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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: March 5, 2015; last reviewed: March 5, 2015)

Rilpivirine (RPV, Edurant, TMC 278)

Rilpivirine (RPV, Edurant, TMC 278)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations

Tablet: 25 mg
Fixed-Dose Combination Tablet:
With emtricitabine and tenofovir disoproxil fumarate (tenofovir):
  • Rilpivirine 25 mg + emtricitabine 200 mg + tenofovir 300 mg (Complera)
Dosing Recommendations

Neonate/Infant Dose:

  • Not approved for use in neonates/infants.
Pediatric Dose:
  • Not approved for use in children. A clinical trial in treatment-naive adolescents (aged 12–18 years) is under way using a 25-mg dose.
Adolescent (>18 years)/Adult Dose
Antiretroviral-Naive Patients with HIV RNA ≤100,000 copies/mL:
  • 25 mg once daily
Virologically-Suppressed (HIV RNA <50 copies/mL) Patients with No History of Virologic Failure or Resistance to Rilpivirine and Other ARVs and Currently on Their First or Second Regimen:
  • 25 mg once daily
Selected Adverse Events
  • Depression, mood changes
  • Insomnia
  • Headache
  • Rash
  • 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
  • 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.
  • 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.

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.
  • Rifabutin and rifampin significantly reduce rilpivirine plasma concentrations; therefore, co-administration of rifabutin or rifampin with rilpivirine is contraindicated.

Major Toxicities

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

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) 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 adults with viral load ≤100,000 copies/mL and in virologically-suppressed patients (HIV RNA <50 copies/mL) on their first or second regimen with no history of virologic failure or resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Pharmacokinetics

The pharmacokinetics (PK), safety, and efficacy of rilpivirine in pediatric patients 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. Results and adult comparison data are listed in the table below.2

Rilpivirine PK 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, 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 slightly higher than results from PAINT in those receiving 25 mg rilpivirine without darunavir/ritonavir (AUC = 2380 ngxh/mL) and substantially higher in those receiving 25 mg rilpivirine with darunavir/ritonavir (AUC = 6740 ngxh/mL). No dose adjustments are currently recommended for adults when rilpivirine is used in combination with darunavir/ritonavir, where a similar 2- to 3-fold increase in rilpivirine exposure has been reported.4

Toxicity

In the PAINT study the observed adverse events were similar to those reported in adults. Eight adverse events were reported in 5 of 25 participants as being at least possibly related to rilpivirine (e.g., somnolence, nausea, upper abdominal pain, fever, dizziness, headache); all were grade 1 in severity.

References

  1. A study to evaluate the pharmacokinetics, safety, tolerability, and antiviral efficacy of TMC278 in HIV infected adolescents. Identifier: NCT00799864. ClinicalTrials.gov Available at http://clinicaltrials.gov/show/NCT00799864. Accessed January 8, 2015
  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, MA2014.
  4. Edurant (Rilpivirine) [Package Insert]. Food and Drug Administration. 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf. Last accessed January 8, 2015.

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