EFAVIRENZ; EMTRICITABINE; 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-dependent and DNA-dependent DNA polymerase activity. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) that, after intracellular phosphorylation, competes with deoxycytidine 5'-triphosphate and incorporates into viral DNA, causing chain termination. Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate that, after hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase and hepatitis B virus DNA polymerase by competing with deoxyadenosine 5'-triphosphate and causing DNA chain termination.
| Metabolism | Efavirenz is primarily metabolized by CYP2B6 and to a lesser extent by CYP3A4 and CYP2A6. Emtricitabine is minimally metabolized; oxidation and glucuronidation are minor pathways. Tenofovir disoproxil fumarate is converted to tenofovir via hydrolysis by esterases; tenofovir is eliminated unchanged by renal excretion. |
| Excretion | Efavirenz: ~14-34% excreted in urine (primarily as metabolites) and ~16-61% in feces. Emtricitabine: ~86% excreted unchanged in urine and ~14% as metabolites. Tenofovir disoproxil fumarate: ~70-80% excreted unchanged in urine via glomerular filtration and active tubular secretion. |
| Half-life | Efavirenz: 40-55 hours (single dose), 52-76 hours (steady state). Emtricitabine: 10 hours (healthy), extended to >20 hours in renal impairment. Tenofovir: 17 hours (healthy), prolonged in renal impairment (up to 7 days with CrCl <30 mL/min). |
| Protein binding | Efavirenz: >99% bound to albumin. Emtricitabine: <4% bound to plasma proteins. Tenofovir: <7% bound to plasma proteins. |
| Volume of Distribution | Efavirenz: 2.5-4.0 L/kg (extensive tissue penetration including CNS). Emtricitabine: 1.4 L/kg (distributes into total body water). Tenofovir: 0.8-1.2 L/kg (primarily extracellular fluid; limited CNS penetration). |
| Bioavailability | Efavirenz: ~40-45% (oral capsules) with high-fat meal increasing absorption. Emtricitabine: 93% (oral capsules). Tenofovir disoproxil fumarate: ~25% (oral) under fasting conditions; increased with high-fat meal. |
| Onset of Action | Oral: Efavirenz reaches peak plasma concentration in 3-5 hours; anti-HIV effect begins within days. Emtricitabine and tenofovir reach peak in 1-2 hours; viral suppression observed within 2-4 weeks. |
| Duration of Action | Efavirenz: Dosing every 24 hours due to long t1/2; persists in plasma for ~3-4 days after discontinuation. Emtricitabine and tenofovir: Dosing every 24 hours; tenofovir's intracellular t1/2 is >60 hours. |
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 if creatinine clearance < 50 mL/min. If 50-80 mL/min, no adjustment required. If < 50 mL/min, use alternative regimen. |
| Liver impairment | Contraindicated in Child-Pugh class C. Use with caution in Child-Pugh class A or B; monitor for CNS and hepatic toxicity. No dose adjustment guidelines available. |
| Pediatric use | Approved for children ≥ 40 kg and ≥ 3 months: one tablet (efavirenz 600 mg / emtricitabine 200 mg / tenofovir disoproxil fumarate 300 mg) once daily. For weight < 40 kg, not recommended; use individual components. |
| Geriatric use | Use with caution due to age-related renal impairment; monitor renal function and adjust if CrCl < 50 mL/min. Increased risk of CNS side effects; consider bedtime dosing. |
| 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 | Contraindicated during breastfeeding due to potential for HIV transmission and adverse effects. M/P ratio not established; evidence suggests low transfer of efavirenz into breastmilk, but safety not confirmed. |
| Teratogenic Risk | FDA Pregnancy Category D. First trimester: neural tube defects, anophthalmia, severe skin reactions in animal models and case reports. Second trimester: risk of hepatotoxicity, lactic acidosis; no specific malformations. Third trimester: risk of preterm delivery, low birth weight, and neonatal mortality. |
■ FDA Black Box Warning
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of nucleoside analogs, including tenofovir disoproxil fumarate and emtricitabine. Post-treatment acute exacerbation of hepatitis B has been reported in patients coinfected with HIV-1 and HBV who discontinued emtricitabine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely in these patients.
| Common Effects | Headache Nausea Dizziness Vomiting Increased liver enzymes Insomnia difficulty in sleeping Sleepiness Abnormal dreams Anxiety Itching Difficulty in paying attention Rash Abdominal pain Diarrhea Depression Fatigue Pain Decreased appetite |
| Serious Effects |
["Previous hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any component of the product","Concomitant use with elbasvir/grazoprevir due to increased risk of ALT elevations (efavirenz)","Concomitant use with voriconazole or other drugs that are highly dependent on CYP2B6 or CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious adverse events (efavirenz)"]
| Precautions |
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| Fetal Monitoring | Maternal: serum creatinine, BUN, urinalysis, liver enzymes, lactic acid, CBC with differential, CD4 count, viral load. Fetal: ultrasound for neural tube defects at 16-20 weeks; serial growth scans if preterm labor suspected. |
| Fertility Effects | No known adverse effects on fertility in males or females; however, efavirenz may cause false-positive urine THC tests, potentially affecting reproductive health monitoring. |
| ["Lactic acidosis and severe hepatomegaly with steatosis","Exacerbation of hepatitis B after discontinuation","Hepatotoxicity and hepatic events","Serious psychiatric symptoms including depression, suicidal ideation, and aggressive behavior (efavirenz)","Convulsions and central nervous system symptoms (efavirenz)","Renal impairment and Fanconi syndrome (tenofovir disoproxil fumarate)","Decreased bone mineral density (tenofovir disoproxil fumarate)","Fat redistribution and immune reconstitution syndrome","Pancreatitis (emtricitabine in pediatric patients)","Interactions with drugs metabolized by CYP enzymes (efavirenz)"] |