FDA Approve U.S. Pediatric Dose for Raltegravir

January/February 2012

On 21 December 2011, the FDA approved dosing recommendations for raltegravir (Isentress) for paediatric patients ages 2 to 18 years and weighing at least 10 kg.

In addition a 100 mg scored chewable tablet and 25 mg chewable tablet was approved for use in paediatric patients.

Safety, efficacy and formulation data were from the IMPAACT P1066 Phase I/II study in 126 treatment experienced children (age 2 to 18 years) who received either the 400 mg film-coated tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than 12 years of age). Raltegravir was administered with an optimised background regimen.

The Dosage and Administration section includes the following dosing recommendations and dosing recommendations for pediatrics. Main changes to the product label are also included below.

General Dosing Recommendation

  • Raltegravir Film-Coated Tablets and Chewable Tablets can be administered with or without food
  • Maximum dose of chewable tablets is 300 mg twice daily.
  • Raltegravir Chewable Tablets may be chewed or swallowed whole.
  • Raltegravir Film-Coated Tablets must be swallowed whole.
  • Because the formulations are not bioequivalent, the chewable tablets should NOT be substituted for the 400 mg film-coated tablet.
  • During coadministration of raltegravir 400 mg film-coated tablets with rifampin, the recommended dosage of raltegravir is 800 mg twice daily in adults. There are no data to guide co-administration of raltegravir with rifampin in patients below 18 years of age. All interaction studies were performed in adults

Paediatric Dosing

Dosing is recommended based on age and weight:

  • 12 years of age and older:
    • One 400 mg film-coated tablet orally, twice daily
  • 6 to less than 12 years of age:
    • If at least 25 kg in weight:
      • One 400 mg film-coated tablet orally, twice daily OR
      • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 -- please refer to prescribing information for details.
    • If less than 25 kg in weight:
      • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 -- Please refer to prescribing information for details.
  • 2 to less than 6 years of age:
    • If at least 10 kg in weight:
      • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 -- Please refer to prescribing information for details.

Warnings and Precautions

Raltegravir chewable tablets contain phenylalanine, a component of aspartame. Each 25 mg raltegravir chewable tablet contains approximately 0.05 mg phenylalanine. Each 100 mg raltegravir chewable tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

Adverse Reactions

In the IMPAACT P1066, frequency, type and severity of drug related adverse reactions through week 24 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

The following information was added to Section 12.3 Pharmacokinetics:

  • Under Absorption: Based on a formulation comparison study in healthy adult volunteers, the chewable tablet has higher oral bioavailability than the film-coated tablet
  • Under Effect of Food on Oral Absorption: Administration of chewable tablet with high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food
  • Special Populations: The doses recommended for HIV-infected children and adolescents 2 to 18 years of age resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. A Table was added to the package insert to display the raltegravir steady state pharmacokinetic parameters in paediatric patients.

Clinical Studies

The median age of the 96 study participants in IMPAACT P106 receiving the recommended raltegravir dose was 13 (range 2 to 18) years, 51% female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0-2361) and median CD4% was 23.3% (range: 0-44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 72% achieved HIV RNA <400 copies/mL or =1 log10 HIV RNA drop from baseline. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).

Source: FDA HIV/AIDS Update (21 December 2011).

For full details please refer to the updated prescribing information:

Links to external websites are current at time of posting but not maintained.

This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

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