ATAZANAVIR SULFATE;RITONAVIR;LAMIVUDINE;ZIDOVUDINE
Clinical safety rating: safe
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and myopathy.
Atazanavir is an HIV-1 protease inhibitor that inhibits viral polyprotein cleavage, resulting in immature non-infectious virions. Ritonavir is a potent CYP3A4 inhibitor that boosts atazanavir exposure. Lamivudine and Zidovudine are nucleoside reverse transcriptase inhibitors (NRTIs) that chain-terminate viral DNA synthesis.
| Metabolism | Atazanavir is metabolized primarily by CYP3A4; ritonavir is a potent inhibitor of CYP3A4 (used as a booster) and is also metabolized by CYP3A4; lamivudine is phosphorylated intracellularly and is eliminated renally as unchanged drug (not extensively metabolized); zidovudine undergoes glucuronidation (UGT2B7) and is metabolized to G-ZDV (5'-glucuronide). |
| Excretion | Atazanavir: 79% fecal (unchanged), 13% renal (7% unchanged). Ritonavir: 86% fecal, 11% renal. Lamivudine: 70% renal (unchanged). Zidovudine: 60-80% renal (metabolite AZT glucuronide), ~19% unchanged. |
| Half-life | Atazanavir: ~7 h (boosted with ritonavir, effective half-life ~8-12 h for once-daily dosing). Ritonavir: 3-5 h. Lamivudine: 5-7 h. Zidovudine: 0.5-3 h. |
| Protein binding | Atazanavir: 86% (alpha-1 acid glycoprotein, albumin). Ritonavir: 98-99% (albumin, alpha-1 acid glycoprotein). Lamivudine: <36%. Zidovudine: 34-38%. |
| Volume of Distribution | Atazanavir: 1.3-2.6 L/kg (extensive tissue distribution). Ritonavir: 0.4 L/kg. Lamivudine: 1.3 L/kg. Zidovudine: 1.6 L/kg. |
| Bioavailability | Atazanavir: 60-70% (enhanced with ritonavir and food). Ritonavir: 60-80% (take with food). Lamivudine: 86-88%. Zidovudine: 60-65% (30% first-pass; take with food reduces nausea). |
| Onset of Action | Oral: Antiviral effect begins within 1-2 weeks but full virologic suppression typically requires 4-8 weeks. |
| Duration of Action | Atazanavir/ritonavir: 24 h (once-daily dosing due to ritonavir boosting). Lamivudine/zidovudine: 12 h (twice-daily). Continuous suppression requires consistent adherence. |
| Molecular Weight | Atazanavir sulfate: 802.93 Da; Ritonavir: 720.95 Da; Lamivudine: 229.26 Da; Zidovudine: 267.24 Da |
One tablet (atazanavir sulfate 300 mg / ritonavir 100 mg / lamivudine 300 mg / zidovudine 300 mg) orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | Not recommended if CrCl <30 mL/min. No adjustment needed for CrCl ≥30 mL/min. |
| Liver impairment | Contraindicated in Child-Pugh Class B or C. Use with caution in mild hepatic impairment; no dose adjustment established. |
| Pediatric use | Not recommended for pediatric patients due to fixed-dose combination; individual components should be used based on weight. |
| Geriatric use | No specific adjustment; monitor renal function and hematologic parameters due to zidovudine-induced anemia and neutropenia. |
| 1st trimester | Use only if benefit outweighs risk. Studies suggest no increased risk of major malformations with atazanavir/ritonavir-based regimens. Zidovudine and lamivudine are generally considered safe in pregnancy. However, avoid use in first trimester if alternative options available due to theoretical concerns. |
| 2nd trimester | Generally considered safe. Recommended for prevention of mother-to-child transmission. Monitor for maternal adverse effects, anemia, and liver function. |
| 3rd trimester | Generally considered safe. Continued use recommended for prevention of perinatal transmission. Monitor for maternal and neonatal toxicity (especially zidovudine-related anemia). |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and myopathy.
| FDA category | Human |
| Placental transfer | All components cross the placenta. Zidovudine and lamivudine show extensive transfer, achieving therapeutic levels in cord blood. Atazanavir has moderate transfer (cord blood: maternal plasma ratio ~0.1-0.3). Ritonavir has minimal transfer (ratio ~0.02-0.1). |
■ FDA Black Box Warning
WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, including fatal cases, have been reported with the use of nucleoside analogues (lamivudine, zidovudine) used alone or in combination. Zidovudine has been associated with hematologic toxicity (neutropenia, severe anemia, especially in patients with advanced HIV-1 disease). Also, prolonged use of zidovudine has been associated with symptomatic myopathy. Additionally, atazanavir has been associated with asymptomatic elevations in bilirubin (unconjugated) and, rarely, symptomatic hepatic injury.
| Common Effects | Anemia |
| Serious Effects |
Concomitant use with alfuzosinConcomitant use with cisaprideConcomitant use with ergot derivatives (e.g., dihydroergotamine, ergotamine)Concomitant use with lomitapideConcomitant use with lovastatinConcomitant use with midazolam (oral)Concomitant use with pimozideConcomitant use with sildenafil (for pulmonary arterial hypertension)Concomitant use with simvastatinConcomitant use with St. John's wortConcomitant use with triazolamConcomitant use with elbasvir/grazoprevirConcomitant use with fusidic acidSevere hepatic impairment (Child-Pugh Class C)Prior hypersensitivity to any component
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| Breastfeeding | All components are excreted in human milk. Lamivudine and zidovudine reach high concentrations in breast milk. Atazanavir is excreted at low levels. In high-income countries, HIV-infected mothers should avoid breastfeeding to prevent postnatal transmission. In resource-limited settings, risks and benefits must be weighed; WHO recommends breastfeeding with antiretroviral therapy due to higher risk of formula-related infections. |
| Lactation Rating | L5 (Contraindicated in high-resource settings; possibly acceptable in low-resource settings with appropriate counseling) |
| Teratogenic Risk | Atazanavir sulfate/ritonavir/lamivudine/zidovudine is a fixed-dose combination antiretroviral. Zidovudine and lamivudine are nucleoside reverse transcriptase inhibitors (NRTIs); atazanavir is a protease inhibitor boosted with ritonavir. In the first trimester, lamivudine and zidovudine are associated with a low risk of birth defects (similar to background). Zidovudine does not increase major malformations. Atazanavir shows no teratogenic signal in humans. Second and third trimesters: No fetal toxicity beyond that of zidovudine/lamivudine combination. Zidovudine may cause transient anemia and neutropenia in neonates. Overall, teratogenic risk is low; combination is considered safe in pregnancy when indicated. |
| Fetal Monitoring | Monitor maternal: complete blood count (CBC) every 2-4 weeks (zidovudine/lamivudine can cause anemia, neutropenia), liver function tests (atazanavir hepatotoxicity), renal function, and viral load regularly. Fetal: ultrasound for growth restriction (zidovudine associated with low birth weight) and for anomalies if indicated. Neonatal: CBC at birth due to zidovudine exposure (risk of anemia, neutropenia). Monitor for HIV infection status. |
| Fertility Effects | No significant adverse effects on fertility reported for this combination in humans. Zidovudine and lamivudine do not impair male or female fertility. Atazanavir has no known effect on fertility. Ritonavir may cause transient menstrual irregularities (e.g., amenorrhea) but long-term fertility is unaffected. |
| Precautions |
| Hematologic toxicity: Monitor CBCs frequently (zidovudine: neutropenia, anemia)., Lactic acidosis and hepatomegaly with steatosis: Discontinue if signs develop., Hepatotoxicity: Elevated bilirubin (atazanavir), transaminases; caution in patients with underlying liver disease or hepatitis B or C., Pancreatitis: Discontinue if suspected., Cardiac conduction abnormalities: PR interval prolongation, atazanavir may cause AV block., Nephrolithiasis (atazanavir): Hydration recommended., Fat redistribution and accumulation., Drug interactions: Atazanavir/ritonavir are potent CYP3A4 inhibitors; monitor for toxicities of coadministered drugs., Immune reconstitution syndrome., Bone loss: Consider monitoring bone density. |
| Food/Dietary | Atazanavir should be taken with food to enhance absorption. Avoid concomitant administration with proton pump inhibitors (PPIs), as they significantly reduce atazanavir plasma concentrations. If antacids are needed, separate by at least 2 hours. Ritonavir, lamivudine, and zidovudine have no significant food restrictions, but consistent administration with or without food is advised. |
| Clinical Pearls | Atazanavir sulfate is boosted with ritonavir to enhance its pharmacokinetic profile. This combination is part of a multi-drug regimen for HIV-1 infection. Monitor for hyperbilirubinemia (especially with atazanavir), renal impairment (lamivudine/zidovudine requires dose adjustment in CrCl <50 mL/min), and hematologic toxicity (zidovudine may cause anemia/neutropenia). Avoid coadministration with proton pump inhibitors (reduce atazanavir absorption) and drugs that prolong QT interval. Atazanavir should be taken with food to improve bioavailability. |
| Patient Advice | Take this combination exactly as prescribed; do not miss doses or stop without consulting your doctor. · Take atazanavir with food (to increase absorption). Ritonavir can be taken with or without food. · This medication does not cure HIV; it helps control the virus. You can still transmit HIV to others. · Report any signs of liver problems (yellowing skin/eyes, dark urine) or severe rash immediately. · Regular blood tests are needed to monitor for side effects, including jaundice, anemia, and kidney function. · Inform your doctor about all other medications, including antacids, proton pump inhibitors, or St. John’s wort. · If you have kidney issues, your dose may need adjustment; do not change your dose on your own. |