ATAZANAVIR SULFATE; RITONAVIR
Clinical safety rating: safe
A strong inhibitor of CYP3A4 affecting many drugs Can cause GI intolerance hepatotoxicity and pancreatitis.
Atazanavir is an azapeptide HIV-1 protease inhibitor that inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, preventing formation of mature virions. Ritonavir is an HIV protease inhibitor that also inhibits CYP3A, boosting atazanavir levels.
| Metabolism | Atazanavir is metabolized primarily by CYP3A4; ritonavir is metabolized by CYP3A4 and CYP2D6, and inhibits CYP3A4. |
| Excretion | Biliary/fecal (major route): atazanavir 79% as unchanged drug, 13% as metabolites; ritonavir 86.4% as metabolites, 3.5% unchanged. Renal: atazanavir 7% (20% as unchanged); ritonavir 11.3% (3.5% unchanged). |
| Half-life | Atazanavir: ~6.5-7 hours (when boosted with ritonavir). Ritonavir: ~3-5 hours. Clinical context: Atazanavir requires ritonavir boosting to achieve therapeutic trough concentrations; once-daily dosing maintains efficacy. |
| Protein binding | Atazanavir: ~86% bound to human serum albumin and alpha-1-acid glycoprotein. Ritonavir: ~98-99% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Atazanavir: Vd/F ~12 L/kg (20-40 L total). Ritonavir: Vd/F ~0.3-0.6 L/kg (20-50 L total). Clinical meaning: Atazanavir widely distributed into tissues; ritonavir moderately distributed. |
| Bioavailability | Atazanavir: ~60-68% (with food). Ritonavir: ~60-80% (with food). Both administered orally only. |
| Onset of Action | Oral: Atazanavir Cmax occurs 2-3 hours post-dose; ritonavir Cmax occurs 2-4 hours. Antiviral effect begins within hours of first dose, but maximal viral suppression requires 2-4 weeks. |
| Duration of Action | Atazanavir: 24 hours (once-daily dosing). Ritonavir: 8-12 hours (subtherapeutic for HIV beyond this; used solely as pharmacokinetic booster). Steady state achieved in 5-7 days. |
Atazanavir 300 mg with ritonavir 100 mg orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment required for renal impairment; not recommended in patients on hemodialysis because of lack of experience. Atazanavir is not significantly removed by hemodialysis. |
| Liver impairment | Atazanavir sulfate: Child-Pugh class A: reduce dose to 300 mg once daily with ritonavir 100 mg once daily. Child-Pugh class B: atazanavir 300 mg once daily with ritonavir 100 mg once daily is not recommended; use alternative therapy. Child-Pugh class C: contraindicated. Ritonavir: Child-Pugh class A and B: no dose adjustment; Child-Pugh class C: contraindicated. |
| Pediatric use | For patients weighing ≥40 kg: atazanavir 300 mg with ritonavir 100 mg once daily. For weights 32 to <40 kg: atazanavir 200 mg with ritonavir 100 mg once daily. For weights 15 to <32 kg: atazanavir 150 mg/m² with ritonavir 100 mg orally once daily (max atazanavir dose 300 mg). For weights <15 kg: not recommended. |
| Geriatric use | No specific dose adjustment recommended. Use with caution due to increased risk of renal and hepatic dysfunction, and monitor renal function and bilirubin levels closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
A strong inhibitor of CYP3A4 affecting many drugs Can cause GI intolerance hepatotoxicity and pancreatitis.
| FDA category | Animal |
| Breastfeeding | Atazanavir excreted in human milk; M/P ratio not established. Ritonavir minimal excretion. HIV-infected mothers should not breastfeed to avoid transmission. |
| Teratogenic Risk | Atazanavir/ritonavir: Pregnancy category B. No increased risk of major malformations in first trimester based on APR data. Second/third trimester: Use only if benefit outweighs risk; monitor for hyperbilirubinemia in neonates. |
■ FDA Black Box Warning
No FDA boxed warning specifically for this combination; however, ritonavir is associated with risk of hepatotoxicity and PR interval prolongation.
| Common Effects | Nausea |
| Serious Effects |
["Hypersensitivity to atazanavir or ritonavir","Coadministration with drugs highly dependent on CYP3A for clearance (e.g., alfuzosin, rifampin, ergot derivatives, pimozide, triazolam, midazolam)","Severe hepatic impairment"]
| Precautions | ["Hepatotoxicity","Cardiac conduction abnormalities (PR interval prolongation)","Nephrolithiasis","Cholelithiasis","Diabetes mellitus/hyperglycemia","Hemophilia","Immune reconstitution syndrome","Lipodystrophy","Hyperbilirubinemia"] |
| Food/Dietary | Atazanavir should be taken with food to improve absorption and reduce GI side effects. Avoid high-fat meals as they may reduce atazanavir concentrations. No specific food restrictions beyond taking with a meal. Grapefruit juice may increase ritonavir levels; avoid excessive consumption. |
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| Fetal Monitoring | Maternal: LFTs, bilirubin, glucose, renal function, CBC; fetal: ultrasound for growth, monitoring for neonatal hyperbilirubinemia. |
| Fertility Effects | Limited data; no known significant impact on fertility. Atazanavir may cause gynecomastia; ritonavir no known effects. |
| Clinical Pearls | Ritonavir-boosted atazanavir requires acidic gastric pH for absorption; avoid concurrent use of proton pump inhibitors (PPIs). If PPI unavoidable, administer atazanavir 300 mg with ritonavir 100 mg and PPI at least 12 hours apart. H2-receptor antagonists can be used with staggered timing. Atazanavir causes indirect hyperbilirubinemia (unconjugated) due to UGT1A1 inhibition, which is benign but may cause jaundice. Monitor for PR interval prolongation, especially in patients with pre-existing conduction defects. Atazanavir should be taken with food to enhance absorption and reduce gastrointestinal intolerance. |
| Patient Advice | Take this medication exactly as prescribed, usually once daily with food. · Do not take antacids or buffered medications within 2 hours of taking atazanavir/ritonavir. · Avoid proton pump inhibitors (e.g., omeprazole) unless specifically instructed by your doctor, as they reduce effectiveness. · Inform your doctor if you develop yellowing of skin or eyes (jaundice) – this is usually harmless but requires monitoring. · Use effective contraception as this combination may reduce the efficacy of hormonal contraceptives. · Do not stop or change your dose without consulting your doctor; missing doses can lead to drug resistance. · Report any signs of heart rhythm changes (dizziness, fainting, palpitations) or liver problems (dark urine, pale stools, nausea). |