The Dosage and Administration section includes the following general dosing recommendations and dosing recommendations for pediatrics.
General Dosing Recommendations• ISENTRESS Film-Coated Tablets and Chewable Tablets can be administered with or without food
• Maximum dose of chewable tablets is 300 mg twice daily.
• ISENTRESS Chewable Tablets may be chewed or swallowed whole.
• ISENTRESS Film-Coated Tablets must be swallowed whole.
• Because the formulations are not bioequivalent, do not substitute chewable tablets for the 400 mg film-coated tablet.
• During coadministration of ISENTRESS 400 mg film-coated tablets with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily in adults. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age
PediatricsFor the treatment of children and adolescents with HIV-1 infection, the dosage of ISENTRESS is as follows:
• 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.
The following was added to Section 5 WARNINGS AND PRECAUTIONS:5.3 Phenylketonurics
ISENTRESS chewable tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS chewable tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS chewable tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
The following was added to Section 6 ADVERSE REACTIONS:6.5 Clinical Trials Experience: Pediatrics
ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 through 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066. Of the 126 patients, 96 received the recommended dose of ISENTRESS.
In these 96 children and adolescents, 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 text was added to Section 7 Drug Interactions subsection 7.2:• There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age
• All interaction studies were performed in adults
The following information was added to Section 8.4 Pediatric Use8.4 Pediatric Use
The safety, tolerability, pharmacokinetic profile, and efficacy of ISENTRESS were evaluated in HIV-1 infected children and adolescents 2 to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066. The safety profile was comparable to that observed in adults. See Dosage and Administration for dosing recommendations for children 2 years of age and older. Safety and effectiveness of ISENTRESS in children under 2 years of age have not been established.
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 pediatric patients.
Q95K/R was added to list of substitutions under 12.4 Microbiology/Antiviral Activity in Cell Culture section
The following was added under Section 14 CLINICAL STUDIES:
14.3 Pediatric SubjectsIMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects 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 optimized background regimen.
The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of ISENTRESS [see Dosage and Administration (2.3)].
These 96 subjects had a median age of 13 (range 2 to 18) years, were 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 2 to 18 years of age 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%).
Isentress is an HIV integrase strand transfer inhibitor manufactured by Merck & Co., Inc.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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