EFAVIRENZ, LAMIVUDINE AND 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: Non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to HIV-1 reverse transcriptase, causing allosteric inhibition and blocking RNA-dependent DNA polymerase activity. LAMIVUDINE: Nucleoside reverse transcriptase inhibitor (NRTI) that is phosphorylated to its active triphosphate metabolite, which competes with endogenous deoxycytidine triphosphate for incorporation into viral DNA, causing chain termination. TENOFOVIR DISOPROXIL FUMARATE: Prodrug of tenofovir, an NRTI that, after hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase by competing with deoxyadenosine triphosphate and causing DNA chain termination.
| Metabolism | EFAVIRENZ: Primarily metabolized by CYP2B6 and CYP3A4 to inactive hydroxylated metabolites. LAMIVUDINE: Minimally metabolized; intracellularly phosphorylated to active triphosphate. TENOFOVIR DISOPROXIL FUMARATE: Rapidly converted to tenofovir via esterases in plasma, then to tenofovir diphosphate intracellularly. Tenofovir is renally excreted by glomerular filtration and active tubular secretion. |
| Excretion | Efavirenz: 14-34% renal (mostly metabolites), 16-61% fecal (parent drug and metabolites). Lamivudine: ~70% renal (unchanged via active tubular secretion). Tenofovir disoproxil fumarate: 70-80% renal (unchanged as tenofovir via glomerular filtration and active secretion). |
| Half-life | Efavirenz: 40-55 h (single dose), 50-76 h (multiple doses). Lamivudine: 5-7 h (adults). Tenofovir: 17 h (single dose), 12-17 h (multiple doses) in cells up to 48-60 h. Clinical context: Efavirenz's long half-life allows once-daily dosing; tenofovir's long intracellular half-life supports once-daily dosing. |
| Protein binding | Efavirenz: 99.5-99.8% (primarily albumin). Lamivudine: <36% (minimal). Tenofovir: <7% (minimal). |
| Volume of Distribution | Efavirenz: 2.3-4.0 L/kg (extensive tissue distribution). Lamivudine: 1.3 L/kg (total body water). Tenofovir: 1.2-1.3 L/kg (extracellular fluid). |
| Bioavailability | Oral: Efavirenz: ~40-45% (with food increases). Lamivudine: ~86-88% (no food effect). Tenofovir disoproxil fumarate: ~25-30% (fasting), increased with high-fat meal (bioequivalent to 300 mg tenofovir disoproxil fumarate). |
| Onset of Action | Oral: Efavirenz: 1-2 weeks for maximal viral suppression (plasma levels steady by ~1 week). Lamivudine: 1-2 weeks for clinical effect. Tenofovir: 1-2 weeks for clinical effect. |
| Duration of Action | Oral: Efavirenz: 24 hours (once-daily dosing). Lamivudine: 12-24 hours (once-daily dosing). Tenofovir: 24 hours (once-daily dosing). Clinical notes: Long half-lives and intracellular persistence allow once-daily fixed-dose combination. |
One tablet (efavirenz 600 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg) orally once daily on an empty stomach, preferably at bedtime.
| Dosage form | TABLET |
| Renal impairment | Not recommended if CrCl < 50 mL/min. For CrCl 50-80 mL/min: no adjustment required. For CrCl < 50 mL/min: use separate components with dose adjustments. Avoid if CrCl < 30 mL/min, or if on hemodialysis. |
| Liver impairment | Contraindicated in Child-Pugh Class C. For Child-Pugh Class B: reduce efavirenz dose to 400 mg once daily (use separate components). |
| Pediatric use | Approved for children ≥3 years and ≥40 kg: same as adult dose. For weight <40 kg: use individual components with weight-based dosing (efavirenz: 15-20 mg/kg once daily; lamivudine: 4 mg/kg twice daily; tenofovir: 8 mg/kg once daily). |
| Geriatric use | No specific dose adjustment, but monitor renal function (CrCl) and consider increased risk of CNS effects from efavirenz. Use with caution due to age-related renal decline. |
| 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 | Efavirenz: Excreted in breast milk; M/P ratio 0.93. Lamivudine: Excreted; M/P ratio ~3.3. Tenofovir: Excreted; M/P ratio ~0.9-1.2. Breastfeeding not recommended due to potential toxicity (efavirenz) and limited safety data; HIV transmission via breast milk possible. |
| Teratogenic Risk | First trimester: Increased risk of neural tube defects with efavirenz; contraindicated in first trimester. Second and third trimesters: Limited data; potential for hepatotoxicity and mitochondrial toxicity; lamivudine and tenofovir disoproxil fumarate are generally considered lower risk. Overall, avoid efavirenz in pregnancy; use alternative antiretroviral regimen. |
■ FDA Black Box Warning
WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B: Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued lamivudine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
| Common Effects | Hepatitis B |
| Serious Effects |
["Coadministration with elbasvir/grazoprevir due to increased risk of alanine aminotransferase elevations.","Coadministration with voriconazole (reduces efavirenz concentration and increases voriconazole concentration) unless benefit outweighs risk.","Coadministration with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious adverse events (e.g., astemizole, cisapride, midazolam, triazolam, ergot derivatives).","History of hypersensitivity reaction (e.g., Stevens-Johnson syndrome) to efavirenz, lamivudine, or tenofovir."]
| Precautions | ["Acute exacerbation of hepatitis B upon discontinuation in HIV/HBV coinfected patients.","Hepatotoxicity, including hepatic steatosis and exacerbation of hepatitis C.","Renal impairment: monitor creatinine clearance, avoid with creatinine clearance <50 mL/min.","Bone effects: decreased bone mineral density, risk of fractures.","Lipodystrophy and metabolic effects: redistribution/accumulation of body fat, hyperlipidemia.","Immune reconstitution syndrome.","Central nervous system symptoms (e.g., dizziness, insomnia, impaired concentration) with efavirenz.","Rash, including Stevens-Johnson syndrome.","QTc prolongation with efavirenz at supratherapeutic doses, avoid with drugs that prolong QTc."] |
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| Fetal Monitoring | Maternal: Liver function tests (baseline and periodic), renal function (serum creatinine), complete blood count, viral load, HIV genotype before therapy. Fetal: Ultrasound for neural tube defects (first trimester if efavirenz exposure), growth monitoring. Consider therapeutic drug monitoring for efavirenz. |
| Fertility Effects | No significant adverse effects on fertility reported for lamivudine or tenofovir. Efavirenz may cause hormonal contraceptive failure (decreased ethinyl estradiol levels); use barrier or alternative contraception. No specific impairment of male or female fertility in animal studies. |