agents

Pregnancy Risk Factor

Pregnancy Implications

Saquinavir soft gelatin capsules (Fortovase®) provide adequate levels when used in normal doses during pregnancy; pharmacokinetic data not available for Invirase®. The Perinatal HIV Guidelines Working Group considers Fortovase® and ritonavir to be a preferred combination for use during pregnancy. Pregnancy and protease inhibitors are both associated with an increased risk of hyperglycemia. Glucose levels should be closely monitored. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to saquinavir or any component of the formulation; exposure to direct sunlight without sunscreen or protective clothing; severe hepatic impairment; coadministration with amiodarone, bepridil, cisapride, flecainide, midazolam, pimozide, propafenone, quinidine, rifampin, triazolam, or ergot derivatives

Warnings/Precautions

Use caution in patients with hepatic insufficiency. May exacerbate pre-existing hepatic dysfunction; use with caution in patients with hepatitis B or C and in cirrhosis. May be associated with fat redistribution (buffalo hump, increased abdominal girth, breast engorgement, facial atrophy). Use caution in hemophilia. May increase cholesterol and/or triglycerides; hypertriglyceridemia may increase risk of pancreatitis.

Saquinavir interacts with multiple medications (including herbal products) when given concurrently; refer to Drug Interactions. Fortovase® and Invirase® are not bioequivalent and should not be used interchangeably; only Fortovase® should be used to initiate therapy. Fortovase® is recommended when saquinavir will be given as the sole protease inhibitor; Invirase® may be used only if combined with ritonavir. Safety and efficacy have not been established in children <16 years of age.

Adverse Reactions

Protease inhibitors cause dyslipidemia which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause increased abdominal girth, buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia.

10%: Gastrointestinal: Diarrhea, nausea

1% to 10%:

Cardiovascular: Chest pain

Central nervous system: Anxiety, depression, fatigue, headache, insomnia, pain

Dermatologic: Rash, verruca

Endocrine & metabolic: Hyperglycemia, hypoglycemia, hyperkalemia, libido disorder, serum amylase increased

Gastrointestinal: Abdominal discomfort, abdominal pain, appetite decreased, buccal mucosa ulceration, constipation, dyspepsia, flatulence, taste alteration, vomiting

Hepatic: AST increased, ALT increased, bilirubin increased

Neuromuscular & skeletal: Paresthesia, weakness, CPK increased

Renal: Creatinine kinase increased

<1% (Limited to important or life-threatening): Acute myeloblastic leukemia, alkaline phosphatase increased, allergic reaction, ascites, ataxia, bullous skin eruption, calcium increased, cholangitis, chronic liver disease exacerbation, confusion, hemoglobin decreased, hemolytic anemia, hepatitis, hypokalemia, jaundice, LFTs increased, neuropathy, pain, pancreatitis, polyarthritis, portal hypertension, seizure, serum phosphate decreased, Stevens-Johnson syndrome, syncope, thrombocytopenia, thrombophlebitis, triglycerides increased, upper quadrant abdominal pain

Drug Interactions

Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP2C8/9 (weak), 2C19 (weak), 2D6 (weak), 3A4 (moderate)

Antiarrhythmics: Serum levels/toxicity may be increased by saquinavir; serious and/or life-threatening reactions may occur. Concurrent use with amiodarone, bepridil, flecainide, propafenone, or quinidine is contraindicated. Use caution with systemic lidocaine.

Anticonvulsants: Saquinavir serum concentrations may be decreased by carbamazepine, phenobarbital, or phenytoin; use with caution.

Azole antifungals (itraconazole, ketoconazole): Serum concentrations of saquinavir may be increased. Dose adjustment was not needed at the study dose when used for a limited time (ketoconazole 400 mg once daily and Fortovase® 1200 mg 3 times daily).

Benzodiazepines: An increase in midazolam and triazolam serum levels may occur resulting in significant over sedation when administered with saquinavir. Concurrent use is contraindicated. A decreased dose may be considered when used with alprazolam, clorazepate, diazepam, or flurazepam.

Calcium channel blockers: Use with caution; serum concentrations of calcium channel blockers may be increased.

Cisapride: Saquinavir inhibits the metabolism of cisapride and should not be administered concurrently due to risk of life-threatening cardiac arrhythmias.

Clarithromycin: Serum concentrations of saquinavir and clarithromycin may both be increased. Dose adjustment not was not needed at the study dose when used for 7 days (clarithromycin 500 mg twice daily and Fortovase® 1200 mg 3 times/day); dosage adjustment of clarithromycin is recommended in patients with renal impairment.

Corticosteroids: Dexamethasone may decrease serum concentrations of saquinavir; use with caution.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of saquinavir. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Saquinavir may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, cyclosporine, mirtazapine, nateglinide, nefazodone, sildenafil (and other PDE-5 inhibitors), tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine and methylergonovine): Serum levels/toxicity may be increased by saquinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

HMG-CoA reductase inhibitors: Saquinavir increased serum concentrations of simvastatin, lovastatin, and atorvastatin; risk of myopathy/rhabdomyolysis may be increased. Avoid use with simvastatin and lovastatin. Use caution with atorvastatin and cerivastatin (fluvastatin, pravastatin, and rosuvastatin are not appreciably metabolized by CYP3A4).

Immunosuppressants: Saquinavir may increase the serum levels of cyclosporine, sirolimus, or tacrolimus.

Methadone: Serum concentrations of methadone may be decreased; an increased dose may be needed when administered with saquinavir

Non-nucleoside reverse transcriptase inhibitors: Saquinavir serum concentrations may be increased by delavirdine. Serum levels of saquinavir and efavirenz may be decreased with concurrent use; saquinavir should not be used as the sole protease inhibitor with efavirenz or nevirapine.

Oral contraceptives: Serum levels of the hormones in oral contraceptives may decrease significantly with administration of saquinavir. Patients should use alternative methods of contraceptives during saquinavir therapy.

PDE-5 inhibitors: Serum concentrations may be increased by saquinavir; dosing adjustment is required. Limit sildenafil dose to 25 mg/48 hours. The maximum dose of tadalafil is 10 mg/72 hours. Vardenafil dosing should not exceed 2.5 mg/24 hours.

Pimozide: Serum levels/toxicity may be increased by saquinavir; serious and/or life-threatening reactions may occur; concurrent use is contraindicated.

Protease inhibitors: Indinavir and ritonavir may increase serum levels of saquinavir. Serum levels of saquinavir and nelfinavir may be increased with concurrent use. Lopinavir/ritonavir (combination product) may increase serum levels of saquinavir. Refer to Dosage section.

Rifabutin: Serum concentrations of saquinavir are decreased and levels of rifabutin are increased. Saquinavir should not be used as the sole protease inhibitor when given with rifabutin.

Rifampin: Serum concentrations of saquinavir are markedly decreased. Risk of hepatotoxicity is increased with concurrent use of ritonavir-boosted saquinavir therapy. Concurrent use is contraindicated.

Tricyclic antidepressants: Serum concentrations of amitriptyline and imipramine may be increased; monitor.

Warfarin: Serum concentrations of warfarin may be affected; monitor.

Ethanol/Nutrition/Herb Interactions

Food: A high-fat meal maximizes bioavailability. Saquinavir levels may increase if taken with grapefruit juice.

Herb/Nutraceutical: Saquinavir serum concentrations may be decreased by St John's wort; avoid concurrent use. Garlic capsules may decrease saquinavir serum concentrations; avoid use if saquinavir is the only protease inhibitor.

Stability

Fortovase®: Store in refrigerator. Stable for 3 months when stored at room temperature.

Invirase®: Store at room temperature.

Mechanism of Action

As an inhibitor of HIV protease, saquinavir prevents the cleavage of viral polyprotein precursors which are needed to generate functional proteins in and maturation of HIV-infected cells

Pharmacodynamics/Kinetics

Absorption: Poor; increased with high fat meal; Fortovase® has improved absorption over Invirase®

Distribution: Vd: 700 L; does not distribute into CSF

Protein binding, plasma: ~98%

Metabolism: Extensively hepatic via CYP3A4; extensive first-pass effect

Bioavailability: Invirase®: ~4%; Fortovase®: 12% to 15%

Excretion: Feces (81% to 88%), urine (1% to 3%) within 5 days

Dosage

Oral:

Children and Adolescents <16 years: Safety and efficacy have not been established; dosages of 50 mg/kg/dose 3 times/day are under study

Children 16 years and Adults: Note: Fortovase® and Invirase® are not bioequivalent and should not be used interchangeably; only Fortovase® should be used to initiate therapy:

Fortovase®: 1200 mg (six 200 mg capsules) 3 times/day within 2 hours after a meal in combination with a nucleoside analog or 1000 mg (five 200 mg capsules) twice daily in combination with ritonavir 100 mg twice daily

Invirase®: 1000 mg (five 200 mg capsules or two 500 mg tablets) twice daily given in combination with ritonavir 100 mg twice daily; this combination should be given together and within 2 hours after a full meal in combination with a nucleoside analog

Note: Dosage adjustments of Fortovase® when administered in combination therapy:

Delavirdine: Fortovase® 800 mg 3 times/day

Lopinavir and ritonavir (Kaletra™): Fortovase® 800 mg twice daily

Nelfinavir: Fortovase® 1200 mg twice daily

Elderly: Clinical studies did not include sufficient numbers of patients 65 years of age; use caution due to increased frequency of organ dysfunction

Administration

Take saquinavir within 2 hours after a full meal. Avoid direct sunlight when taking saquinavir. When used with ritonavir, saquinavir and ritonavir should be administered at the same time.

Monitoring Parameters

Monitor viral load, CD4 count, triglycerides, cholesterol, glucose

Dietary Considerations

Administer within 2 hours of a meal. Invirase® capsules contain lactose 63.3 mg/capsule (not expected to induce symptoms of intolerance).

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Ritonavir is not a cure for HIV, nor has it been found to reduce transmission of HIV. Take as directed, with meals. Avoid grapefruit juice. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Saquinavir may be prescribed with a combination of other medications; time these medications as directed by prescriber. You may be advised to check your glucose levels (this drug can cause exacerbation or new-onset diabetes). Avoid exposure to direct sunlight (wear protective clothing and use sunblock). May cause body changes due to redistribution of body fat, facial atrophy, or breast enlargement (normal effects of drug); dizziness, insomnia, abnormal thinking (use caution when driving or engaging in potentially hazardous tasks until response to drug is known); nausea, vomiting, or taste perversion (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); mouth sores (frequent oral care is necessary); muscle weakness (consult prescriber for approved analgesic); headache; or insomnia (consult prescriber for medication). Report any persistent adverse effects. Breast-feeding precaution: Do not breast-feed.

Nursing Implications

Observe for signs of opportunistic infections and other illnesses associated with HIV; administer on a full stomach, if possible

Additional Information

The indication for saquinavir for the treatment of HIV infection is based on changes in surrogate markers. At present, there are no results from controlled clinical trials evaluating the effect of regimens containing saquinavir on patient survival or the clinical progression of HIV infection, such as the occurrence of opportunistic infections or malignancies; in cell culture, saquinavir is additive to synergistic with AZT, ddC, and DDI without enhanced toxicity. According to the manufacturer, Invirase® will be phased out over time and completely replaced by Fortovase®. Potential compliance problems, frequency of administration and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

Anesthesia and Critical Care Concerns/Other Considerations

Potential compliance problems, frequency of administration, and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May rarely cause confusion or ataxia; report of acute paranoia reaction to saquinavir

Mental Health: Effects on Psychiatric Treatment

Contraindicated with triazolam and midazolam; barbiturates and carbamazepine may increase the metabolism of saquinavir. Concomitant use of saquinavir and St John's wort is not recommended. Coadministration of protease inhibitors (saquinavir) with St John's wort is expected to substantially decrease protease inhibitor serum concentrations leading to a loss of virologic response and possible resistance to saquinavir or to the class of protease inhibitors.

Dosage Forms

Note: Strength expressed as base.

Capsule, as mesylate (Invirase®): 200 mg [contains lactose 63.3 mg/capsule]

Capsule, soft gelatin, as base (Fortovase®): 200 mg

Tablet, as base (Invirase®): 500 mg

References

Collier AC, Coombs RW, Schoenfeld DA, et al, "Treatment of Human Immunodeficiency Virus Infection With Saquinavir, Zidovudine, and Zalcitabine," N Engl J Med , 1996, 334(16):1011-7.

Deeks SG, Smith M, Holodniy M, et al, "HIV-1 Protease Inhibitors. A Review for Clinicians," JAMA , 1997, 277(2):145-53.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," October 29, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed January 12, 2005.

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Hsu A, Granneman GR, Cao G, et al, "Pharmacokinetic Interactions Between Two Human Immunodeficiency Virus Protease Inhibitors, Ritonavir and Saquinavir," Clin Pharmacol Ther , 1998, 63(4):453-64.

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International Brand Names

Fortovase® (AT, AU, BE, BG, BR, CA, CH, CL, CN, DE, DK, EC, ES, FI, FR, GB, GR, HU, IE, IL, IN, IS, IT, LU, LV, NL, NO, NZ, PL, PT, RO, RU, SE, SG, SK, TH, TW, UY, ZA); Invirase® (AT, AU, BE, BR, CA, CH, CL, CZ, DE, DK, ES, FI, FR, GB, HR, IE, IL, IT, LU, MX, NL, NZ, PL, PT, RO, RU, SE); Invi-rase® (ZA)

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