LAMIVUDINE; ZIDOVUDINE; EFAVIRENZ
Clinical safety rating: safe
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and myopathy.
Lamivudine and zidovudine are nucleoside reverse transcriptase inhibitors (NRTIs) that inhibit HIV reverse transcriptase by competing with natural substrates and causing chain termination. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds directly to reverse transcriptase, causing allosteric inhibition and preventing RNA-dependent DNA polymerization.
| Metabolism | Lamivudine: minimal hepatic metabolism, primarily renally excreted unchanged. Zidovudine: hepatic glucuronidation (UGT2B7) to inactive metabolites, with some renal excretion. Efavirenz: hepatic metabolism via CYP2B6 and CYP3A4/5, with autoinduction of CYP2B6. |
| Excretion | Lamivudine: renal (approximately 70% unchanged via glomerular filtration and active tubular secretion). Zidovudine: renal (approximately 14% unchanged, major metabolite G-ZDV 60-80% excreted in urine). Efavirenz: hepatic metabolism (CYP2B6, CYP3A4) with fecal (14-34%) and urinary (<1%) elimination. |
| Half-life | Lamivudine: 5-7 hours in adults (prolonged in renal impairment). Zidovudine: 0.5-3 hours (terminal half-life), with intracellular active triphosphate half-life ~3 hours. Efavirenz: 40-55 hours (single dose), 10-20 hours at steady state (due to autoinduction), supporting once-daily dosing. |
| Protein binding | Lamivudine: <36% bound to albumin. Zidovudine: 34-38% bound primarily to albumin. Efavirenz: >99% bound primarily to albumin. |
| Volume of Distribution | Lamivudine: 1.3 L/kg (extensive total body water distribution, including CNS). Zidovudine: 1.6 L/kg (good tissue penetration, including CSF). Efavirenz: 2.5-4.0 L/kg (highly lipophilic, extensive tissue distribution including CNS). |
| Bioavailability | Lamivudine: 80-88% oral (well absorbed, no food effect). Zidovudine: 60-70% oral (absorbtion affected by food). Efavirenz: 40-50% oral (enhanced with high-fat meal, but avoid high-fat meal to reduce side effects). |
| Onset of Action | Lamivudine and Zidovudine: antiretroviral effect begins within hours of administration due to rapid intracellular phosphorylation, with maximal effect reached in 2-4 weeks. Efavirenz: antiretroviral effect detectable within 3-5 days, with full effect by 2-4 weeks. |
| Duration of Action | Lamivudine: dosing interval every 12 hours, but intracellular triphosphate half-life of 12-18 hours supports twice-daily dosing. Zidovudine: short plasma half-life requires dosing every 12 hours; intracellular triphosphate half-life extends to ~3 hours. Efavirenz: once-daily dosing due to long half-life. |
| Molecular Weight | 719.85 |
One tablet (lamivudine 300 mg; zidovudine 300 mg; efavirenz 600 mg) orally once daily on an empty stomach, preferably at bedtime.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if CrCl < 50 mL/min (zidovudine and lamivudine require dose reduction; fixed-dose combination not appropriate). For CrCl 50-79 mL/min, no adjustment. For CrCl < 50 mL/min, use individual components. For hemodialysis: not recommended. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B or C: contraindicated due to efavirenz (potential CNS toxicity; use alternative). |
| Pediatric use | Not typically used as fixed-dose combination in children <12 years. For ≥12 years and weight ≥40 kg: same adult dose. For children 3 months-12 years: use weight-based dosing of individual components (lamivudine 4 mg/kg twice daily, max 150 mg; zidovudine 160 mg/m² three times daily; efavirenz weight-based, e.g., 10-<15 kg: 200 mg, 15-<20 kg: 250 mg, 20-<25 kg: 300 mg, 25-<32.5 kg: 350 mg, 32.5-<40 kg: 400 mg, ≥40 kg: 600 mg; all once daily). |
| Geriatric use | Caution due to age-related renal and hepatic decline; monitor renal function and adjust if CrCl < 50 mL/min. Consider increased risk of CNS adverse effects from efavirenz (dizziness, confusion) and hematologic toxicity from zidovudine. Use lowest effective dose if necessary. |
| 1st trimester | Use only if clearly needed; risk of neural tube defects in first 6 weeks. Consider alternative if possible. |
| 2nd trimester | Use with caution; monitor for anemia and lactic acidosis. |
| 3rd trimester | Use with caution; monitor for anemia and lactic acidosis. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and myopathy.
| FDA category | Human |
| Placental transfer | Lamivudine and zidovudine cross the placenta readily; efavirenz crosses at moderate levels. |
| Breastfeeding | Both lamivudine and zidovudine are excreted in breast milk; efavirenz is excreted in low concentrations. Risk of infant toxicity and development of resistance in HIV-infected infants. Recommend avoidance of breastfeeding if alternative is available. |
■ FDA Black Box Warning
WARNING: HEMATOLOGIC TOXICITY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B. Zidovudine has been associated with severe hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV disease. Prolonged use of NRTIs has been associated with lactic acidosis and severe hepatomegaly with steatosis. Severe acute exacerbations of hepatitis B have been reported in patients co-infected with HBV who discontinue lamivudine-containing products.
| Common Effects | Anemia |
| Serious Effects |
Hypersensitivity to any componentConcurrent use of elvitegravir/cobicistat due to decreased efavirenz exposureSevere hepatic impairment (Child-Pugh class C)Breastfeeding in HIV-infected mothers (in resource rich settings)Concurrent use with astemizole, cisapride, midazolam, triazolam, ergot alkaloids, pimozide, or St. John's wort due to CYP3A induction by efavirenz
| Precautions | Hematologic toxicity (neutropenia, anemia): monitor complete blood counts frequently, Lactic acidosis and severe hepatomegaly with steatosis: discontinue if clinical or laboratory findings suggest, Exacerbations of hepatitis B upon discontinuation of lamivudine in co-infected patients, Hepatotoxicity and hepatic failure, especially in patients with underlying liver disease, Severe skin reactions including Stevens-Johnson syndrome, Neuropsychiatric effects including dizziness, insomnia, impaired concentration, and vivid dreams, QTc interval prolongation with efavirenz; use with caution with QT-prolonging agents, Lipid abnormalities with efavirenz (elevated cholesterol and triglycerides), Pancreatitis: monitor for signs and symptoms, Immune reconstitution syndrome: may occur during initial treatment, Use with caution in patients with renal impairment (adjust dose for CrCl <50 mL/min), Bone mineral density loss with zidovudine |
Loading safety data…
| Lactation Rating | L4 (Hazardous) |
| Teratogenic Risk | Lamivudine: Crosses placenta; human data for first trimester do not show increased risk of major malformations; limited second/third trimester data show no specific fetal toxicity. Zidovudine: Crosses placenta; human data show no increased risk of congenital anomalies; associated with transient neonatal anemia and neutropenia. Efavirenz: Contraindicated in first trimester due to neural tube defects (anencephaly, microphthalmia) based on retrospective case reports; avoid in women of childbearing potential unless effective contraception. After first trimester, risk of major malformations not significantly increased but limited data. |
| Fetal Monitoring | Maternal: Complete blood count, hepatic function, renal function, HIV viral load, CD4 count, serum lactate, lipase if symptoms of pancreatitis; monitor for efavirenz neuropsychiatric effects (dizziness, insomnia). Fetal/Neonatal: Ultrasound for neural tube defects if first-trimester efavirenz exposure; neonatal CBC for anemia from zidovudine; monitor for mitochondrial toxicity in neonates (rare). |
| Fertility Effects | Lamivudine and zidovudine: No known adverse effects on fertility in animal studies or human data. Efavirenz: No known adverse effects on fertility in animal studies; limited human data suggest no significant effect. However, untreated HIV infection may impair fertility; antiretroviral therapy may improve fertility. |
| Food/Dietary | Take on an empty stomach at least 1 hour before or 2 hours after a meal, especially avoiding high-fat meals which increase efavirenz absorption and worsen CNS side effects. |
| Clinical Pearls | This fixed-dose combination is indicated for HIV-1 infection. Zidovudine can cause hematologic toxicity such as anemia and neutropenia; monitor CBC at baseline and periodically. Lamivudine may cause hepatic steatosis and pancreatitis. Efavirenz is associated with CNS effects (e.g., dizziness, vivid dreams) and rash; administer on an empty stomach at bedtime to reduce CNS symptoms. Avoid in pregnancy due to efavirenz teratogenicity; use effective contraception. Monitor hepatic function due to potential hepatotoxicity. Assess renal function before use; adjust dosing for CrCl <50 mL/min. |
| Patient Advice | Take exactly as prescribed; do not skip doses to prevent drug resistance. · Take on an empty stomach at bedtime to reduce CNS side effects like dizziness and abnormal dreams. · Report any signs of rash, jaundice, dark urine, or abdominal pain immediately. · Use effective contraception during treatment and for 12 weeks after stopping efavirenz. · Blood counts and liver function will be monitored regularly. · Do not breastfeed while taking this medication. |