EMTRICITABINE AND TENOFOVIR ALAFENAMIDE FUMARATE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) that is phosphorylated to emtricitabine triphosphate, which competes with the natural substrate deoxycytidine-5'-triphosphate and incorporates into viral DNA, causing chain termination. Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) that is converted intracellularly to tenofovir diphosphate, which inhibits HIV-1 reverse transcriptase by competing with deoxyadenosine-5'-triphosphate and causing DNA chain termination.
| Metabolism | Emtricitabine: limited metabolism via oxidation and glucuronidation; not significantly metabolized by CYP450 enzymes. Tenofovir alafenamide: metabolized by cathepsin A in primary cells (e.g., peripheral blood mononuclear cells, macrophages) and by CYP3A4 in hepatocytes. |
| Excretion | Emtricitabine: 86% excreted unchanged in urine, 14% as metabolites via urine. Tenofovir alafenamide: <1% excreted unchanged in urine; majority metabolized to tenofovir, which is eliminated renally via glomerular filtration and active tubular secretion. Overall, renal elimination is predominant. |
| Half-life | Emtricitabine: terminal half-life ~10 hours; Tenofovir alafenamide: terminal half-life ~0.51 hours (rapid conversion to tenofovir); Intracellular tenofovir-diphosphate half-life >60 hours. Clinical context: daily dosing achieves steady state in 7 days. |
| Protein binding | Emtricitabine: <4% bound to plasma proteins. Tenofovir alafenamide: ~80% bound to plasma proteins. Tenofovir (active metabolite): <0.7% bound. |
| Volume of Distribution | Emtricitabine: Vd ~1.4 L/kg (extensive distribution). Tenofovir alafenamide: Vd ~0.7 L/kg; tenofovir: Vd ~1.2 L/kg. Indicates good tissue penetration including lymph nodes and genital secretions. |
| Bioavailability | Oral: Emtricitabine ~93%; Tenofovir alafenamide ~40% (enhanced by food). |
| Onset of Action | Oral: Time to maximum plasma concentration (Tmax) ~1–2 hours for emtricitabine and ~0.5–1 hour for tenofovir alafenamide. Clinical antiviral effect begins within hours, but maximal suppression requires 2–4 weeks of daily dosing. |
| Duration of Action | Duration of antiviral effect is >24 hours due to long intracellular half-life of tenofovir-diphosphate. Supports once-daily dosing. Continuous adherence required for sustained virologic suppression. |
| Molecular Weight | Emtricitabine: 247.24 Da; Tenofovir alafenamide fumarate: 477.33 Da (tenofovir alafenamide free base: 374.29 Da) |
One tablet (emtricitabine 200 mg / tenofovir alafenamide fumarate 25 mg) orally once daily.
| Dosage form | TABLET |
| Renal impairment | Not recommended in patients with creatinine clearance (CrCl) < 30 mL/min. No dose adjustment required for CrCl ≥ 30 mL/min. |
| Liver impairment | No dose adjustment required for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Not recommended in severe (Child-Pugh C) hepatic impairment. |
| Pediatric use | Approved for children weighing ≥ 25 kg: one tablet (emtricitabine 200 mg / tenofovir alafenamide fumarate 25 mg) orally once daily. For children < 25 kg, safety and efficacy not established. |
| Geriatric use | No specific dose adjustment required; use with caution due to age-related decreased renal function and monitor CrCl regularly. |
| 1st trimester | Data in pregnant women are insufficient to determine a drug-associated risk. However, in animal reproduction studies, no adverse developmental effects were observed at exposures up to 6 times the human therapeutic dose. Use only if clearly needed. |
| 2nd trimester | Available human data from the Antiretroviral Pregnancy Registry show no increased risk of major birth defects compared to the background rate. Continue therapy to prevent HIV transmission. |
| 3rd trimester | Use during third trimester is considered safe. No evidence of fetal harm. Continued use recommended to prevent perinatal transmission. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer | Emtricitabine and tenofovir alafenamide cross the placenta. Cord blood concentrations of emtricitabine are comparable to maternal plasma; tenofovir alafenamide is rapidly metabolized to tenofovir, which achieves cord blood levels approximately 60% of maternal levels. |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued emtricitabine and/or tenofovir disoproxil fumarate (TDF). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue this product and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
| Common Effects | Hepatitis B |
| Serious Effects |
Concomitant use with aminoglycosides (increased nephrotoxicity)Severe hepatic impairment (Child-Pugh class C)Hypersensitivity to emtricitabine or tenofovir alafenamide
| Precautions | New onset or worsening renal impairment: assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein before and during therapy, Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) reported with NRTIs, Immune reconstitution syndrome (including autoimmune disorders) may occur, Decreased bone mineral density (mainly with TDF; less with TAF) and osteomalacia reported, Risk of HIV-1 resistance in undiagnosed HIV-1 infection when used for PrEP; confirm HIV-1 negative status before and every 3 months during PrEP use, Hepatotoxicity (elevated transaminases, hepatitis) reported |
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| Breastfeeding | Emtricitabine and tenofovir alafenamide are excreted in human milk at low concentrations. The CDC recommends that women with HIV in the US not breastfeed to avoid potential postnatal transmission. In settings where breastfeeding is the standard of care, the benefits may outweigh risks, but alternative antiretrovirals with more extensive breastfeeding safety data are preferred. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: No significant increase in major malformations above baseline based on registry data from over 6000 exposures. Second/third trimester: Preclinical studies show no fetal harm; human data show no evidence of toxicity. Cases of lactic acidosis and hepatic steatosis reported with nucleoside analogs, but not specifically attributed. |
| Fetal Monitoring | Monitor HIV viral load and CD4 count throughout pregnancy. Assess renal function (serum creatinine, urine glucose/protein) prior to and during therapy due to tenofovir effects. Liver function tests, especially in patients with hepatitis B co-infection. Fetal ultrasound for growth and anomaly screening per standard obstetrical care. |
| Fertility Effects | No evidence of impaired fertility in animal studies. In humans, no significant impact on male or female fertility reported. Data limited, but no signal for reproductive toxicity. |
| Food/Dietary | No significant food interactions. May be taken with or without food. Avoid St. John's wort as it may decrease the effectiveness of this medication. |
| Clinical Pearls | Contains emtricitabine (FTC), a nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir alafenamide (TAF), a prodrug of tenofovir. TAF has higher intracellular tenofovir concentrations and lower plasma levels than tenofovir disoproxil fumarate (TDF), resulting in reduced renal and bone toxicity. Not recommended for use in patients with creatinine clearance <15 mL/min. Severe acute exacerbation of hepatitis B (HBV) may occur in co-infected patients who discontinue therapy; monitor hepatic function closely. Drug interactions: avoid concurrent use with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifabutin, rifapentine, and St. John's wort (reduce TAF concentrations). Can be taken with or without food. |
| Patient Advice | Take this medication exactly as prescribed by your healthcare provider. · Do not stop taking this medication without consulting your doctor, as hepatitis B may worsen if you have HIV/HBV co-infection. · This medication does not cure HIV infection; you may continue to experience illnesses associated with HIV, including opportunistic infections. · You should have blood tests before and during treatment to monitor kidney function, liver function, and hepatitis B status. · If you have hepatitis B, tell your doctor; you will need close follow-up after stopping treatment. · Take this medication with food to improve absorption. · Missed dose: If you miss a dose, take it as soon as you remember unless it is almost time for your next dose. Do not double up doses. · Store at room temperature between 20°C to 25°C (68°F to 77°F), away from moisture and heat. |