AGENERASE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AGENERASE (AGENERASE).
AGENERASE (amprenavir) is a HIV-1 protease inhibitor that binds to the active site of HIV-1 protease, preventing the cleavage of viral polyprotein precursors into functional proteins, resulting in the formation of immature, non-infectious viral particles.
| Metabolism | Amprenavir is extensively metabolized in the liver via cytochrome P450 3A4 (CYP3A4) isoenzyme. |
| Excretion | Hepatic metabolism (CYP3A4) to inactive metabolites; <1% excreted unchanged in urine, major fecal elimination (approximately 30% as metabolites). |
| Half-life | Terminal elimination half-life approximately 7-10 hours in adults with normal hepatic function; supports twice-daily dosing for HIV-1 infection. |
| Protein binding | Approximately 90% bound to human plasma proteins, primarily alpha-1-acid glycoprotein and albumin. |
| Volume of Distribution | Vd ~ 0.6 L/kg (range 0.4-0.8 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is variable, approximately 50-60% under fed conditions; food increases absorption (high-fat meal enhances AUC by ~60%). |
| Onset of Action | Oral: Antiviral activity detectable within 1-2 weeks of initiation. |
| Duration of Action | Antiviral effect persists over dosing interval (12 hours); continuous therapy required to maintain viral suppression. |
1200 mg orally twice daily, or 600 mg orally twice daily when co-administered with ritonavir 100 mg twice daily.
| Dosage form | SOLUTION |
| Renal impairment | No adjustment required for renal impairment. Not significantly removed by hemodialysis. |
| Liver impairment | Child-Pugh Class A: 600 mg orally twice daily (with ritonavir 100 mg twice daily) or 1200 mg orally twice daily without ritonavir. Child-Pugh Class B: 450 mg orally twice daily (with ritonavir 100 mg twice daily) or 900 mg orally twice daily without ritonavir. Child-Pugh Class C: 300 mg orally twice daily (with ritonavir 100 mg twice daily) or 600 mg orally twice daily without ritonavir. |
| Pediatric use | For patients aged 4 to 16 years: 20 mg/kg orally twice daily (max 1200 mg twice daily) or 15 mg/kg orally twice daily (max 600 mg twice daily) when co-administered with ritonavir 1.5 mg/kg twice daily (max 100 mg twice daily). |
| Geriatric use | Limited data; use with caution due to age-related hepatic and renal decline. Monitor for adverse effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AGENERASE (AGENERASE).
| Breastfeeding | No human data on excretion in breast milk. HIV-positive mothers in developed countries should not breastfeed to avoid postnatal transmission of HIV. M/P ratio unknown. |
| Teratogenic Risk | Pregnancy Category C. No adequate studies in pregnant women. In animal studies, no teratogenic effects at doses up to 2.5 times human AUC exposure; however, embryotoxicity and maternal toxicity observed at higher doses. Risk of neural tube defects in first trimester cannot be excluded. Use only if benefit outweighs risk. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Concomitant use with drugs highly dependent on CYP3A4 for clearance (e.g., triazolam, midazolam, ergot derivatives)","Hypersensitivity to amprenavir or any component of the formulation"]
| Precautions | ["Severe or life-threatening skin reactions including Stevens-Johnson syndrome","Hepatotoxicity","Hyperglycemia and new-onset diabetes mellitus","Increased bleeding in hemophiliacs","Redistribution/accumulation of body fat","Increased cholesterol and triglycerides","Drug interactions with medications metabolized by CYP3A4"] |
| Food/Dietary | Take with high-fat meals to increase bioavailability. Avoid grapefruit juice as it may alter drug levels. |
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| Fetal Monitoring |
| Monitor liver function tests, blood glucose, lipid profile, and complete blood count. Check HIV RNA viral load and CD4 count regularly. Assess for signs of hypersensitivity (rash, fever, GI symptoms). Fetal ultrasound for neural tube defects if first-trimester exposure. |
| Fertility Effects | No evidence of impaired fertility in animal studies. In humans, no significant effect on male or female fertility reported. However, HIV infection itself may affect fertility. |
| Clinical Pearls |
| Monitor for hepatotoxicity; contraindicated in severe hepatic impairment. Use with caution with oral contraceptives and rifampin. Administer with food to improve absorption. |
| Patient Advice | Take this medication with a meal or light snack to enhance absorption. · Do not stop taking this medication without consulting your doctor, even if you feel better. · Report any signs of liver problems (e.g., yellowing of skin or eyes, dark urine, abdominal pain) immediately. · This medication may reduce the effectiveness of hormonal contraceptives; use additional barrier methods. · Avoid taking rifampin (an antibiotic) while on this medication unless directed by your doctor. |