Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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Entry and Fusion Inhibitors

Maraviroc

Last Updated: April 27, 2017; Last Reviewed: April 27, 2017

Maraviroc (MVC, Selzentry)
Maraviroc (MVC, Selzentry)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Tablets: 25 mg, 75mg, 150 mg and 300 mg
Oral Solution: 20 mg/mL
Dosing Recommendations Selected Adverse Events
Neonate/Infant Dose:
  • Not approved for use in neonates/infants.
Pediatric Dose:
  • Approved for use by children aged ≥2 years and weighing ≥10 kg
Recommended Dosage in Antiretroviral Experienced Children Aged ≥2 Years and Weighing ≥10 kg: Tablets or Oral Suspension
When given with potent cytochrome P (CYP) 3A inhibitors (with or without a potent CYP3A inducer) including elvitegravir/ritonavir (EVG/r) and protease inhibitors (PIs) (except tipranavir/ritonavir [TPV/r]):
Weight Band Twice-Daily Dosing Liquid 20 mg/mL Tablets
10 kg to <20 kg 50 mg 2.5 mL 2 25-mg
20 kg to <30 kg 75 mg 4 mL 1 75-mg
30 kg to <40 kg 100 mg 5 mL 1 25-mg & 1 75-mg
>40 kg 150 mg 7.5 mL 1 150-mg
When given with nucleoside reverse transcriptase inhibitors (NRTIs), enfuvirtide, TPV/r, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or inducers:
Weight Band Twice-Daily Dosing Liquid 20 mg/mL Tablets
10 kg to <20 kg Not recommended
20 kg to <30 kg Not recommended
30 kg to <40 kg 300 mg 15 mL 1 300-mg
>40 kg 300 mg 15 mL 1 300-mg
When given with potent CYP3A inducers including efavirenz and etravirine (without a potent CYP3A inhibitor):
Not recommended


Adult Dose
When given with potent CYP3A inhibitors (with or without a potent CYP3A inducer) including PIs (except TPV/r) and EVG/r 150 mg twice daily
When given with NRTIs, enfuvirtide, TPV/r, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or inducers 300 mg twice daily
When given with potent CYP3A inducers including efavirenz and etravirine (without a potent CYP3A inhibitor) 600 mg twice daily
  • Vomiting, diarrhea
  • Cough
  • Upper respiratory tract infections
  • Dizziness
  • Fever
  • Rash
  • Hepatotoxicity (which may be preceded by severe rash and/or other signs of systemic allergic reaction)
  • Postural hypotension (generally in patients with severe renal insufficiency)
Special Instructions
  • Maraviroc is recommended for patients with only CCR5-tropic HIV-1. Conduct testing with HIV tropism assay (see Antiretroviral Drug-Resistance Testing in Adult and Adolescent Antiretroviral Guidelines) before using MVC to exclude the presence of CXCR4-using or mixed/dual-tropic HIV. Do not use if CXCR4 or mixed/dual-tropic HIV is present.
  • Maraviroc can be given without regard to food.
  • Instruct patients on how to recognize symptoms of allergic reactions or hepatitis.
  • Use caution when administering maraviroc to patients with underlying cardiac disease.
Metabolism/Elimination
  • Cytochrome P450 3A4 (CYP3A4) substrate
  • Dosing of maraviroc in patients with hepatic impairment: Use caution when administering maraviroc to patients with hepatic impairment. Because maraviroc is metabolized by the liver, concentrations may be increased in patients with hepatic impairment.
  • Dosing of maraviroc in adults and adolescents with renal impairment: refer to the manufacturer’s prescribing information.
  • Data are insufficient to make dosing recommendations for use of maraviroc in children concomitantly receiving non-interacting medications and weighing less than 30 kg or in all children concomitantly receiving potent CYP3A inducers without a potent CYP3A inhibitor.

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/)

Absorption
Absorption of maraviroc is slightly reduced with ingestion of a high-fat meal. There were no food restrictions in the adult trials (using the tablet formulation) or in the pediatric trial (using both tablet and oral solution formulations) that demonstrated the efficacy/antiviral activity and safety of maraviroc. Therefore, maraviroc can be given with or without food.

Metabolism
Maraviroc is a cytochrome P (CYP)3A and p-glycoprotein (Pgp) substrate and requires dosage adjustments when administered with CYP- or Pgp-modulating medications.

Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions with maraviroc; recommended maraviroc dosages are based on concomitant medications and their anticipated effect on maraviroc metabolism.

Major Toxicities

  • More common: Cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.
  • Less common (more severe): Hepatotoxicity that may be preceded by evidence of a systemic allergic reaction (such as pruritic rash, eosinophilia or elevated immunoglobulin) has been reported. Serious adverse events (AEs) occurred in fewer than 2% of maraviroc-treated adult patients and included cardiovascular abnormalities (e.g., angina, heart failure, myocardial infarction), hepatic cirrhosis or failure, cholestatic jaundice, viral meningitis, pneumonia, myositis, osteonecrosis, and rhabdomyolysis.

Resistance

HIV tropism assay should be performed before use. The International AIDS 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). Clinical failure may also represent the outgrowth of CXCR4-using (naturally resistant) HIV variants.

Pediatric Use

Approval
Maraviroc is approved by the Food and Drug Administration in children aged ≥2 years and weighing ≥10 kg who have CCR5-tropic HIV-1.1

Pharmacokinetics and Efficacy
The pharmacokinetics, safety, and efficacy of maraviroc have been examined in a dose-finding and efficacy study involving treatment experienced children aged 2 to 17 years weighing at least 10 kg and having HIV-1 plasma RNA >1000 copies/mL. In this trial, maraviroc dose was based upon body surface area and the composition of the optimized background therapy: most (90/103; 87%) received maraviroc in combination with potent CYP3A inhibitors, and only 3 participants received maraviroc with CYP3A inducers. The key pharmacologic target (geometric mean Caverage of >100 ng/mL) was achieved with both the tablet and oral solution formulations of maraviroc. From a mean baseline plasma HIV-1 RNA of 4.4 log10 copies/mL, a decrease of >1 log10 occurred in all 4 age-based cohorts. Overall, 48% of participants achieved a decrease to <48 copies/mL at Study Week 48 and 65% of subjects achieved plasma HIV-1 RNA <400 copies/mL. The most common maraviroc-related AEs through 48 weeks were diarrhea (16.5%), vomiting (16.5%), and upper respiratory infections (13.6%).2

References

  1. Maravirioc (Selezentry) [package insert]. Food and Drug Administration. 2016. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208984_022128s017lbl.pdf.
  2. Giaquinto C, Mawela MP, Chokephaibulkit C, et al. Pharmacokinetics, safety and efficacy of maraviroc in pediatric patients with R5 HIV. Presented at: Conference on Retroviruses and Opportunistic Infections. 2016.Boston, MA.

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