EMTRICITABINE, RILPIVIRINE 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.
Emtricitabine and tenofovir disoproxil fumarate are nucleoside reverse transcriptase inhibitors (NRTIs) that inhibit HIV-1 reverse transcriptase by competing with natural substrates and causing chain termination after incorporation into viral DNA. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to a hydrophobic pocket near the active site of HIV-1 reverse transcriptase, causing allosteric inhibition and preventing RNA-dependent DNA polymerization.
| Metabolism | Emtricitabine is metabolized by oxidation and conjugation to form 3'-sulfoxide diastereomers and glucuronide conjugates; metabolism is not mediated by CYP450 enzymes. Rilpivirine is primarily metabolized by CYP3A4. Tenofovir disoproxil fumarate is a prodrug that is converted to tenofovir, which undergoes minimal metabolism; tenofovir is eliminated unchanged in urine. |
| Excretion | Emtricitabine: 86% excreted unchanged in urine via glomerular filtration and active tubular secretion; 14% as metabolites. Rilpivirine: ~85% fecal as unchanged drug (25%) and metabolites (60%); ~6% urinary. Tenofovir disoproxil fumarate: 70-80% excreted unchanged in urine via glomerular filtration and active tubular secretion. |
| Half-life | Emtricitabine: terminal half-life ~10 hours (clinical context: supports once-daily dosing; prolonged in renal impairment). Rilpivirine: terminal half-life ~50 hours (clinical context: supports once-daily dosing; long half-life allows missed dose forgiveness). Tenofovir: terminal half-life ~17 hours (clinical context: supports once-daily dosing; prolonged in renal impairment). |
| Protein binding | Emtricitabine: <4% bound to plasma proteins. Rilpivirine: ~99.7% bound to albumin. Tenofovir: <7% bound to plasma proteins. |
| Volume of Distribution | Emtricitabine: Vd ~1.4 L/kg (widespread distribution, including cerebrospinal fluid). Rilpivirine: Vd ~152 L/kg (extensive tissue binding, limited CNS penetration). Tenofovir: Vd ~1.3 L/kg (primarily extracellular; poor CNS penetration). |
| Bioavailability | Oral, fixed-dose combination tablet: Emtricitabine ~93%; Rilpivirine ~95% (with food, especially fat-containing meal); Tenofovir disoproxil fumarate ~25% (prodrug; bioavailability enhanced by food). |
| Onset of Action | Oral administration: Emtricitabine reaches peak plasma concentrations in 1-2 hours; Rilpivirine in ~4-5 hours; Tenofovir in ~1 hour. Antiviral effect: Rapid inhibition of HIV replication within days; maximal suppression by 2-4 weeks. |
| Duration of Action | Once-daily dosing maintains therapeutic concentrations for 24 hours. Clinical note: Adherence is critical due to risk of resistance with missed doses, especially with rilpivirine (long half-life but low genetic barrier). |
| Molecular Weight | Emtricitabine: 247.2 Da; Rilpivirine: 366.4 Da; Tenofovir disoproxil fumarate: 635.5 Da |
One tablet (200 mg emtricitabine/25 mg rilpivirine/300 mg tenofovir disoproxil fumarate) orally once daily with a meal.
| Dosage form | TABLET |
| Renal impairment | Contraindicated when creatinine clearance (CrCl) <30 mL/min. For CrCl 30-49 mL/min, no dose adjustment of the combination; use individual components and adjust if needed. Not recommended in patients with CrCl <50 mL/min on hemodialysis. |
| Liver impairment | Child-Pugh Class A: No dose adjustment. Child-Pugh Class B or C: Not recommended due to lack of data; rilpivirine is not studied in moderate to severe hepatic impairment. |
| Pediatric use | Approved for patients weighing at least 35 kg and aged ≥12 years: One tablet (200 mg/25 mg/300 mg) orally once daily with a meal. For weight <35 kg, safety and efficacy not established; use individual components. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor renal function closely (CrCl) due to tenofovir disoproxil fumarate renal elimination and increased risk of renal impairment in elderly. |
| 1st trimester | Use only if potential benefit outweighs risk. Studies in animals have shown reproductive toxicity. Limited human data; however, antiretroviral therapy is generally recommended during pregnancy to prevent mother-to-child transmission. Monitor for anemia and neutropenia in neonates. |
| 2nd trimester | Use only if clearly needed. No teratogenic effects reported in human studies, but data are limited. Continued therapy is recommended to maintain viral suppression. |
| 3rd trimester | Use only if clearly needed. No adverse fetal outcomes reported. Tenofovir disoproxil fumarate may cause decreased bone mineral density in neonates; monitor bone health. |
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 cross the placenta; tenofovir reaches cord blood concentrations similar to maternal. Rilpivirine also crosses the placenta. |
■ FDA Black Box Warning
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate and emtricitabine. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued emtricitabine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely in these patients.
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to any componentConcurrent use with drugs that induce CYP3A (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) due to decreased rilpivirine levelsSevere renal impairment (CrCl < 30 mL/min) as tenofovir and emtricitabine require dose adjustmentHepatic decompensation in patients with cirrhosis
| Precautions | Hepatotoxicity: Monitor liver function; discontinue if signs of hepatotoxicity develop., Bone effects: Tenofovir DF may decrease bone mineral density; monitor in patients with osteoporosis risk., Renal impairment: Not recommended for patients with CrCl <30 mL/min; monitor renal function., Depressive disorders: Rilpivirine has been associated with depressive symptoms., Fat redistribution: Redistribution/accumulation of body fat may occur., Immune reconstitution syndrome: Monitor for inflammatory responses to indolent infections. |
Loading safety data…
| Breastfeeding | Emtricitabine and tenofovir are excreted into human breast milk in low concentrations; rilpivirine is also excreted. The risk of infant toxicity is low. However, due to potential for HIV transmission via breastfeeding, alternative feeding is recommended in developed countries. In resource-limited settings, breastfeeding may be considered under appropriate medical guidance. |
| Lactation Rating | L3: Limited data - probably compatible |
| Teratogenic Risk | Emtricitabine, rilpivirine, and tenofovir disoproxil fumarate: No increased risk of major malformations above baseline in first trimester (2-3%). Limited data, but no signal in second/third trimester. Animal studies show no teratogenicity at human doses. |
| Fetal Monitoring | Monitor maternal HIV RNA, CD4 count, LFTs, renal function (creatinine, phosphate, urine glucose/protein). Fetal ultrasound if delayed growth. Newborn HIV testing. |
| Fertility Effects | No significant effect on fertility in animal studies. Human data limited. HIV infection itself may impair fertility; ART may improve reproductive function. |
| Food/Dietary | Take with a meal (≥400 kcal) to ensure adequate rilpivirine absorption. Avoid St. John's wort supplements. |
| Clinical Pearls | Do not coadminister with rifamycins, proton pump inhibitors, or St. John's wort. Administer with a meal to optimize rilpivirine absorption. Monitor renal function at baseline and periodically due to tenofovir disoproxil fumarate nephrotoxicity. Screen for hepatitis B virus before initiation; discontinuation may cause severe HBV exacerbation. Use caution with medications that prolong QT interval. |
| Patient Advice | Take one tablet daily with a meal; do not take on an empty stomach. · Do not use antacids or proton pump inhibitors; separate H2 blockers by at least 12 hours. · Avoid St. John's wort and rifampin as they reduce drug levels and may cause treatment failure. · Complete laboratory monitoring including kidney function and hepatitis B status is required. · Report signs of kidney problems (decreased urine output, swelling) or liver problems (jaundice, dark urine). · This drug does not cure HIV or prevent transmission; use condoms and practice safe sex. |