STAVUDINE; LAMIVUDINE W/NEVIRAPINE
Clinical safety rating: safe
Other drugs that cause peripheral neuropathy or pancreatitis increase risk Can cause peripheral neuropathy and pancreatitis.
Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) that inhibits HIV-1 reverse transcriptase by competing with the natural substrate thymidine triphosphate and by causing DNA chain termination after incorporation. Lamivudine is an NRTI that inhibits HIV-1 reverse transcriptase via similar mechanisms. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds directly to reverse transcriptase and blocks RNA-dependent and DNA-dependent DNA polymerase activities.
| Metabolism | Stavudine is phosphorylated intracellularly to its active triphosphate metabolite. It is not significantly metabolized by hepatic cytochrome P450 enzymes. Lamivudine is phosphorylated intracellularly to its active triphosphate metabolite and undergoes limited hepatic metabolism (about 5-10%) via glucuronidation. Nevirapine is extensively metabolized by the liver via cytochrome P450 (CYP3A4 and CYP2B6) to several hydroxylated metabolites. |
| Excretion | Stavudine: 50% excreted unchanged in urine via glomerular filtration and active tubular secretion; lamivudine: ~70% excreted unchanged in urine via active secretion; nevirapine: ~80% metabolized by liver, with <5% excreted unchanged in urine (metabolites eliminated renally and fecally). |
| Half-life | Stavudine: 0.9–1.6 h (normal renal function), prolonged in renal impairment; lamivudine: 5–7 h (adults), 2–4 h (children); nevirapine: 25–30 h (terminal, after multiple doses), allowing once-daily dosing. |
| Protein binding | Stavudine: negligible (<5%); lamivudine: <36% (minimal); nevirapine: ~60% (primarily albumin). |
| Volume of Distribution | Stavudine: 0.5–0.6 L/kg, suggesting good tissue penetration; lamivudine: 1.0–1.3 L/kg, indicating extensive distribution; nevirapine: 1.4 L/kg, reflecting wide distribution including CNS. |
| Bioavailability | Stavudine: >80% (oral capsules, solution); lamivudine: 86–88% (oral tablets, solution); nevirapine: >90% (oral tablets). |
| Onset of Action | Oral: Stavudine and lamivudine achieve peak plasma concentrations in 1–1.5 h; nevirapine reaches peak in 4 h. Antiviral effect begins within hours, with maximal suppression over days. |
| Duration of Action | Stavudine and lamivudine: 8–12 h due to intracellular phosphorylation (active triphosphates with longer half-lives ~3.5 and 10.5–15.5 h, respectively); nevirapine: ~24 h, supporting once-daily dosing. Clinical duration: continuous daily therapy required for viral suppression. |
One tablet (stavudine 30 mg / lamivudine 150 mg / nevirapine 200 mg) orally twice daily.
| Dosage form | TABLET |
| Renal impairment | If CrCl 26-50 mL/min: stavudine 15 mg + lamivudine 150 mg + nevirapine 200 mg every 12 hours. If CrCl 15-25 mL/min: stavudine 15 mg + lamivudine 150 mg + nevirapine 200 mg every 24 hours. If CrCl <15 mL/min or on hemodialysis: not recommended. |
| Liver impairment | Child-Pugh class B or C: avoid nevirapine; other components may require adjustment per individual prescribing information. |
| Pediatric use | Weight-based dosing: For weight 10-14 kg: stavudine 15 mg + lamivudine 7.5 mg + nevirapine 100 mg twice daily; For weight 15-20 kg: stavudine 20 mg + lamivudine 10 mg + nevirapine 100 mg twice daily; For weight 21-25 kg: stavudine 20 mg + lamivudine 15 mg + nevirapine 100 mg twice daily; For weight 26-30 kg: stavudine 30 mg + lamivudine 15 mg + nevirapine 100 mg twice daily. Administer with food. |
| Geriatric use | No specific dose adjustment recommended; use with caution due to age-related renal impairment and potential for increased toxicity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other drugs that cause peripheral neuropathy or pancreatitis increase risk Can cause peripheral neuropathy and pancreatitis.
| FDA category | Animal |
| Breastfeeding | All three drugs are excreted into human breast milk. The milk-to-plasma (M/P) ratio for stavudine is approximately 0.5–1.0; for lamivudine, 0.6–1.5; for nevirapine, 1.0–1.5. Breastfeeding is not recommended due to the potential for adverse effects in the nursing infant and the risk of HIV transmission. WHO advises avoidance of breastfeeding if formula is available. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine, lamivudine, and other antiretrovirals. Fatal and non-fatal pancreatitis has occurred with stavudine in combination with didanosine, with or without hydroxyurea. Severe, life-threatening, and fatal hepatotoxicity, particularly in women, has been reported with nevirapine, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure. Severe, life-threatening skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions, have occurred with nevirapine.
| Common Effects | Peripheral neuropathy |
| Serious Effects |
["Hypersensitivity to stavudine, lamivudine, or nevirapine","Coadministration with dofetilide or rilpivirine (due to nevirapine)","Coadministration with drugs that are highly dependent on CYP3A4 for clearance (nevirapine)","Severe hepatic impairment (Child-Pugh Class B or C) for nevirapine","Concurrent use with other NNRTIs"]
| Precautions |
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| Stavudine, lamivudine, and nevirapine are classified as FDA Pregnancy Category C. Nevirapine crosses the placenta with cord blood concentrations approximately 100% of maternal levels. Stavudine and lamivudine also cross the placenta. There is no evidence of major human teratogenicity based on Antiretroviral Pregnancy Registry data, except a possible association between first-trimester nevirapine exposure and rash with hepatic toxicity. Second and third trimester risks include potential for mitochondrial toxicity, lactic acidosis, and hepatotoxicity in the fetus and neonate. |
| Fetal Monitoring | Monitor maternal liver function tests (AST, ALT) and bilirubin frequently due to nevirapine hepatotoxicity, especially in the first 18 weeks. Monitor for maternal lactic acidosis and hepatic steatosis with stavudine. Fetal growth ultrasound and assessment for mitochondrial toxicity symptoms in the newborn. Perform neonatal blood glucose and hepatic panels. Monitor maternal complete blood count and renal function. |
| Fertility Effects | No significant adverse effects on fertility have been reported in human studies. Animal studies with stavudine and lamivudine showed no impairment of fertility. Nevirapine did not affect fertility in animal models. However, HIV infection itself may reduce fertility; ART generally improves reproductive outcomes. |
| ["Lactic acidosis and severe hepatomegaly with steatosis","Pancreatitis (especially with stavudine and didanosine combination)","Hepatotoxicity and hepatic failure (nevirapine)","Severe skin reactions including SJS/TEN (nevirapine)","Hematologic toxicity (neutropenia, anemia)","Peripheral neuropathy (stavudine)","Immune reconstitution syndrome","Lipodystrophy","Exacerbation of hepatitis B after discontinuation of lamivudine","Drug interactions (nevirapine induces CYP3A4, reducing levels of coadministered drugs)"] |