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On December 20, 2013, FDA approved a new dosage form, ISENTRESS® (raltegravir) for oral suspension, in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients 4 weeks of age and older, weighing at least 3 kg to less than 20 kg. This also includes a new Instructions for Use document as part of the patient labeling. Below is a summary of the label changes.
Merck expects to have ISENTRESS® (raltegravir) for oral suspension commercially available by the third quarter of 2014.
INDICATIONS AND USAGE
ISENTRESS® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in patients 4 weeks of age and older.
DOSAGE AND ADMINISTRATION
General Dosing Recommendations
• ISENTRESS Film-Coated Tablets, Chewable Tablets and For Oral Suspension can be administered with or without food
• Because the formulations are not bioequivalent, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
• Maximum dose of chewable tablets is 300 mg twice daily.
• Maximum dose of oral suspension is 100 mg twice daily.
• Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 5 mL of water giving a final concentration of 20 mg/mL.
Pediatrics
- If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.
If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1.
Table 1: Alternative Dose* with ISENTRESS Chewable Tablets for Pediatric Patients Weighing at Least 25 kg
|
Body Weight (kg) |
Dose
|
Number of Chewable Tablets |
|
25 to less than 28 |
150 mg twice daily |
1.5 x 100 mg† twice daily |
|
28 to less than 40 |
200 mg twice daily |
2 x 100 mg twice daily |
|
At least 40 |
300 mg twice daily |
3 x 100 mg twice daily |
|
*The weight-based dosing recommendation for the chewable tablet is based on approximately 6 mg/kg/dose twice daily [see Clinical Pharmacology (12.3)]. †The 100 mg chewable tablet can be divided into equal halves. |
||
- If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.
- For patients weighing between 11 and 20 kg, either the chewable tablet or oral suspension can be used, as specified in Table 2. Patients can remain on the oral suspension as long as their weight is below 20 kg. Refer to Table 2 for appropriate dosing
Table 2: Recommended Dose* for ISENTRESS for Oral Suspension and Chewable Tablets in Pediatric Patients Weighing Less than 25 kg
|
Body Weight (kg) |
Volume (Dose) of Suspension to be Administered |
Number of Chewable Tablets |
|
|
|
3 to less than 4 |
1 mL (20 mg) twice daily |
|
|
|
|
4 to less than 6 |
1.5 mL (30 mg) twice daily |
|
||
|
6 to less than 8 |
2 mL (40 mg) twice daily |
|
||
|
8 to less than 11 |
3 mL (60 mg) twice daily |
|
||
|
11 to less than 14† |
4 mL (80 mg) twice daily |
3 x 25 mg twice daily |
|
|
|
14 to less than 20† |
5 mL (100 mg) twice daily |
1 x 100 mg twice daily |
|
|
|
20 to less than 25 |
|
1.5 x 100 mg‡ twice daily |
|
|
|
|
*The weight-based dosing recommendation for the chewable tablet and oral suspension is based on approximately 6 mg/kg/dose twice daily [see Clinical Pharmacology (12.3)]. †For weight between 11 and 20 kg either formulation can be used. Note: The chewable tablets are available as 25 mg and 100 mg tablets. ‡The 100 mg chewable tablet can be divided into equal halves. |
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Method of Administration
ISENTRESS For Oral Suspension
Each single-use ISENTRESS packet for oral suspension contains 100 mg of raltegravir which is to be suspended in 5 mL of water giving a final concentration of 20 mg/mL.
- Pour packet contents of ISENTRESS for oral suspension into 5 mL of water and mix
- Once mixed, measure the recommended volume (dose) of suspension with a syringe and administer the dose orally
- The volume (dose) of suspension should be administered orally within 30 minutes of mixing
- Discard any remaining suspension
- For more details on preparation and administration of the suspension, see Instructions for Use.
ADVERSE REACTIONS
4 Weeks to less than 2 Years of Age
ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations (8.4) and Clinical Studies (14.3)].
In these 26 infants and toddlers, the frequency, type and severity of drug-related adverse reactions through Week 48 were comparable to those observed in adults.
One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation.
CLINICAL PHARMACOLOGY
Effect of Food on Oral Absorption
The effect of food on the formulation for oral suspension was not studied.
Special Populations
Pediatric
Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 9, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age [see Dosage and Administration (2.3)] resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily.
Overall, dosing in pediatric patients achieved exposures (Ctrough) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM) [see Clinical Studies (14.3)]. As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet [see Dosage and Administration (2.3)]. In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.
Table 9: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Doses
|
Body Weight |
Formulation |
Dose |
N* |
Geometric Mean (%CV†) AUC0-12hr (μM●hr) |
Geometric Mean (%CV†) C12hr (nM) |
|
≥25 kg |
Film-coated tablet |
400 mg twice daily |
18 |
14.1 (121%) |
233 (157%) |
|
≥25 kg |
Chewable tablet |
Weight based dosing, see Table 1 |
9 |
22.1 (36%) |
113 (80%) |
|
11 to less than 25 kg |
Chewable tablet |
Weight based dosing, see Table 2 |
13 |
18.6 (68%) |
82 (123%) |
|
3 to less than 20 kg |
Oral suspension |
Weight based dosing, see Table 2 |
19 |
24.5 (43%) |
113 (69%) |
|
*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. †Geometric coefficient of variation. |
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The pharmacokinetics of raltegravir in infants under 4 weeks of age has not been established.
CLINICAL STUDIES
4 Weeks to Less Than 2 Years of Age
IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.
The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log10 copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm3 (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 patients were completely treatment naïve. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of patients greater than 6 months of age had received two or more antiretrovirals.
Of the 26 treated subjects, 23 subjects were included in the Week 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.
At Week 24, 39% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 500 cells/mm
At Week 48, 44% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 492 cells/mm3 (7.8%).
The revised label will be posted at Drugs@FDA.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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