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. |
| Molecular Weight | Lamivudine: 229.26 Da; Tenofovir disoproxil fumarate: 635.51 Da (tenofovir: 287.22 Da); Nevirapine: 266.30 Da |
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 | Lamivudine, tenofovir disoproxil fumarate, and nevirapine are used in combination for HIV treatment during pregnancy. Lamivudine and tenofovir are generally considered safe; nevirapine is associated with hepatotoxicity and severe rash, especially in women with CD4 >250 cells/μL, but benefits may outweigh risks. |
| 2nd trimester | Use with caution; monitor for nevirapine-induced toxicity. All three drugs cross the placenta. Data do not show major teratogenicity. |
| 3rd trimester | Safe for prevention of mother-to-child transmission. Lamivudine and tenofovir are preferred; nevirapine may be used if benefits outweigh risks. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer | All three drugs cross the placenta. Lamivudine achieves cord blood concentrations similar to maternal serum; tenofovir has moderate transfer (cord-to-maternal ratio ~0.6-1.0); nevirapine readily crosses (cord-to-maternal ratio ~0.7-1.0). |
■ 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 |
Concomitant use with other antiretrovirals containing lamivudine, tenofovir, or nevirapine without dose adjustmentSevere hepatic impairment (Child-Pugh class C) for nevirapine-containing regimensHypersensitivity to any componentBreastfeeding in HIV-infected women where formula is available and safe
| Precautions | 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. |
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| Breastfeeding | Lamivudine and tenofovir are excreted into breast milk at low concentrations; nevirapine is also present. In HIV-infected women, breastfeeding is contraindicated in developed countries due to risk of transmission; in resource-limited settings, WHO recommends exclusive breastfeeding with maternal ART. Monitor infant for adverse effects. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | 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. |
| Food/Dietary | Can be taken with or without food. High-fat meals may increase absorption of tenofovir and nevirapine but no significant clinical impact. Avoid grapefruit juice with nevirapine due to potential CYP3A4 interaction. No specific dietary restrictions. |
| Clinical Pearls | Fixed-dose combination for HIV-1. Nevirapine can cause severe hepatotoxicity and rash; avoid in women with CD4 >250 cells/mm³ and men with CD4 >400 cells/mm³. Tenofovir DF may cause renal impairment; monitor eGFR and urine glucose. Lamivudine has minimal toxicity. Do not restart after nevirapine discontinuation due to hypersensitivity risk. |
| Patient Advice | Take this medication exactly as prescribed, at the same time each day. · Do not miss doses; if a dose is missed, take it as soon as remembered unless it's almost time for the next dose. · Report any skin rash, especially if accompanied by fever, blisters, or mouth sores, immediately. · Watch for signs of liver problems: dark urine, light stools, yellowing of skin or eyes, abdominal pain. · This medication does not cure HIV or prevent transmission; use barrier protection. · Avoid alcohol and other drugs that may stress the liver. · Stay hydrated; tenofovir can affect kidney function. · Do not change dose or stop without consulting your doctor. |