Dosing and uses of Invirase (saquinavir)
Adult dosage forms and strengths
capsule
- 200mg
tablet
- 500mg
HIV Infection
1000 mg (with ritonavir 100 mg) PO q12hr, or in combination with ritonavir-enhanced lopinavir
Treatment-naïve patients
- Initial dose: 500 mg PO BID plus ritonavir 100 mg BID x 7 days, THEN increase to 1000mg/100mg PO BID
- This gradual increase is due to potential for increased risk of PR and QT interval prolongation with standard 1000/100-mg BID dose
- Patients with a baseline QT interval <450 msec, an on-treatment ECG is recommended after ~10 days of therapy
- Patients with a QT interval prolongation over pretreatment by >20 msec should discontinue saquinavir/ritonavir therapy
Pediatric dosage forms and strengths
capsule
- 200mg
tablet
- 500mg
HIV Infection
<16 years: Safety and efficacy not established
≥16 years: 1000 mg (plus ritonavir 100 mg) PO q12hr, or in combination with ritonavir-enhanced lopinavir
Treatment-naïve patients
- Initial dose: 500 mg PO BID plus ritonavir 100 mg BID x 7 days, THEN increase to 1000mg/100mg PO BID
- This gradual increase is due to potential for increased risk of PR and QT interval prolongation with standard 1000/100-mg BID dose
- Patients with a baseline QT interval <450 msec, an on-treatment ECG is recommended after ~10 days of therapy
- Patients with a QT interval prolongation over pretreatment by >20 msec should discontinue saquinavir/ritonavir therapy
Investigational in treatment-experienced children
- <2 years: Not recommended – no dose has been determined
- ≥2 years, 5 to <15 kg: 50 mg/kg (plus ritonavir 3 mg/kg) PO q12hr
- ≥2 years, 15-40 kg: 50 mg/kg (plus ritonavir 2.5 mg/kg) PO q12hr
- ≥2 years, ≥40 kg: 50 mg/kg (plus ritonavir 100mg) PO q12hr
- In combination with lopinavir/ritonavir (LPV/r): Regimens listed below
- <7 years: Safety and efficacy not established
- ≥7 years:: 750 mg/m² (not to exceed 1,600 mg ) + LPV/r 400/100 mg/m² PO q12hr, OR 50 mg/kg + LPV/r 230/57.5 mg/m² PO q12hr
Invirase (saquinavir) adverse (side) effects
1-10%
Rash
Hyperglycemia
Diarrhea
Abdominal discomfort
Nausea
Abdominal pain
Buccal mucosa ulceration
Paresthesia
Weakness
Increased CPK
<1%
Headache
Confusion
Seizures
Ataxia
Pain
Stevens-Johnson syndrome
Hypoglycemia
Hyper- & hypokalemia
Low serum amylase
AML
Hemolytic anemia
Thrombocytopenia
Jaundice
Ascites
Warnings
Black box warnings
Saquinavir mesylate (Invirase) capsules and tablets, and saquinavir (Fortovase) soft gelatin capsules, are not bioequivalent and cannot be used interchangeably
Fortovase is no longer available in the United States
Use saquinavir mesylate (Invirase) only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with saquinavir (Fortovase)
Contraindications
Hypersensitivity (eg, anaphylactic reaction, Stevens-Johnson syndrome)
QT and PR interval prolonation and torsades de pointes have been reported rarely; do not use saquinavir/ritonavir with congenital or documented acquired QT prolongation (≥450 msec), refractory hypokalemia or magnesemia, and in combination with drugs that prolong QT intervaL
Complete atrioventricular (AV) block without implanted pacemakers or high risk of complete AV block
Severe hepatic impairment
Coadministration of saquinavir/ritonavir with rifampin due to the risk of severe hepatotoxicity
Drugs that are contraindicated with saquinavir (when coadministered 'boosted' with ritonavir) include CYP3A inhibitors that may result in increased saquinavir plasma levels and cause serious or life-threatening reactions (eg, prolonged QT interval)
Drug contraindicated with saquinavir/ritonavir include alfuzosin, antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, quinidine), trazodone, rifampin, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, HMG-CoA reductase inhibitors (lovastatin, simvastatin), lurasidone, pimozide, sildenafil (when used for PAH), midazolam, and triazolam
Cautions
Hyperlipidemia may occur
Take within 2 hr after meal; absorption increased with high-fat meaL
Must be used in combination with ritonavir (ie, boosted therapy) to achieve necessary levels for effectiveness
Autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; however, time to onset is variable, and can occur many months after treatment initiation
Risk of QT and PR prolongation that might lead to Torsades de Pointes (particularly if used with ritonavir); perform ECG prior to initiation of treatment; patients with a baseline QT interval < 450 msec, an on-treatment ECG is recommended after approximately 10 days of therapy; patients with a QT interval prolongation over pre-treatment by > 20 msec should discontinue saquinavir/ritonavir therapy
May develop new onset or exacerbations of diabetes mellitus, hyperglycemia, elevated cholesterol and/or triglyceride concentrations, redistribution/accumulation of body fat, and immune reconstitution syndrome; monitor cholesterol and triglycerides prior to therapy and periodically thereafter
In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease
Spontaneous bleeding may occur and additional factor VII may be required
Various degrees of cross-resistance have been observed
Not recommended for use in combination with cobicistat
Pregnancy and lactation
Pregnancy category: B
Lactation: unknown whether present in breast milk, do not breast feed; HIV+ women may cause postnatal vertical transmission to infant with ingestion of HIV in the breast milk
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Invirase (saquinavir)
Mechanism of action
Protease Inhibitor; inhibits cleavage of Gag-Pol polyprotein precursors, which in turn causes the formation of immature, noninfectious viral particles.
Combination (boosted therapy) use recommended
Absorption
Poor absorption; increased with high fat meaL
Protein Bound: ~98%
Distribution
Does not distribute into CSF
Vd: 700 L
Metabolism
Extensively metabolized via hepatic CYP3A4; extensive first-pass effect
Elimination
Excretion: Fece: 81-88%; urine: 1-3%
Administration
Oral Administration
Saquinavir plus ritonavir should be taken with 2 hr after a meaL
