LAMIVUDINE; ZIDOVUDINE; NEVIRAPINE
Clinical safety rating: safe
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and myopathy.
Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) that inhibits HIV-1 and HBV reverse transcriptase. Zidovudine is also an NRTI that inhibits HIV-1 reverse transcriptase. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that directly binds to HIV-1 reverse transcriptase and inhibits RNA-dependent and DNA-dependent DNA polymerase activities. The combination inhibits HIV replication.
| Metabolism | Lamivudine is primarily eliminated unchanged in urine via active renal secretion; minor hepatic metabolism. Zidovudine is metabolized via glucuronidation (UGT2B7) to inactive metabolites; also undergoes phosphorylation to active triphosphate. Nevirapine is extensively metabolized by cytochrome P450 (CYP3A4, CYP2B6); induces its own metabolism. |
| Excretion | Lamivudine: ~70% unchanged in urine via glomerular filtration and active tubular secretion; Zidovudine: ~75% metabolized to inactive glucuronide (G-ZDV), ~20% excreted unchanged in urine; Nevirapine: ~80% metabolized by CYP3A4/2B6, ~10% unchanged in urine, ~1% in feces. |
| Half-life | Lamivudine: 5-7 hours in adults, prolonged in renal impairment; Zidovudine: 0.5-3 hours, prolonged in hepatic impairment; Nevirapine: 25-30 hours (single dose), 40-45 hours after multiple doses due to autoinduction. |
| Protein binding | Lamivudine: <36% bound to plasma albumin; Zidovudine: 30-38% bound; Nevirapine: 60% bound, primarily to albumin. |
| Volume of Distribution | Lamivudine: 1.3 L/kg (distributes widely including CSF); Zidovudine: 1.6-2.0 L/kg (crosses blood-brain barrier); Nevirapine: 1.2-1.5 L/kg (distributes freely, including CNS). |
| Bioavailability | Lamivudine: 86-88% oral; Zidovudine: 60-70% oral; Nevirapine: >90% oral. |
| Onset of Action | Oral: Lamivudine and Zidovudine achieve maximum plasma concentrations within 0.5-2 hours; Nevirapine reaches peak at 4 hours. Antiviral effects start within days; clinical benefit in HIV typically 2-4 weeks. |
| Duration of Action | Lamivudine: Dosing interval 12 hours (half-life 5-7h); Zidovudine: Dosing interval 12 hours (half-life <3h); Nevirapine: Dosing interval 12 hours (half-life 25-45h). Continuous suppression requires strict adherence. |
| Molecular Weight | Lamivudine: 229.26 Da; Zidovudine: 267.24 Da; Nevirapine: 266.30 Da |
One tablet (150 mg lamivudine, 300 mg zidovudine, 200 mg nevirapine) orally twice daily.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if CrCl < 50 mL/min: lamivudine requires dose reduction (not fixed-dose combination). For CrCl 30-49 mL/min: not recommended due to fixed combination. If unavoidable, use individual components with adjusted lamivudine dose (150 mg once daily) and zidovudine (300 mg once or twice daily depending on CrCl). Nevirapine no adjustment required. |
| Liver impairment | Child-Pugh A: no adjustment for lamivudine and zidovudine; nevirapine contraindicated if moderate to severe hepatic impairment. Child-Pugh B or C: contraindicated due to nevirapine (avoid) and potential for zidovudine accumulation; use individual components with caution. |
| Pediatric use | Weight-based dosing: For children ≥14 kg and able to swallow tablets: one tablet (150/300/200 mg) twice daily. For weight 14-21 kg: consider alternative formulations (e.g., lamivudine/zidovudine solution plus nevirapine suspension) due to fixed-dose tablet strength. Dose lamivudine 4 mg/kg twice daily (max 150 mg), zidovudine 240 mg/m² twice daily (max 300 mg), nevirapine 4-7 mg/kg twice daily (max 200 mg) for 2 weeks then 7 mg/kg twice daily (max 200 mg) if weight-based. Refer to specific guidelines for pediatric antiretroviral therapy. |
| Geriatric use |
| 1st trimester | Use with caution; limited data suggest no increase in major malformations, but consider risk-benefit. Monitor for hepatotoxicity and mitochondrial toxicity. |
| 2nd trimester | Safe for use; treatment of HIV recommended to prevent vertical transmission. Monitor for maternal hepatotoxicity. |
| 3rd trimester | Safe for use; continuation recommended to prevent perinatal transmission. Monitor for neonatal anemia and neutropenia. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and myopathy.
| FDA category | Human |
| Placental transfer | All three drugs cross the placenta. Zidovudine and lamivudine achieve cord blood concentrations similar to maternal. Nevirapine achieves higher cord blood concentrations due to long half-life. |
■ FDA Black Box Warning
Hepatotoxicity: Severe, life-threatening hepatotoxicity, including fulminant hepatitis and hepatic failure, reported in patients taking nevirapine. Women with CD4+ counts >250 cells/mm³ and men with CD4+ counts >400 cells/mm³ are at higher risk. Monitor liver function closely. Discontinue permanently if severe hepatotoxicity occurs. Also, severe, life-threatening skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) requiring discontinuation.
| Common Effects | Anemia |
| Serious Effects |
Hypersensitivity to any componentBody weight < 40 kg (for fixed-dose combination due to zidovudine dosing)Severe hepatic impairment (Child-Pugh C) due to nevirapineHistory of severe rash or Stevens-Johnson syndrome with nevirapine
| Precautions | Hematologic toxicity (neutropenia, anemia) with zidovudine; monitor CBC. Lactic acidosis and severe hepatomegaly with steatosis (NRTIs). Pancreatitis (especially in children). Immune reconstitution syndrome. Drug interactions (CYP inducers/inhibitors with nevirapine). Nevirapine hypersensitivity reactions; discontinue if rash with systemic symptoms. Severe hepatotoxicity; avoid use in women with CD4 >250 and men with CD4 >400 unless benefit outweighs risk. Monitor liver enzymes closely. Do not restart nevirapine after severe hepatic or skin reactions. |
Loading safety data…
| Caution due to age-related renal decline (CrCl may be <50 mL/min necessitating avoidance of fixed combination), hepatic function changes, and increased sensitivity to hematologic toxicity (zidovudine). Monitor renal function, hemoglobin, and neutrophil counts. No specific dose adjustments; use lowest effective doses of individual components if needed. |
| Breastfeeding |
| Lamivudine and zidovudine are excreted into breast milk in low concentrations; nevirapine is excreted in moderate amounts. In high-resource settings, breastfeeding is not recommended due to risk of HIV transmission. In low-resource settings, WHO recommends breastfeeding with maternal ART. |
| Lactation Rating | L4 (Possibly Hazardous) in high-resource settings due to HIV transmission risk; L2 (Safer) in low-resource settings when maternal ART is used. |
| Teratogenic Risk | First trimester: Zidovudine and lamivudine are not associated with increased risk of major malformations. Nevirapine carries a risk of severe hepatotoxicity and Stevens-Johnson syndrome, but no known teratogenic effects. Second and third trimesters: No evidence of fetal harm; combination antiretroviral therapy recommended for prevention of vertical transmission. |
| Fetal Monitoring | Monitor maternal hepatic function (AST, ALT) monthly due to nevirapine hepatotoxicity; rash monitoring for Stevens-Johnson syndrome; fetal ultrasound for growth and anomaly screening; maternal complete blood count (zidovudine may cause anemia); viral load at regular intervals. |
| Fertility Effects | No known adverse effects on fertility based on animal studies and clinical data. Antiretroviral therapy may improve fertility in HIV-infected individuals by improving overall health. |
| Food/Dietary | Take with or without food; no significant food interactions. |
| Clinical Pearls | Fixed-dose combination for HIV-1; do not use as monotherapy; contraindicated in moderate-to-severe hepatic impairment; monitor for severe hepatotoxicity and skin reactions (e.g., Stevens-Johnson syndrome) especially in women with CD4 >250 cells/μL; assess LFTs at baseline and frequently; if treatment is interrupted for >7 days, restart with lead-in dose of nevirapine 200 mg daily for 14 days; avoid in patients requiring dose adjustment due to renal impairment (CrCl <50 mL/min). |
| Patient Advice | Take exactly as prescribed; do not miss doses. · Report any signs of liver problems (dark urine, yellowing of eyes/skin, abdominal pain) or severe skin rash immediately. · Use barrier contraception to prevent transmission of HIV to others. · Avoid breastfeeding; HIV can be transmitted via breast milk. · Do not discontinue without consulting your doctor; restarting may require a lead-in dose. |