Section 1 Indications and Usage, Section 2 Dosage and Administration, and Section 3 Dosage Forms and Strenghts were modified to reflect the changes.

Dosing recommendations are provided based on the pharmacokinetic, activity and safety data from study TMC114-C212 in children 6- <18 years of age. A description of study TMC114-C212 including the pharmacokinetic, safety and activity results, and rationale for dose selection for children were included in Section 6 Adverse Reactions, Section 8 Use in Specific Populations, Section 12 Clinical Pharmacology and Section 14 Clinical Studies as shown below.

1 Indications and Usage

1.2 Pediatric Patients.
PREZISTA, co-administered with ritonavir (PREZISTA/rtv), and with other antiretroviral agents, is indicated for the treatment of HIV infection in pediatric patients 6 years of age and older [see Use in Specific Populations (8.4)].

This indication is based on 24-week analyses of plasma HIV RNA levels and CD4+ cell counts from an open-label Phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to < 18 years of age.

2 Dosage and Administration

2.2 Pediatric Patients (age 6 to < 18 years)
Do not use once daily dosing in pediatric patients.

Healthcare professionals should pay special attention to accurate dose selection of PREZISTA, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should select the appropriate dose of PREZISTA/rtv for each individual child based on body weight (kg) and should not exceed the recommended dose for treatment-experienced adults.

Before prescribing PREZISTA, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA tablets may not be appropriate.

The recommended dose of PREZISTA/rtv for pediatric patients (6 to < 18 years of age and weighing at least 44 lbs (20 kg)) is based on body weight (see Table 1) and should not exceed the recommended treatment-experienced adult dose (PREZISTA/rtv 600/100 mg b.i.d.). PREZISTA tablets should be taken with ritonavir twice daily and with food.

The safety and efficacy of PREZISTA/rtv in pediatric patients 3 to < 6 years of age have not been established.

PREZISTA/rtv should not be used in pediatric patients below 3 years of age [see Warnings and Precautions (5.11) and Nonclinical Toxicology (13.2)].

3 Dosage Forms and Strengths

3.1 PREZISTA 75 mg Tablets
PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with “75” on one side and “TMC” on the other side.

6 Adverse Reactions

6.6 Clinical Trials Experience: Treatment-Experienced Pediatric Patients
PREZISTA/rtv has been studied in 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) in combination with other antiretroviral agents [see Use in Specific Populations (8.4) and Clinical Studies (14.4)].

Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults. ADRs to PREZISTA/rtv (all grades, ≥ 3%), excluding laboratory abnormalities reported as ADRs, were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%).

Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%, Grade 4: 0%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%, Grade 4: 0%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).

8 Use in Specific Populations
 

8.4 Pediatric Use
PREZISTA/rtv should not be used in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Warnings and Precautions (5.11), Use in Specific Populations (8.1), Clinical Pharmacology (12.3) and Nonclinical Toxicology (13.2)].

The pharmacokinetics, safety, tolerability, and efficacy of PREZISTA/rtv in pediatric patients 3 to < 6 years of age have not been established.

PREZISTA/rtv once daily should not be used in pediatric patients.

The safety, pharmacokinetic profile, and virologic and immunologic responses of PREZISTA/rtv were evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) [see Adverse Reactions (6.6), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.6)]. Please see Dosage and Administration (2.2) for dosing recommendations for pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg).

12.3 Pharmacokinetics

Pediatric Patients
The pharmacokinetics of darunavir in combination with ritonavir in 74 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg) showed that the administered weight-based dosages resulted in darunavir exposure comparable to that in treatment-experienced adults receiving PREZISTA/rtv 600/100 mg twice daily [see Dosage and Administration (2.2)].

14 CLINICAL STUDIES

Pediatric Patients:
The pharmacokinetic profile, safety and antiviral activity of PREZISTA/rtv was evaluated in a randomized, open-label, multicenter study. This study enrolled treatment-experienced pediatric subjects between the ages of 6 and < 18 years and weighing at least 44 lbs (20 kg). Patients were stratified according to their weight (≥ 20 - < 30 kg, ≥ 30 - < 40 kg, ≥ 40 kg) and received PREZISTA/rtv plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of PREZISTA/rtv. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.

The 80 randomized pediatric subjects had a median age of 14 (range 6 - < 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm3 (range: 6 to 1505 cells/mm3). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ³ 100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.

Seventy-seven pediatric subjects (96%) completed the 24 week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation.

The proportion of pediatric subjects with HIV-1 RNA < 400 copies/mL and < 50 copies/mL was 64% and 50%, respectively. The mean CD4+ cell count increase from baseline was 117 cells/mm3.

The dose selection was based on the following:

• Similar darunavir plasma exposures in children compared to adults
• Similar virologic response rates and safety profile in children compared to adults

The complete revised labeling will be posted soon on the FDA web site at Drugs@FDA.
 

Prezista is a Protease Inhibitor, manufactured by Tibotec Inc.
 

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration