EMTRICITABINE; RILPIVIRINE; 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); rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI); tenofovir alafenamide is an NRTI. Combination inhibits HIV-1 replication by blocking reverse transcriptase.
| Metabolism | Emtricitabine: minimal metabolism; Rilpivirine: metabolized primarily by CYP3A4; Tenofovir alafenamide: hydrolyzed to tenofovir by cathepsin A in hepatocytes and by carboxylesterase 1 in peripheral blood mononuclear cells, then further metabolized by intracellular kinases to tenofovir diphosphate. |
| Excretion | Emtricitabine: 86% renal (glomerular filtration and active tubular secretion), 14% fecal. Rilpivirine: 85% fecal (65% as parent drug), 6.1% renal (negligible unchanged). Tenofovir alafenamide: <1% renal; >80% fecal as metabolites; hydrolyzed intracellularly to tenofovir, which is eliminated renally (70-80% unchanged) via glomerular filtration and active tubular secretion. |
| Half-life | Emtricitabine: 10 h (healthy subjects); 8-9 h (HIV-1 infected, once-daily dosing achieves therapeutic plasma concentrations). Rilpivirine: 45 h (terminal, supports once-daily dosing). Tenofovir alafenamide: 0.51 h (parent); tenofovir metabolite: 32-37 h (intracellular, supports once-daily dosing). |
| Protein binding | Emtricitabine: <4% (no specific binding). Rilpivirine: 99.7% (plasma proteins, primarily albumin). Tenofovir alafenamide: ~80% (plasma proteins, primarily albumin). |
| Volume of Distribution | Emtricitabine: 1.4 L/kg (extensive distribution into tissues including PBMCs). Rilpivirine: 152 L (total, not weight-adjusted; extensive tissue distribution). Tenofovir alafenamide: 0.3 L/kg (moderate; concentrates in PBMCs and other target tissues). |
| Bioavailability | Emtricitabine: 93% (oral). Rilpivirine: 32% (oral with food, increases ~50% with normal-calorie meal). Tenofovir alafenamide: 25% (oral with food; increased 60% with high-fat meal). |
| Onset of Action | Oral: Emtricitabine: peak plasma concentration 1-2 h; Rilpivirine: peak 4-5 h; Tenofovir alafenamide: peak 0.5-1 h. Virologic suppression typically achieved within 4-8 weeks of once-daily dosing. |
| Duration of Action | Once-daily dosing maintains plasma and intracellular concentrations above therapeutic thresholds for 24 h. Rilpivirine has a long half-life allowing forgiveness of occasional delayed doses. Tenofovir alafenamide intracellular tenofovir-diphosphate half-life >60 h in PBMCs. |
| Molecular Weight | Emtricitabine: 247.24 Da; Rilpivirine: 366.42 Da; Tenofovir alafenamide: 476.47 Da |
One tablet (emtricitabine 200 mg, rilpivirine 25 mg, tenofovir alafenamide 25 mg) orally once daily with a meal.
| Dosage form | TABLET |
| Renal impairment | Not recommended in patients with CrCl <30 mL/min. No dose adjustment required for CrCl ≥30 mL/min. |
| Liver impairment | Contraindicated in Child-Pugh class B or C hepatic impairment. Use with caution in mild hepatic impairment (Child-Pugh class A). |
| Pediatric use | Approved for patients weighing ≥35 kg: one tablet (emtricitabine 200 mg, rilpivirine 25 mg, tenofovir alafenamide 25 mg) orally once daily with a meal. Not recommended for patients <35 kg. |
| Geriatric use | No specific dose adjustment recommended. Monitor renal function due to age-related decline in CrCl. |
| 1st trimester | Avoid unless benefit outweighs risk; case series and cohort studies show no significant increase in major birth defects, but data limited. |
| 2nd trimester | Use only if clearly needed; studies show no increased risk of adverse fetal outcomes, but safety data are insufficient. |
| 3rd trimester | Use with caution; tenofovir alafenamide has lower placental transfer than tenofovir disoproxil fumarate, but safety not established. |
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: high placental transfer (cord blood/maternal plasma ratio ~1.0). Rilpivirine: low (ratio ~0.5). Tenofovir alafenamide: lower than tenofovir disoproxil fumarate due to prodrug properties; estimated minimal transfer. |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with tenofovir alafenamide. Hepatic function should be monitored closely in these patients.
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to any componentCo-administration with rifampin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or St. John's wort (reduces rilpivirine levels)
| Precautions | Post-treatment acute exacerbation of hepatitis B (see boxed warning), New onset or worsening renal impairment: monitor renal function before and during therapy, Risk of hepatotoxicity, especially in patients with underlying liver disease or coinfection with hepatitis C, Depressive disorders: monitor for depressive symptoms, Bone mineral density reductions and increased fracture risk with tenofovir alafenamide, Immune reconstitution syndrome, Fat redistribution and accumulation, Lactic acidosis and severe hepatomegaly with steatosis (rare) |
Loading safety data…
| Breastfeeding | Emtricitabine and tenofovir are excreted into human milk; rilpivirine also present. Potential for infant toxicity and HIV transmission; HIV-infected mothers in developed countries should avoid breastfeeding. In resource-limited settings, consider risks and benefits. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Emtricitabine: No significant teratogenic risk in animal studies; human data from Antiretroviral Pregnancy Registry show no increased risk of major birth defects (first trimester prevalence 2.3%, second/third trimester 2.5%). Rilpivirine: No increased risk of birth defects; limited human data. Tenofovir alafenamide: No teratogenic risk observed in animals; human data show no increased birth defects. Overall, risk of major malformations is low across all trimesters, but data are limited. |
| Fetal Monitoring | Monitor HIV viral load and CD4 count regularly; assess liver function tests, renal function (serum creatinine, eGFR, urine protein), and bone density periodically. Screen for hepatitis B co-infection (TDF component). Fetal ultrasound for growth and anatomy as per standard obstetrical care; no specific fetal monitoring required. Consider drug interaction checks with concomitant medications. |
| Fertility Effects | No evidence of adverse effects on male or female fertility in animal studies. Emtricitabine, rilpivirine, and tenofovir alafenamide do not impair fertility in humans. HIV infection itself may reduce fertility. No impact on assisted reproductive technologies. |
| Food/Dietary | Rilpivirine requires administration with a meal (≥390 kcal) to achieve adequate absorption. Coadministration with a high-fat meal increases exposure (AUC 24h ~50% higher vs fasting). Tofu and other soy products may decrease rilpivirine absorption and should be avoided within 2 hours of dosing. There are no significant food interactions for emtricitabine or tenofovir alafenamide beyond general dietary considerations. Grapefruit juice does not significantly affect rilpivirine levels but caution with other CYP3A4 substrates. |
| Clinical Pearls | Monitor renal function (serum creatinine, eGFR, urine glucose and protein) before and during therapy; TAF has less renal toxicity than TDF but still caution. Rilpivirine should be taken with a meal (≥390 kcal) to ensure adequate absorption. Contraindicated with proton pump inhibitors; H2 receptor antagonists and antacids require staggered dosing. Assess HBV co-infection prior to initiation; discontinuation may cause severe acute HBV exacerbation. Perform HLA-B*5701 testing before abacavir use (not applicable here but reminder for NRTI allergy). Monitor for depressive symptoms (rilpivirine). Drug interactions: rifampin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, St. John's wort contraindicated. Avoid use with strong CYP3A4 inducers. |
| Patient Advice | Take this medication exactly as prescribed — do not skip doses or stop without consulting your doctor. · Always take rilpivirine/emtricitabine/tenofovir alafenamide with a meal (at least 390 calories) for it to work properly. · Do not take this medication with proton pump inhibitors (e.g., omeprazole, esomeprazole). If you need antacids, take them at least 2 hours before or 4 hours after your dose. For H2 blockers (e.g., famotidine), take them at least 12 hours before or 4 hours after your dose. · Your doctor will perform regular blood tests to monitor kidney function and other health parameters. · If you have hepatitis B virus (HBV) infection, do not stop this medication without medical supervision, as it can cause a serious flare of hepatitis. · Report any symptoms of depression, mood changes, or suicidal thoughts to your healthcare provider immediately. · Contact your doctor if you experience signs of kidney problems (e.g., decreased urination, swelling in legs/ankles) or bone pain. · Do not breastfeed while taking this medication if you are living with HIV, to avoid transmission of the virus. · Inform all healthcare providers that you are taking this medication, especially before starting any new prescription, over-the-counter, or herbal products. · Practice consistent and correct condom use to prevent HIV transmission to others. |