APTIVUS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for APTIVUS (APTIVUS).
Tipranavir is a nonpeptidic HIV-1 protease inhibitor that binds to the active site of HIV-1 protease, thereby preventing the cleavage of viral polyprotein precursors into functional proteins, resulting in the production of immature, noninfectious viral particles.
| Metabolism | Tipranavir is metabolized primarily by cytochrome P450 (CYP) 3A4. Coadministration with ritonavir (a potent CYP3A4 inhibitor) significantly increases tipranavir plasma concentrations. |
| Excretion | Fecal (79.5% unchanged), renal (4.4% unchanged). |
| Half-life | Terminal elimination half-life is 2.1 hours during multiple dosing with ritonavir (due to CYP3A inhibition), 5.5 hours when given alone. |
| Protein binding | 81.5% bound to human plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Apparent Vd/F is 3.5 L/kg (range 1.7-5.5 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Absolute bioavailability not established; oral bioavailability is estimated to be low (~30-40%), but is significantly increased when coadministered with ritonavir. |
| Onset of Action | Oral: Approximately 2-4 hours after administration; time to peak plasma concentration (Tmax) is 1.3-2 hours. |
| Duration of Action | Approximately 8-12 hours; frequency of dosing is twice daily with ritonavir boosting. |
Oral: 500 mg twice daily with ritonavir 200 mg twice daily. Oral solution: 500 mg (1.25 mL) twice daily with ritonavir 200 mg twice daily. Must be taken with food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for renal impairment; not significantly removed by hemodialysis. |
| Liver impairment | Child-Pugh Class A and B: No dose adjustment. Child-Pugh Class C: Contraindicated (safety and efficacy not established). |
| Pediatric use | Approved for age ≥6 years. Weight-based dose: 14 to <20 kg: 275 mg twice daily; 20 to <36 kg: 375 mg twice daily; 36 to <50 kg: 475 mg twice daily; ≥50 kg: 500 mg twice daily. All doses with ritonavir 200 mg twice daily. Use oral solution for doses <500 mg for accuracy. |
| Geriatric use | No specific dose adjustment; limited data in elderly. Use with caution due to increased risk of hepatotoxicity and comorbidities. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for APTIVUS (APTIVUS).
| Breastfeeding | It is not known whether tipranavir is excreted in human breast milk. In lactating rats, tipranavir was detected in milk at concentrations approximately 30% of maternal plasma levels. Due to the potential for adverse reactions in nursing infants, breastfeeding should be discontinued during therapy. M/P ratio in humans is unknown. |
| Teratogenic Risk | Pregnancy category C. No adequate and well-controlled studies in pregnant women. In animal studies, no evidence of teratogenicity at systemic exposures 1.3-fold (rats) and 1.4-fold (rabbits) the human AUC at the recommended oral dose (250 mg). However, decreased fetal body weights and increased skeletal variations were observed at maternally toxic doses. Use only if potential benefit justifies potential risk to the fetus. |
■ FDA Black Box Warning
Tipranavir has been associated with clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.
| Serious Effects |
Absolute: Hypersensitivity to tipranavir or any of its components; moderate-to-severe hepatic impairment (Child-Pugh class B or C); coadministration with drugs highly dependent on CYP3A4 clearance and for which elevated plasma concentrations are associated with serious adverse events (e.g., alfuzosin, amiodarone, bepridil, ergot derivatives, lovastatin, simvastatin, oral midazolam, triazolam, and sildenafil when used for pulmonary arterial hypertension).
| Precautions | Hepatotoxicity (including clinical hepatitis and hepatic decompensation); intracranial hemorrhage (including fatalities); increased bleeding risk, particularly in patients with hemophilia; hyperglycemia/diabetes mellitus; redistribution/accumulation of body fat; immune reconstitution syndrome; increased lipid levels; hypersensitivity reactions (e.g., rash, Stevens-Johnson syndrome); and drug interactions (especially with other CYP3A4 substrates). |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) and complete blood counts periodically. Assess for signs of hepatotoxicity, including fatigue, malaise, jaundice, and coagulopathy. In pregnant women, monitor HIV viral load and CD4+ count regularly. Fetal ultrasound may be considered to assess for growth abnormalities. |
| Fertility Effects | No human data on fertility. In animal studies, tipranavir did not impair fertility in male or female rats at doses up to 1000 mg/kg/day (approximately 1.3 times the human AUC). No significant reproductive toxicity observed. |
| Food/Dietary |
| Take with food to improve absorption (high-fat meal increases AUC by 30%). Avoid grapefruit juice as it may alter drug levels. |
| Clinical Pearls | Tipranavir is a non-peptide protease inhibitor for HIV-1. It requires co-administration with low-dose ritonavir (500/200 mg BID). Monitor liver function closely due to hepatotoxicity risk. Avoid in moderate to severe hepatic impairment. Caution with sulfonamide allergy (contains sulfonamide moiety). May cause intracranial hemorrhage; discontinue if signs/symptoms occur. Use with caution in patients with hemophilia A or B due to increased bleeding risk. |
| Patient Advice | Take APTIVUS with ritonavir exactly as prescribed, twice daily with food. · Do not change dose or stop without consulting your doctor. · APTIVUS does not cure HIV or prevent transmission; use safer sex practices. · Report any signs of liver problems: yellow skin/eyes, dark urine, pale stools, nausea, vomiting, or abdominal pain. · Contact doctor immediately if you experience unusual bleeding or bruising. · Inform your doctor of all medications, including over-the-counter drugs and supplements. · If you have a sulfa allergy, tell your doctor before starting APTIVUS. · Attend all scheduled blood tests to monitor liver function and viral load. |