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saquinavir (Invirase, Fortovase)

Tradenames: Invirase, Fortovase. Indications: 1) treatment of advanced HIV infection in selected patients 2) used in combination with nucleoside analogs & other retroviral agents - may be used in combination with atazanvir - acceptable for use during pregnancy [9] Contraindications: Caution: 1) patients with hepatic insufficiency 2) safety & efficacy has not been established for children < 16 years of age Dosage: 600 mg PO TID (with meals or up to 2 hours after full meal). Capsules: 200 mg. Notes: 1) MUST be used with AZT, or other NRTI (nucleoside reverse transcriptase inhibitor) 2) do NOT use suboptimal dose Pharmacokinetics: 1) absorption is incomplete; high fats foods may increase absorption 5-fold 2) bioavailability: Invirase: 4%; Fortovase: 13% 3) widely distributed, CSF penetration is minimal 4) protein binding: 98% 5) metabolized by cyt P450 3A4 a) undergoes extensive 1st pass metabolism b) no known active metabolites 6) elimination: 88% in feces, 1% in urine Adverse effects: 1) not common (1-10%) - rash, hyperglycemia, elevated serum creatine kinase, diarrhea, abdominal pain/discomfort, nausea, ulceration of buccal mucosa, paresthesia, weakness 2) uncommon (< 1%) - headache, confusion, seizures, ataxia, Stevens-Johnson syndrome, hypoglycemia, hyperkalemia, hypokalemia, low serum amylase, acute myeloblastic leukemia, anemia, hemolytic anemia, thrombocytopenia, jaundice, ascites, exacerbation of chronic liver disease, abnormal liver function tests (AST, ALT, bilirubin), thrombophlebitis 3) hyperlipidemia, lipodystrophy syndrome 4) arrhythmias - prolonged QT interval -> torsades de pointes - prolonged PR interval -> complete heart block [8] Drug interactions: 1) rifampin may decrease plasma levels of saquinavir (40-80%) 2) rifabutin may increase plasma levels of saquinavir 3) ketoconazole may increase plasma levels of saquinavir 4) saquinavir may decrease metabolism of: a) terfenadine, b) astemizole c) cisapride 5) calcium channel blockers 6) clindamycin 7) dapsone 8) quinidine 9) triazolam 10) garlic supplements may enhance metabolism & diminish saquinavir levels by 50% [5] 11) any drug that inhibits cyt P450 3A4 may increase levels of saquinavir 12) any drug that induces cyt P450 3A4 may diminish levels of saquinavir 13) saquinavir inhibits cyt P450 3A4, thus inhibits its own metabolism & metabolism of other cyt P450 3A4 substrates 14) ritonavir in combination with saquinavir may increase risk of torsades de pointes or complete heart block [8] Laboratory: - saquinavir in serum/plasma

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

antiretroviral protease inhibitor

Properties

INHIBITS: HIV protease MISC-INFO: elimination route LIVER protein-binding 98% pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Physician's Desk Reference (PDR) 56th edition, Medical Economics, 2002
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  5. Prescriber's Letter 8(3):17 2001
  6. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  7. Department of Veterans Affairs, VA National Formulary
  8. FDA MedWatch 10/21/2010 Invirase (saquinavir): Label Change - Risk of Abnormal Heart Rhythm http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm230449.htm
  9. Zuger A Use of Antiretroviral Drugs in Pregnancy. Physician's First Watch, April 22, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2014. AIDSinfo. Clinical Guidelines Portal. March 28, 2014. http://aidsinfo.nih.gov/Guidelines/HTML/3/perinatal-guidelines/0 (corresponding NGC guideline withdrawn March 2016)
  10. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015