On October 6, 2006, The Food and Drug Administration approved dosing
recommendations for NORVIR (ritonavir) in pediatric patients one month to
two years of age. The major revisions to the package insert include the
following:

CLINICAL PHARMACOLOGY
This section was modified to include pharmacokinetic data in
children 1 month to 2 years of age. The new Clinical Pharmacology section
for Pediatric Patients reads as follows:

Pediatric Patients

Steady-state pharmacokinetics were evaluated in 37 HIV infected
patients ages 2 to 14 years receiving doses ranging from 250 mg/m2
twice-daily to 400 mg/m2 twice daily in PACTG Study 310, and in 41
HIV-infected patients ages 1 month to 2 years at doses 350 and 450 mg/m2
twice daily in PACTG Study 345. Across dose groups, ritonavir steady-state
oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in
pediatric patients than in adult subjects. Ritonavir concentrations obtained
after 350 to 400 mg/m2 twice daily in pediatric patients > 2 years were
comparable to those obtained in adults receiving 600 mg (approximately 330
mg/m2) twice daily. The following observations were seen regarding ritonavir
concentrations after administration with 350 or 450 mg/m2 twice daily in
children < 2 years of age. Higher ritonavir exposures were not evident with
450 mg/m2 twice daily compared to the 350 mg/m2 twice daily. Ritonavir
trough concentrations were somewhat lower than those obtained in adults
receiving 600 mg twice daily. The area under the ritonavir plasma
concentration-time curve and trough concentrations obtained after
administration with 350 or 450 mg/m2 twice daily were approximately 16% and
60% lower, respectively, than that obtained in adults receiving 600 mg twice
daily. 

PRECAUTIONS
The following information was added under the section of Pediatric
Use subsection:

Pediatric Use

In HIV-infected patients age > 1 month to 21 years, the antiviral
activity and adverse event profile seen during clinical trials and through
postmarketing experience were similar to that for adult patients. 

ADVERSE REACTIONS
The following information was added under the section of Pediatric
Use subsection. Of note, the treatment-emergent adverse events and
laboratory abnormalities shown in the label reflect the summary of the
adverse events and laboratory abnormalities observed in pediatric studies
M95-310, PACTG 366, and PACTG 345.

Pediatrics

Treatment-Emergent Adverse Events

NORVIR has been studied in 265 pediatric patients > 1 month to 21
years of age. The adverse event profile observed during pediatric clinical
trials was similar to that for adult patients. 

Vomiting, diarrhea, and skin rash/allergy were the only drug-related
clinical adverse events of moderate to severe intensity observed in ≥ 2% of
pediatric patients enrolled in NORVIR clinical trials.

Laboratory Abnormalities

The following Grade 3-4 laboratory abnormalities occurred in ≥ 3% of
pediatric patients who received treatment with NORVIR either alone or in
combination with reverse transcriptase inhibitors: neutropenia (9%),
hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST
(3%).

DOSAGE AND ADMINISTRATION
The section of Pediatric Patients has been modified to include
dosing recommendations for children > 1 month to 2 years of age. The new
Dosage and Administration section for Pediatric Patients is:

Pediatric Patients

Ritonavir should be used in combination with other antiretroviral
agents (see General Dosing Guidelines). The recommended dosage of ritonavir
in children > 1 month is 350 to 400 mg/m2 twice daily by mouth and should
not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m2 and
increased at 2 to 3 day intervals by 50 mg/m2 twice daily. If patients do
not tolerate 400 mg/m2 twice daily due to adverse events, the highest
tolerated dose may be used for maintenance therapy in combination with other
antiretroviral agents, however, alternative therapy should be considered.
When possible, dose should be administered using a calibrated dosing
syringe.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration