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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Rilpivirine

(Last updated: April 26, 2016; last reviewed: April 26, 2016)

Rilpivirine (RPV, Edurant)
Rilpivirine (RPV, Edurant)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Tablet: 25 mg
Fixed-Dose Combination Tablets:
  • [Complera] Emtricitabine 200 mg plus rilpivirine 25 mg plus tenofovir disoproxil fumarate (TDF) 300 mg
  • [Odefsey] Emtricitabine 200 mg plus rilpivirine 25 mg plus tenofovir alafenamide (TAF) 25 mg
Dosing Recommendations Selected Adverse Events
Neonate/Infant Dose:
  • Not approved for use in neonates/infants.
Children Aged <12 Years:
  • Not approved for use in children aged <12 years.
Adolescent (Weighing ≥35 kg) and Adult Dose
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:
  • 25 mg once daily
Combination Tablet
[Complera] Emtricitabine plus Rilpivirine plus TDF
Adolescent (Weighing ≥35 kg) and Adult Dose:
  • 1 tablet once daily in treatment-naive patients with baseline viral load <100,000 copies/mL or to replace a stable ARV regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months with no history of treatment failure and have no known current or past substitutions associated with resistance to the individual components of Complera, and currently on their first or second regimen.
[Odefsey] Emtricitabine plus Rilpivirine plus TAF
Adolescent (Weighing ≥35 kg) and Adult Dose:
  • 1 tablet once daily with a meal as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA <50 copies per mL) for at least 6 months with no history of treatment failure and have no known current or past substitutions associated with resistance to the individual components of Odefsey.
  • Depression
  • Insomnia
  • Headache
  • Rash (can be severe and include Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS])
  • Hepatotoxicity
Special Instructions
  • Patients must be able to take rilpivirine with a meal of at least 500 calories on a regular schedule (a protein drink alone does not constitute a meal).
  • Do not use rilpivirine with other non-nucleoside reverse transcriptase inhibitors.
  • Do not use rilpivirine with proton pump inhibitors.
  • Antacids should only be taken either at least 2 hours before or at least 4 hours after rilpivirine.
  • Use rilpivirine with caution when co-administered with a drug with a known risk of torsades de pointes (see https://www.crediblemeds.org/).
  • Do not start rilpivirine in patients with HIV RNA >100,000 copies/mL because of increased risk of virologic failure.
Metabolism/Elimination
  • Cytochrome P450 (CYP) 3A substrate
  • Dosing in patients with hepatic impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment.
  • Rilpivirine decreases tubular secretion of creatinine and slightly increases measured serum creatinine, but does not affect glomerular filtration.
  • Dosing in patients with renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment.
  • Complera (fixed-dose combinations) should not be used in patients with CrCl <50 mL/min or in patients requiring dialysis.
  • Use rilpivirine with caution in patients with severe renal impairment or end-stage renal disease. Increase monitoring for adverse effects because rilpivirine concentrations may be increased in patients with severe renal impairment or end-stage renal disease.
  • When using Complera see the TDF section; when using Odefsey see the TAF section.

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.

Major Toxicities

  • More common: Insomnia, headache, and rash
  • Less common (more severe): Depression or mood changes, suicidal ideation

Resistance

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/).

Pediatric Use

Approval
Rilpivirine is approved in combination with other antiretroviral (ARV) agents for treatment-naive, HIV-infected adolescents aged ≥12 years, weighing at least 35 kg, and with viral load ≤100,000 copies/mL. In addition, the combination tablet rilpivirine/emtricitabine/tenofovir disoproxil fumarate (Complera) is approved in virologically suppressed adults (HIV RNA <50 copies/mL) on their first or second regimen with no history of virologic failure or current or past history of resistance to any of the components of Complera.

Pharmacokinetics and Efficacy

The pharmacokinetics (PK), safety, and efficacy of rilpivirine in children aged <12 years have not been established. An international (India, Thailand, Uganda, and South Africa) Phase II trial, Pediatric Study in Adolescents Investigating a New NNRTI TMC278 (PAINT) is investigating a 25-mg dose of rilpivirine in combination with 2 nucleoside reverse transcriptase inhibitors in ARV-naive adolescents aged 12 to <18 years who weigh ≥32 kg and have a viral load ≤100,000 copies/mL.1

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.2

Rilpivirine Pharmacokinetics in Adolescents and Adolescent/Adult Ratio: PAINT Study2
PK Parameter, Geometric Mean (Range) Adolescent PK Adolescent/Adult Ratio (95% CI)
Time to Reach Maximum Concentration,
Median (range in hours)
5 (2–9) N/A
Cmax (ng/mL)
102 (49–182) 0.88 (0.68–1.14)
Cmin (ng/mL) 51 (20–115)a N/A
C0h (ng/mL)
71 (20–191)   
1.21 (0.91–1.61)
C24h (ng/mL) 64 (33–162) 1.10 (0.85–1.41)
AUC24h (ngxh/mL)
1750 (887–3573) 0.98 (0.78–1.25)
a Correction provided by personal communication via email from Herta Crauwels, November 11, 2014.
Key to Acronyms: AUC = area under the curve; CI = confidence interval; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; PK = pharmacokinetic


In a PK study of youth aged 13 to 23 years receiving rilpivirine,3 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 = 6740 ngxh/mL). No dose adjustments are currently recommended for adults when rilpivirine is used in combination DRV/r , where a similar 2- to 3-fold increase in rilpivirine exposure has been reported.4

In the efficacy analysis of the PAINT Study most participants (75%, 28/36) had a baseline viral load ≤100,000 copies/mL. Twenty-two of those 28 (79%) achieved a viral load <50 copies/mL at week 48, while only 50% (4/8) with a baseline viral load >100,000 copies/mL achieved a viral load <50 copies/mL at week 48.5

Toxicity

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).4

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.

References

  1. ClinicalTrials.gov. A study to evaluate the pharmacokinetics, safety, tolerability, and antiviral efficacy of tmc278 TMC278 in human Human immunodeficiency Immunodeficiency virus Virus infected adolescents. ClinicalTrials.gov Identifier: NCT00799864. Available at http://clinicaltrials.gov/show/NCT00799864. Accessed April 8, 2016.
  2. 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.
  3. Foca M, Yogev, R, Andrew, W, et al. rilpinivirine pharmacokinetics with/without darunavir/r in adolescents and young adults. Presented at: 21st Conference on Retroviruses and Opportunistic Infection; . 2014; . Boston, MA.
  4. Rilpivirine [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf. Accessed January 29, 2016.
  5. Lombaard J, Bunupuradah T. Week 48 safety and efficacy of a rilpivirine (TMC278)-based regimen in HIV-infected treatment-naïve adolescents: PAINT phase II trial. Presented at: 7th International Workshop on HIV Pediatrics. 2015. Vancouver, Canada.

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