EMTRICITABINE, RILPIVIRINE, AND TENOFOVIR ALAFENAMIDE
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 its active metabolite, emtricitabine triphosphate, which competes with the natural substrate deoxycytidine 5'-triphosphate and incorporates into viral DNA, causing chain termination. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to a hydrophobic pocket near the active site of reverse transcriptase, causing a conformational change that inhibits enzyme activity. Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) that is converted intracellularly to tenofovir diphosphate, which competes with deoxyadenosine 5'-triphosphate and causes DNA chain termination.
| Metabolism | Emtricitabine: not extensively metabolized; minor oxidation and glucuronidation. Rilpivirine: primarily metabolized by CYP3A4. Tenofovir alafenamide: primarily metabolized by cathepsin A in peripheral blood mononuclear cells and by carboxylesterase 1 in hepatocytes; minor metabolism by CYP3A4. |
| Excretion | Emtricitabine: 86% renal (glomerular filtration and active tubular secretion), 14% fecal; Rilpivirine: 85% fecal (unchanged and metabolites), 6.1% renal (0.03% unchanged); Tenofovir alafenamide: <1% renal (as tenofovir), 31.7% fecal (as tenofovir), 32% urine (as tenofovir; 18.2% as TAF and metabolites). |
| Half-life | Emtricitabine: 10 h; Rilpivirine: 45 h (range 41–55 h); Tenofovir alafenamide: 0.51 h (converted to tenofovir), tenofovir: 32–49 h. |
| Protein binding | Emtricitabine: <4% (primarily albumin and alpha-1 acid glycoprotein); Rilpivirine: 99.7% (mainly albumin); Tenofovir alafenamide: ~80% (to albumin), tenofovir: <0.7% (no clinically relevant binding). |
| Volume of Distribution | Emtricitabine: 1.4 L/kg (large Vd indicating extensive tissue penetration); Rilpivirine: 1.4 L/kg (large Vd, extensive distribution); Tenofovir alafenamide: 0.11 L/kg (small Vd, limited tissue distribution; tenofovir: 1.2 L/kg). |
| Bioavailability | Oral: Emtricitabine 93% (not affected by food); Rilpivirine 20% (increased to 30% with a high-fat meal; must be taken with food); Tenofovir alafenamide 40–70% (increased ~15% with a high-fat meal, but no food restriction). |
| Onset of Action | Oral: Steady-state for emtricitabine and tenofovir alafenamide within 7 days; sustained virologic response typically observed after 4–8 weeks of therapy. |
| Duration of Action | Dosing interval 24 h; once-daily dosing maintains therapeutic concentrations; virologic suppression requires continuous adherence; missed doses lead to rapid decline in tenofovir alafenamide and emtricitabine levels. |
| Molecular Weight | Emtricitabine: 247.24 Da; Rilpivirine: 366.42 Da; Tenofovir alafenamide: 476.47 Da (of the fumarate salt, 534.47 Da). |
One tablet (200 mg emtricitabine/25 mg rilpivirine/25 mg tenofovir alafenamide) orally once daily with a meal.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in CrCl <30 mL/min. For CrCl 30-59 mL/min, no dose adjustment is required for this fixed-dose combination; alternative agents recommended due to potential for accumulation in renal impairment. For patients on dialysis, not recommended. |
| Liver impairment | Contraindicated in Child-Pugh C. No dose adjustment needed for Child-Pugh A or B, but use with caution and monitor for adverse effects. |
| Pediatric use | Approved for patients weighing at least 35 kg: one tablet (200/25/25 mg) orally once daily with a meal. For patients <35 kg, not recommended. |
| Geriatric use | No specific dose adjustment required solely for age. Monitor renal function closely due to age-related decline in CrCl; consider alternatives if CrCl <30 mL/min. |
| 1st trimester | Limited data; no evidence of increased risk of major birth defects. Use if benefit outweighs risk. |
| 2nd trimester | No adverse fetal effects reported in animal studies; limited human data. Use if clearly needed. |
| 3rd trimester | No known fetal harm; consider use during labor if maternal benefit justifies risk. |
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; rilpivirine likely crosses based on molecular weight. |
| Breastfeeding |
■ 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 coinfected with HIV-1 and hepatitis B virus (HBV) and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate. Hepatic function should be monitored closely in these patients after discontinuation. If appropriate, initiation of anti-hepatitis B therapy may be warranted. Also, tenofovir alafenamide is not approved for the treatment of chronic HBV infection; safety and efficacy have not been established.
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to any componentCo-administration with rifampin or rifapentineCo-administration with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or St. John's wort
| Precautions | Risk of post-treatment acute exacerbation of hepatitis B (see black box warning), New onset or worsening renal impairment: tenofovir alafenamide may cause renal toxicity; monitor serum creatinine, creatinine clearance, urine glucose, and urine protein, Lactic acidosis/severe hepatomegaly with steatosis: use with caution in patients with hepatic risk factors; discontinue if clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity occur, Immune reconstitution syndrome: may occur, leading to inflammatory responses to indolent or residual opportunistic infections, Decreases in bone mineral density (BMD): tenofovir alafenamide may cause decreases in BMD; consider monitoring in patients with osteoporosis risk, Depression and suicidal ideation: reported with rilpivirine; monitor for mood changes, Hepatotoxicity: elevated liver enzymes reported; monitor in patients with underlying hepatic disease |
Loading safety data…
| Emtricitabine and tenofovir alafenamide are excreted in human milk at low levels; rilpivirine is present in animal milk. Consider risk of HIV transmission and potential infant adverse effects (e.g., bone toxicity). |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Limited human data; in animal studies, no teratogenic effects at exposures up to 37-65 times human dose for emtricitabine and tenofovir alafenamide; rilpivirine shown no fetal harm at 15 times human exposure. Caution in first trimester due to theoretical neural tube defect risk with folate antagonism (tenofovir), though not confirmed. Second and third trimester: no evidence of increased malformation risk, but monitor for anemia and mitochondrial toxicity. |
| Fetal Monitoring | Monitor HIV viral load, CD4 count, renal function (serum creatinine, CrCl, urine glucose/protein), liver function, and bone mineral density. Fetal ultrasound for growth and anomalies. Monitor infant for anemia, neutropenia, and mitochondrial toxicity. |
| Fertility Effects | No known significant effect on fertility in animal studies; in humans, no evidence of impaired fertility. Rilpivirine may cause modest increases in prolactin but clinical relevance unknown. |
| Food/Dietary | Rilpivirine must be taken with a meal containing at least 400 kcal for optimal absorption. Grapefruit juice does not significantly interact, but high-fat or high-calorie meals may enhance absorption. No specific food restrictions, but consistent meal timing is important. |
| Clinical Pearls | This fixed-dose combination is indicated for HIV-1 treatment in patients with viral suppression (HIV-1 RNA <50 copies/mL) who have no resistance to any component. Rilpivirine must be taken with a meal (≥400 kcal) to ensure adequate absorption. Tenofovir alafenamide (TAF) has lower renal toxicity than tenofovir disoproxil fumarate (TDF), but renal monitoring (creatinine clearance, urine protein) is still recommended. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin) as they reduce rilpivirine exposure. Proton pump inhibitors (PPIs) are contraindicated; antacids should be separated by at least 2 hours. The combination has a low pill burden and is generally well tolerated, but may cause depression, insomnia, and hepatotoxicity. |
| Patient Advice | Take this medication exactly as prescribed, once daily at the same time with a meal (at least 400 calories). · Do not take with proton pump inhibitors (e.g., omeprazole, esomeprazole). If you take antacids, separate by at least 2 hours. · Report any symptoms of depression, mood changes, or suicidal thoughts to your healthcare provider immediately. · Stay on routine HIV care and lab monitoring (kidney function, liver enzymes, viral load). · Inform all healthcare providers you are taking this medication, especially before starting new prescriptions. · If you miss a dose and remember within 12 hours, take it with food. If more than 12 hours, skip and take next dose at regular time. |