STAVUDINE; LAMIVUDINE; 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 analog reverse transcriptase inhibitor (NRTI) that inhibits HIV reverse transcriptase. Lamivudine is an NRTI that inhibits HIV reverse transcriptase. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to HIV reverse transcriptase, causing enzyme inhibition.
| Metabolism | Stavudine: Intracellular phosphorylation to active triphosphate; undergoes hepatic metabolism via glucuronidation (approximately 40% excreted unchanged in urine). Lamivudine: Intracellular phosphorylation to active triphosphate; undergoes renal excretion (70% unchanged). Nevirapine: Primarily metabolized by CYP3A4 and CYP2B6 to hydroxy metabolites, which are glucuronidated and excreted renally. |
| Excretion | Stavudine: Renal (approximately 60% unchanged) and hepatic metabolism. Lamivudine: Renal (approximately 70% unchanged) via glomerular filtration and active tubular secretion. Nevirapine: Hepatic metabolism (CYP3A4, CYP2B6) followed by renal excretion of metabolites (about 80% in urine, 10% in feces). |
| Half-life | Stavudine: 1.0-1.6 hours (mean ~1.5 h) in adults with normal renal function; prolonged in renal impairment. Lamivudine: 5-7 hours in adults; prolonged in renal impairment. Nevirapine: 25-30 hours (single dose); 40-45 hours with multiple dosing due to autoinduction. |
| Protein binding | Stavudine: <5% bound to plasma proteins. Lamivudine: <36% bound to plasma albumin. Nevirapine: Approximately 60% bound to plasma albumin. |
| Volume of Distribution | Stavudine: 0.5-1.0 L/kg; distributes into total body water. Lamivudine: 1.3-1.5 L/kg; extensive distribution into tissues, including CNS (CSF/plasma ratio ~0.12). Nevirapine: 1.2-1.4 L/kg; wide distribution including CSF (approximately 45% of plasma concentration). |
| Bioavailability | Stavudine: Oral bioavailability >80%. Lamivudine: Oral bioavailability 80-85%. Nevirapine: Oral bioavailability >90%. |
| Onset of Action | Oral administration: Stavudine and Lamivudine: Peak plasma concentrations in 1-1.5 hours; antiviral effect begins within hours. Nevirapine: Peak in 4 hours; onset of antiviral effect within 24-48 hours. |
| Duration of Action | Stavudine: Dosing interval of 12 hours; maintains therapeutic levels for ~12 hours. Lamivudine: Dosing interval of 12 hours; maintains efficacy for 12-24 hours. Nevirapine: Dosing interval of 12 hours after induction; sustained effect due to long half-life. |
One tablet (stavudine 30 mg + lamivudine 150 mg + nevirapine 200 mg) orally twice daily. For patients weighing ≥60 kg, stavudine 40 mg may be used; however, due to toxicity, 30 mg is preferred. Nevirapine requires a 14-day lead-in dose of 200 mg once daily.
| Dosage form | TABLET |
| Renal impairment | If CrCl 26-50 mL/min: administer stavudine 15 mg + lamivudine 150 mg + nevirapine 200 mg every 24 hours. If CrCl <26 mL/min: stavudine and lamivudine are not recommended; nevirapine dosing adjustment not established (consider alternative regimen). |
| Liver impairment | Contraindicated in Child-Pugh class B or C due to nevirapine hepatotoxicity. In Child-Pugh class A: no dose adjustment necessary, but monitor closely. |
| Pediatric use | Weight-based dosing for oral solution: stavudine 1 mg/kg, lamivudine 4 mg/kg, nevirapine 7 mg/kg (lead-in: 4 mg/kg once daily for 14 days) every 12 hours. Maximum doses: stavudine 30 mg/dose, lamivudine 150 mg/dose, nevirapine 200 mg/dose. For children ≥8 years or ≥30 kg, use adult fixed-dose combination tablets adjusted for weight. |
| Geriatric use | No specific dose adjustments solely based on age; however, monitor renal function closely and adjust stavudine and lamivudine doses per CrCl. Elderly are more susceptible to peripheral neuropathy and hepatotoxicity. |
| 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 | Breastfeeding not recommended (HIV transmission risk). Lamivudine excreted into breast milk (M/P ratio ~1.7). Stavudine and nevirapine also present. Avoid breastfeeding. |
| Teratogenic Risk | Stavudine: Crosses placenta; animal studies show embryotoxicity, but human data insufficient. Lamivudine: Low risk; increased early pregnancy loss in animals, not confirmed in humans. Nevirapine: Avoid in first trimester; associated with severe hepatotoxicity and rash; use only if benefit outweighs risk. Overall: Use only if clearly needed in pregnancy; no major human teratogenicity consistently documented. |
■ FDA Black Box Warning
Hepatotoxicity: Severe, life-threatening hepatotoxicity, including fatal hepatic events, has been reported. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs. Nevirapine-based therapy should not be initiated in women with CD4+ cell counts >250 cells/mm³ or men with CD4+ cell counts >400 cells/mm³ unless benefit outweighs risk due to increased risk of symptomatic hepatic events.
| Common Effects | Peripheral neuropathy |
| Serious Effects |
History of clinically significant hypersensitivity to any component; patients with moderate to severe hepatic impairment (Child-Pugh Class B or C); females with CD4+ cell counts >250 cells/mm³ or males with CD4+ cell counts >400 cells/mm³ (nevirapine initiation); coadministration with St. John's wort or rifampin (nevirapine).
| Precautions | Lactic acidosis/severe hepatomegaly with steatosis; hepatotoxicity including hepatic events; severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis); immune reconstitution syndrome; pancreatitis (associated with stavudine); peripheral neuropathy (stavudine); lipodystrophy; monitoring of hepatic enzymes and CD4 count. |
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| Fetal Monitoring | Monitor maternal liver function (ALT, AST) and skin (nevirapine rash). Fetal ultrasound for growth. Maternal HIV viral load and CD4 count regularly. |
| Fertility Effects | No known significant effects on fertility in humans. Animal studies show no impairment. |