EFAVIRENZ; LAMIVUDINE; TENOFOVIR DISOPROXIL FUMARATE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to reverse transcriptase and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) that inhibits HIV reverse transcriptase via DNA chain termination. Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor (NtRTI) that competes with natural substrates and causes DNA chain termination after phosphorylation to tenofovir diphosphate.
| Metabolism | Efavirenz is primarily metabolized by CYP2B6 and to a lesser extent by CYP3A4. Lamivudine is not significantly metabolized and is eliminated renally as unchanged drug. Tenofovir disoproxil fumarate is hydrolyzed to tenofovir, which is then phosphorylated to tenofovir diphosphate; tenofovir is eliminated renally by glomerular filtration and active tubular secretion. |
| Excretion | Efavirenz: 14-34% unchanged in urine, 16-61% as metabolites in feces; Lamivudine: ~70% unchanged in urine via glomerular filtration and active tubular secretion; Tenofovir disoproxil fumarate: 70-80% unchanged in urine via glomerular filtration and active tubular secretion. |
| Half-life | Efavirenz: 40-55 hours (single dose), 52-76 hours (multiple doses); Lamivudine: 5-7 hours; Tenofovir: 12-18 hours (prolonged to 24-30 hours when co-administered with efavirenz). |
| Protein binding | Efavirenz: 99.5-99.75% bound to albumin; Lamivudine: <36% bound to serum proteins; Tenofovir: <7% bound to proteins. |
| Volume of Distribution | Efavirenz: 2.5-4 L/kg; Lamivudine: 1.3 L/kg; Tenofovir: 0.8-1.2 L/kg. High Vd indicates extensive tissue penetration. |
| Bioavailability | Efavirenz: 40-45% (oral); Lamivudine: 86% (oral) in adults, higher in children; Tenofovir disoproxil fumarate: 25-40% under fasting conditions (increased with high-fat meal). |
| Onset of Action | Oral: Efavirenz reaches peak plasma concentration in 3-5 hours; Lamivudine: 0.5-1 hour; Tenofovir: 1-2 hours. Antiviral effect begins within days, maximal suppression by 4-6 weeks. |
| Duration of Action | Efavirenz: 24-48 hours due to long half-life; Lamivudine: ~8-12 hours; Tenofovir: >24 hours. Dosing interval for fixed-dose combination is once daily. |
One tablet (efavirenz 600 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg) orally once daily on an empty stomach (preferably at bedtime to reduce CNS side effects).
| Dosage form | TABLET |
| Renal impairment | Not recommended for CrCl <50 mL/min. For CrCl 30-49 mL/min: use individual components with dose adjustment (e.g., lamivudine 150 mg daily, tenofovir 300 mg every 48 hours, efavirenz 600 mg daily). For CrCl <30 mL/min: contraindicated (tenofovir and lamivudine require significant reduction). |
| Liver impairment | Contraindicated in Child-Pugh class C. For Child-Pugh class A or B: limited data; efavirenz may be used with caution (consider lower dose if intolerant), but lamivudine and tenofovir dose adjustment not typically required unless severe hepatic impairment. Monitor LFTs. |
| Pediatric use | Approved for patients weighing ≥40 kg: one tablet (efavirenz 600 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg) orally once daily on empty stomach. For weight 25-40 kg: use individual components (efavirenz 400-600 mg once daily, lamivudine 150-300 mg once daily, tenofovir 150-300 mg once daily based on weight). Not recommended for <25 kg. |
| Geriatric use | No specific dose adjustment; monitor renal function (CrCl) and bone mineral density. Increased risk of renal toxicity and bone loss with tenofovir, and CNS effects with efavirenz. Use with caution if multiple comorbidities or polypharmacy. |
| 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 | M/P ratio unknown; breastfed infants may be exposed to subtherapeutic levels. Lamivudine and tenofovir are excreted in human milk; efavirenz is excreted with infant dose <1% of therapeutic dose. Avoid breastfeeding due to potential HIV transmission and unknown long-term effects. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: HEPATOTOXICITY, POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B, and TERATOGENICITY. Severe acute exacerbation of hepatitis B has been reported in patients who are co-infected with hepatitis B virus (HBV) and discontinue lamivudine or tenofovir disoproxil fumarate. Efavirenz can cause teratogenic effects; avoid use during first trimester of pregnancy.
| Common Effects | Hepatitis B |
| Serious Effects |
["Hypersensitivity to any component","Co-administration with drugs that are highly dependent on CYP3A4 for clearance (e.g., ergot derivatives, midazolam, triazolam, pimozide, cisapride, voriconazole)","Co-administration with elbasvir/grazoprevir due to risk of ALT elevations","Severe hepatic impairment (Child-Pugh Class C)","Breastfeeding (due to potential adverse effects in infants)"]
| Precautions | ["Hepatotoxicity: Monitor hepatic function; discontinue if evidence of hepatotoxicity.","Exacerbation of hepatitis B: Monitor HBV-infected patients for several months after discontinuation.","Teratogenicity: Avoid use in pregnancy, especially first trimester.","Lactic acidosis and severe hepatomegaly with steatosis: Reported with NRTIs.","Renal impairment: Monitor renal function; adjust dose or avoid with creatinine clearance <30 mL/min.","Bone effects: Decreased bone mineral density reported with tenofovir; monitor in patients with risk factors.","Immune reconstitution syndrome: May occur during initial treatment.","CNS effects: Efavirenz may cause dizziness, impaired concentration, and abnormal dreams; avoid driving.","Lipid increases: Monitor lipid levels.","QT prolongation: Caution with drugs that prolong QT interval.","Seizures: Use caution in patients with history of seizures."] |
Loading safety data…
| Efavirenz is contraindicated in pregnancy (first trimester) due to neural tube defects; lamivudine and tenofovir disoproxil fumarate have low teratogenic risk. Risk summary: First trimester – efavirenz associated with CNS defects (risk ratio 2.3); second/third trimester – low risk for lamivudine and tenofovir; combination use requires careful risk-benefit assessment. |
| Fetal Monitoring | Maternal: HIV viral load, CD4 count, liver function tests, renal function (creatinine, BUN), complete blood count; fetal: ultrasound for neural tube defects if efavirenz used in first trimester (consider alternative ART). Monitor for anemia, neutropenia, hepatotoxicity. |
| Fertility Effects | No known significant impact on fertility. Efavirenz may cause dizziness, which could affect sexual activity; no direct effects on spermatogenesis or oocyte development reported. Lamivudine and tenofovir are not associated with fertility impairment. |