Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)
Last Updated: April 27, 2017; Last Reviewed: April 27, 2017
|Rilpivirine (RPV, Edurant)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf
|Tablet: 25 mg
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
Antiretroviral-Naive Patients with HIV RNA ≤100,000 copies/mL or Virologically-Suppressed (HIV RNA <50 copies/mL) Patients with No History of Virologic Failure or Resistance to Rilpivirine and Other Antiretroviral (ARV) Drugs and Currently on Their First or Second Regimen:
[Complera] Emtricitabine plus Rilpivirine plus TDF
Adolescent (Weighing ≥35 kg) and Adult Dose:
Adolescent (Weighing ≥35 kg) and Adult Dose:
Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)
- Metabolism: Rilpivirine is a CYP 3A substrate and requires dosage adjustments when administered with CYP 3A-modulating medications.
- Before rilpivirine is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions.
- Co-administration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine.
- Antacids should only be taken either at least 2 hours before or at least 4 hours after rilpivirine.
- H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after rilpivirine.
- Do not use rilpivirine with proton pump inhibitors.
- Rifampin and rifabutin significantly reduce rilpivirine plasma concentrations; co-administration of rifampin with rilpivirine is contraindicated. For patients concomitantly receiving rifabutin, rilpivirine dose should be increased (doubled) to 50 mg once daily, taken with a meal.
- More common: Insomnia, headache, and rash
- Less common (more severe): Depression or mood changes, suicidal ideation.
- In adult studies, 7.3% of patients treated with rilpivirine showed a change in adrenal function identified by an abnormal 250-microgram ACTH stimulation test (peak cortisol level <18.1 micrograms/dL). In adolescent studies, 6/30 (20%) developed this abnormality.1 The clinical significance of these results is unknown.
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).
With the viral load and antiretroviral (ARV) resistance restrictions noted above, rilpivirine in combination with other antiretroviral agents,1 the combination tablet rilpivirine/emtricitabine/tenofovir disoproxil fumarate (Complera)2 and the combination tablet rilpivirine/emtricitabine/tenofovir alafenamide (TAF) (Odefsey) are Food and Drug Administration-approved in persons aged ≥12 years and weighing >35 kg.3
Efficacy in Clinical Trials
A rilpivirine-containing regimen has been compared to an efavirenz-containing regimen in 2 large clinical trials in adults, ECHO and THRIVE. In both studies, rilpivirine was demonstrated to be non-inferior to efavirenz. Subjects with pretreatment HIV viral loads ≥100,000 copies/mL receiving rilpivirine had higher rates of virologic failure compared to those receiving efavirenz. These findings resulted in licensure for initial therapy with rilpivirine only in patients with HIV viral load ≤100,000 copies/mL.4-7
A study of rilpivirine, 25 mg daily in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-naive adolescents aged 12 to 18 years, demonstrated that the regimen was well tolerated over 48 weeks. Among adolescents with baseline viral loads ≤100,000 copies/mL, 86% had a virologic response at 24 weeks and 79% at 48 weeks. Among adolescents with baseline viral loads >100,000 copies/mL, 38% had a virologic response at 24 weeks and 50% at 48 weeks.8
Patients selected for rilpivirine use need to be able to take the drug on a regular schedule and with a full meal, which may limit its usefullness for some adolescents with an irregular schedule. Odefsey is a small pill, and can be useful for select patients who do not have any drug resistance mutations who might want to switch from a multi-pill regimen.
The pharmacokinetics (PK), safety, and efficacy of rilpivirine in children aged <12 years have not been established but are under study in patients aged 6 to <12 years and weighing ≥17 kg (ClinicalTrials.gov identifier NCT00799864). The Panel considers that rilpivirine may be appropriate in select children aged <12 years as long as they weigh ≥35 kg; an expert in pediatric HIV infection should be consulted.
An international (India, Thailand, Uganda, and South Africa) Phase II trial, PAINT TMC278, investigated a 25-mg dose of rilpivirine in combination with 2 NRTIs in ARV-naive adolescents aged 12 to <18 years who weigh ≥32 kg and have a viral load ≤100,000 copies/mL.8 In the dose-finding phase of the study, 11 youth aged >12 to ≤15 years and 12 youth aged >15 to ≤18 years underwent intensive PK evaluations after an observed dose of rilpivirine taken with a meal. PK were comparable to those in adults; results are listed in the table below.9
|Parameter||Adults||Adolescents Aged 12 to <18 years|
|Dose||25 mg once daily||25 mg once daily|
|Mean ± Standard Deviation||2,235 ± 851||2,424 ± 1,024|
|Median (Range)||2,096 (198–7,307)||2,269 (417–5,166)|
|Mean ± Standard Deviation||79 ± 35||85 ± 40|
|Median (Range)||73 (2–288)||79 (7–202)|
|Key to Acronyms: AUC = area under the curve; C0 = plasma concentration just prior to next dose.|
In a PK study of youth aged 13 to 23 years receiving rilpivirine,10 rilpivirine exposure was comparable to the results from PAINT in those receiving 25 mg rilpivirine without darunavir/ritonavir (DRV/r) and substantially higher in those receiving 25 mg rilpivirine with DRV/r (AUC = 6,740 ngxh/mL). No dose adjustments are currently recommended for adults when rilpivirine is used in DRV/r , where a similar 2- to 3-fold increase in rilpivirine exposure has been reported.1
In the PAINT study the observed adverse events (AEs) were similar to those reported in adults (e.g., somnolence, nausea, vomiting, abdominal pain, dizziness, headache). The incidence of depressive disorders was 19.4% (7/36) compared to 9% in the Phase III trials in adults. The incidence of grades 3 and 4 depressive disorders was 5.6% (2/36).1
Six of 30 (20%) adolescents with a normal adrenocotropic hormone stimulation test at baseline developed an abnormal test during the trial. There were no serious AEs, deaths, or treatment discontinuations attributed to adrenal insufficiency. The clinical significance of these results is not known but warrants further evaluation.1
- Rilpivirine (Edurant) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf.
- Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (Complera) [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202123s021s024lbl.pdf.
- Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208351s000lbl.pdf.
- Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378(9787):229-237. Available at http://www.ncbi.nlm.nih.gov/pubmed/21763935.
- Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr. 2012;60(1):33-42. Available at http://www.ncbi.nlm.nih.gov/pubmed/22343174.
- Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27(6):939-950. Available at http://www.ncbi.nlm.nih.gov/pubmed/23211772.
- Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246. Available at http://www.ncbi.nlm.nih.gov/pubmed/21763936.
- Lombaard J, Bunupuradah T, Flynn PM, et al. Rilpivirine as a treatment for HIV-infected antiretroviral-naive adolescents: Week 48 safety, efficacy, virology and pharmacokinetics. Pediatr Infect Dis J. 2016. Available at http://www.ncbi.nlm.nih.gov/pubmed/27294305.
- Crauwels H, Hoogstoel A, Vanveggel S, et al. Rilpivirine pharmacokinetics in HIV-1-infected adolescents: a substudy of PAINT (Phase II trial). Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
- Foca M, Yogev R, Wiznia A, et al. Rilpivirine pharmacokinetics without and with darunavir/ritonavir once daily in adolescents and young adults. Pediatr Infect Dis J. 2016;35(9):e271-274. Available at http://www.ncbi.nlm.nih.gov/pubmed/27187753.