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. |
| Molecular Weight | Eff: 315.68 Da; Emtricitabine: 247.25 Da; Tenofovir disoproxil fumarate: 635.52 Da (combined formulation variable). For individual: Efavirenz 315.68, Emtricitabine 247.25, Tenofovir disoproxil fumarate 635.52. |
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 | Human data suggest low teratogenic risk; neural tube defects reported but rare. Use only if benefit outweighs risk. Avoid first trimester if possible. |
| 2nd trimester | No evidence of fetal harm; continue if clinically indicated. Monitor for maternal hepatotoxicity and lactic acidosis. |
| 3rd trimester | Safe to continue; no known adverse fetal effects. Use standard monitoring for toxicity. |
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 components cross the placenta. Efavirenz: high transfer (cord blood:maternal ratio ~0.5-1.0). Emtricitabine: extensive transfer. Tenofovir: moderate transfer (ratio ~0.6-0.9). |
■ 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 |
Coadministration with elbasvir/grazoprevirCoadministration with voriconazole (due to reduced voriconazole levels and increased efavirenz toxicity)Severe hepatic impairment (Child-Pugh class C)Known hypersensitivity to any componentConcurrent use of St. John's wort
| 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. |
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| Breastfeeding |
| Emtricitabine and tenofovir are excreted into human milk in low concentrations; efavirenz is excreted but negligible levels. Potential for infant toxicity from efavirenz (CNS effects) and tenofovir (bone/renal). Consider risk-benefit; alternative agents preferred if breastfeeding. |
| Lactation Rating | L5 (Contraindicated) or 'Avoid' due to potential for severe adverse effects in infant. |
| 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. |
| 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. |
| Food/Dietary | Avoid high-fat meals as they increase absorption and worsen CNS side effects. Take on an empty stomach at least 1 hour before or 2 hours after a meal. No specific food-drug interactions beyond fat content; grapefruit juice does not significantly interact. |
| Clinical Pearls | Administer on an empty stomach to reduce CNS side effects. Monitor renal function (creatinine clearance, urine glucose/protein) before and during therapy. Counsel about CNS symptoms (dizziness, vivid dreams) which often improve within 2-4 weeks. Do not co-administer with other tenofovir-containing products. Check for hepatitis B co-infection before starting and monitor for HBV flare upon discontinuation. |
| Patient Advice | Take this medication on an empty stomach, preferably at bedtime, to reduce dizziness and abnormal dreams. · Do not stop taking this medicine without talking to your doctor; stopping can cause worsening of hepatitis B infection. · Common side effects include dizziness, trouble sleeping, drowsiness, and vivid dreams; these usually improve after a few weeks. · Avoid alcohol or limit alcohol intake as it may increase liver problems or worsen side effects. · Seek medical attention if you experience signs of kidney problems (e.g., decreased urination, swelling in legs/ankles) or liver problems (e.g., yellowing skin/eyes, dark urine). · This medication does not cure HIV or prevent the spread of HIV to others; continue safe sex practices and avoid sharing needles. · Take exactly as prescribed; missing doses can lead to drug resistance and treatment failure. |