EFAVIRENZ, EMTRICITABINE, 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 is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds reversibly to HIV-1 reverse transcriptase, causing a conformational change and inhibiting RNA-directed DNA polymerase activity. Emtricitabine and tenofovir disoproxil fumarate are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that compete with natural substrates and incorporate into viral DNA, causing chain termination.
| Metabolism | Efavirenz is primarily metabolized by cytochrome P450 (CYP) 2B6 and to a lesser extent by CYP3A4/5. Emtricitabine undergoes limited metabolism via oxidation and glucuronidation. Tenofovir disoproxil fumarate is rapidly hydrolyzed to tenofovir, which is then phosphorylated to the active metabolite; tenofovir is eliminated renally by glomerular filtration and active tubular secretion. |
| Excretion | Efavirenz: 14-34% renal (as metabolites), <1% unchanged; 16-61% fecal. Emtricitabine: ~86% renal (65-70% unchanged), 14% fecal. Tenofovir: 70-80% renal (20-30% unchanged via glomerular filtration and active tubular secretion), 20% fecal. |
| Half-life | Efavirenz: 52-76 h (single dose), 40-55 h (multiple doses); autoinduction reduces t1/2. Emtricitabine: ~10 h (healthy), extended to 18-24 h in renal impairment. Tenofovir: ~17 h (healthy), >40 h in renal impairment. |
| Protein binding | Efavirenz: >99% bound (albumin). Emtricitabine: <4% bound. Tenofovir: <0.7% bound. |
| Volume of Distribution | Efavirenz: 252 L (central Vd) – extensive tissue distribution, including CNS. Emtricitabine: 1.4 L/kg – distributes into total body water. Tenofovir: 1.2 L/kg – distributes into total body water, accumulates in kidney. |
| Bioavailability | Oral: Efavirenz: 40-45% (fasting) increased with high-fat meal (tablet); 50-66% (capsule). Emtricitabine: 93% (capsule), rapid absorption. Tenofovir: 25% (fasting) increased 40% with high-fat meal. |
| Onset of Action | Oral: Efavirenz: viral load reduction within 1-2 weeks; CNS effects within hours to days. Emtricitabine and Tenofovir: antiretroviral effect within days. |
| Duration of Action | Efavirenz: once-daily dosing maintains therapeutic levels; t1/2 of 40-55 h allows sustained exposure. Emtricitabine and Tenofovir: once-daily dosing; tenofovir's long intracellular t1/2 (60+ h) supports 24-h coverage. |
One tablet (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) orally once daily on an empty stomach, preferably at bedtime.
| Dosage form | TABLET |
| Renal impairment | Not recommended for patients with creatinine clearance (CrCl) < 50 mL/min. No dose adjustment required for CrCl ≥ 50 mL/min. |
| Liver impairment | Contraindicated in Child-Pugh Class B or C. Use with caution in mild hepatic impairment (Child-Pugh Class A) with close monitoring. |
| Pediatric use | Approved for children ≥3 years old and weighing ≥10 kg. Dosing by body weight: 10–<14 kg: efavirenz 200 mg/emtricitabine 100 mg/tenofovir disoproxil fumarate 100 mg; 14–<25 kg: efavirenz 300 mg/emtricitabine 133 mg/tenofovir disoproxil fumarate 150 mg; 25–<40 kg: efavirenz 400 mg/emtricitabine 167 mg/tenofovir disoproxil fumarate 200 mg; ≥40 kg: adult dose. All doses are fixed-dose combinations given orally once daily on an empty stomach. |
| Geriatric use | No specific dose adjustments recommended for elderly patients. Monitor renal function and adjust tenofovir disoproxil fumarate component as per CrCl (not recommended if CrCl < 50 mL/min). Consider increased risk of CNS and psychiatric effects from efavirenz. |
| 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 | Not recommended during breastfeeding due to potential for HIV transmission and adverse effects in infants. Efavirenz is excreted into breast milk (M/P ratio ~0.49); emtricitabine (M/P ratio ~3.0); tenofovir (M/P ratio ~0.03). Insufficient data on infant safety. |
| Teratogenic Risk | FDA Pregnancy Category D. First trimester: Associated with neural tube defects (e.g., anencephaly, myelomeningocele) based on prospective cohort studies; avoid in first trimester unless no alternative. Second/third trimesters: No increased risk of major malformations, but risk of mitochondrial toxicity and lactic acidosis in neonates. Efavirenz is the primary teratogenic component. |
■ 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 products containing emtricitabine and/or tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue this drug.
| Common Effects | Hepatitis B |
| Serious Effects |
["Concomitant use with drugs highly dependent on CYP2B6 or CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious adverse events (e.g., voriconazole, midazolam, triazolam, ergot derivatives, pimozide, cisapride, rifampin, St. John's wort)","Hypersensitivity to any component of the product"]
| Precautions | ["Hepatotoxicity: monitor liver enzymes; avoid in patients with moderate to severe hepatic impairment.","Renal toxicity: monitor renal function; tenofovir may cause acute renal failure, Fanconi syndrome.","Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogs.","Immune reconstitution syndrome: may occur during initial phase of treatment.","Psychiatric symptoms: efavirenz associated with depression, suicidal ideation, and aggressive behavior.","Bone effects: tenofovir may decrease bone mineral density.","Fat redistribution and accumulation."] |
Loading safety data…
| Fetal Monitoring | Maternal: Liver function tests, serum creatinine, urine glucose and protein, complete blood count, viral load every 1-3 months. Fetal: Targeted ultrasound at 18-20 weeks for neural tube defects; monitor for fetal growth restriction via serial ultrasound. Neonatal: Monitor for hyperbilirubinemia, lactic acidosis, and mitochondrial dysfunction. |
| Fertility Effects | No evidence of impaired fertility in humans. Animal studies at high doses showed reduced fertility with tenofovir. Efavirenz may cause reversible testicular atrophy in rats; clinical significance unknown. Emtricitabine showed no fertility effects in animals. |