LAMIVUDINE; TENOFOVIR DISOPROXIL FUMARATE; NEVIRAPINE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) that inhibits HIV-1 reverse transcriptase via DNA chain termination after intracellular phosphorylation to lamivudine triphosphate. Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor (NtRTI) that, after hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase by competing with deoxyadenosine 5'-triphosphate and causing DNA chain termination. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that directly binds to and inhibits HIV-1 reverse transcriptase, causing a conformational change and reducing enzyme activity.
| Metabolism | Lamivudine undergoes minimal hepatic metabolism (primarily unchanged). Tenofovir disoproxil fumarate is hydrolyzed to tenofovir, which is then phosphorylated intracellularly; unchanged tenofovir is eliminated renally. Nevirapine is extensively metabolized by CYP3A4 and CYP2B6 to several hydroxylated metabolites. |
| Excretion | Lamivudine: 70% renal (glomerular filtration and tubular secretion) as unchanged drug. Tenofovir: 70-80% renal (glomerular filtration and tubular secretion) as unchanged drug. Nevirapine: ~81% renal (metabolites, <5% unchanged), ~10% fecal. |
| Half-life | Lamivudine: 5-7 hours in adults (extended to 20-30 hours in renal impairment). Tenofovir: 17-18 hours in adults (prolonged in renal impairment). Nevirapine: ~45 hours (single dose) to 25-30 hours (multiple doses due to autoinduction). |
| Protein binding | Lamivudine: <36% (serum albumin). Tenofovir: <7% (serum proteins). Nevirapine: ~60% (albumin). |
| Volume of Distribution | Lamivudine: 1.3 L/kg (extensive tissue distribution including CNS). Tenofovir: 0.8-1.2 L/kg (distribution into tissues, not highly bound). Nevirapine: 1.2 L/kg (extensive distribution, crosses placenta and breast milk). |
| Bioavailability | Lamivudine: 86% (oral). Tenofovir disoproxil fumarate: 25-39% (oral, increased with high-fat meal). Nevirapine: >90% (oral). |
| Onset of Action | Oral: Antiviral effect begins within hours; clinical delay due to pharmacokinetic and pharmacodynamic distribution. |
| Duration of Action | Dosing interval: Lamivudine and tenofovir (fixed-dose) and nevirapine (extended-release formulations) maintain therapeutic levels over 24 hours; nevirapine's long half-life allows once-daily dosing. |
One tablet (300 mg lamivudine, 300 mg tenofovir disoproxil fumarate, 400 mg nevirapine) orally once daily. Nevirapine requires a 14-day lead-in dose of 200 mg once daily when initiating therapy.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if creatinine clearance (CrCl) < 30 mL/min. No dose adjustment required for CrCl ≥ 50 mL/min. For CrCl 30-49 mL/min: extend dosing interval to every 48 hours. Not recommended for CrCl < 30 mL/min or hemodialysis. |
| Liver impairment | Contraindicated in Child-Pugh class B or C (moderate to severe hepatic impairment). Use with caution in Child-Pugh class A; nevirapine should not be used in patients with moderate to severe hepatic impairment due to risk of hepatotoxicity. |
| Pediatric use | Recommended for adolescents ≥ 35 kg only (adult dosing): 1 tablet orally once daily. Not approved for children < 35 kg or < 12 years due to fixed-dose combination. |
| Geriatric use | Select dose with caution due to higher frequency of decreased renal function; monitor renal function (CrCl) and adjust accordingly. Consider alternative antiretroviral regimens in elderly with renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Breastfeeding | Lamivudine and nevirapine are excreted into breast milk in clinically significant amounts (M/P ratio: lamivudine ~3.3, nevirapine ~0.6-1.0). Tenofovir is poorly excreted (M/P ratio ~0.17). In HIV-infected mothers, breastfeeding is contraindicated due to risk of HIV transmission, regardless of antiretroviral therapy. |
| Teratogenic Risk |
■ FDA Black Box Warning
Severe, life-threatening hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine. Severe, life-threatening skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions (e.g., drug reaction with eosinophilia and systemic symptoms [DRESS]), have occurred. Patients developing signs or symptoms of hepatitis, severe skin reactions, or hypersensitivity must permanently discontinue nevirapine. Female gender, higher CD4+ count, and higher viral load are risk factors for hepatotoxicity.
| Common Effects | Hepatitis B |
| Serious Effects |
["Hypersensitivity to any component of the product","Moderate to severe hepatic impairment (Child-Pugh class B or C) for nevirapine-containing regimens","Concomitant use with rifampin, St. John's wort, or other drugs that significantly reduce nevirapine levels","Concomitant use with other NRTIs (e.g., emtricitabine) unless dose adjustment is appropriate","Severe renal impairment (CrCl <30 mL/min) for tenofovir-containing products (unless dose adjusted)"]
| Precautions |
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| Lamivudine and tenofovir disoproxil fumarate (TDF) are FDA Pregnancy Category B. Nevirapine is FDA Pregnancy Category C. Animal studies show no evidence of teratogenicity for lamivudine or TDF at exposures similar to human. Nevirapine crosses placenta and has been associated with rash and hepatotoxicity in pregnant women; no increased risk of birth defects beyond background in human studies. First trimester: no known major teratogenic risk. Second and third trimesters: monitor for maternal hepatotoxicity with nevirapine, especially if CD4 >250 cells/mm3. Overall, benefits of preventing mother-to-child transmission of HIV outweigh risks. |
| Fetal Monitoring | Maternal: baseline and periodic liver function tests (ALT, bilirubin) due to nevirapine hepatotoxicity; serum creatinine and urinalysis for tenofovir nephrotoxicity; CBC with differential; viral load and CD4 count; blood pressure and glucose. Fetal: ultrasound for growth and anatomy, especially if tenofovir exposure (low risk of fetal growth restriction); consider neonatal bone density assessment if TDF used. |
| Fertility Effects | No significant adverse effects on male or female fertility reported for lamivudine, TDF, or nevirapine in animal or human studies. HIV infection itself may affect fertility. No evidence of permanent impairment. |
| ["Hepatotoxicity: Monitor liver function tests; discontinue if severe hepatic injury occurs.","Severe skin reactions: Teach patients to recognize and report rash; discontinue if signs of Stevens-Johnson syndrome or hypersensitivity develop.","Immune reconstitution syndrome: May occur during initial treatment.","Lactic acidosis/severe hepatomegaly with steatosis: Rare but potentially fatal mitochondrial toxicity (NRTIs).","Renal impairment: Tenofovir can cause renal toxicity; monitor creatinine and urinary abnormalities.","Bone effects: Tenofovir has been associated with decreased bone mineral density.","Lipodystrophy: Redistribution/accumulation of body fat."] |