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Sustiva (efavirenz) pediatric patients labeling update




 

On May 2, 2013, the FDA expanded the indication for Sustiva (efavirenz) to include pediatric patients at least three months old and weighing at least 3.5 kg. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration.

The updated labeling includes a table for dosing along with the corresponding number of capsules or tablets and strength to administer...

Patient Body Weight

Sustiva Daily Dose

Number of Capsulesa or Tablets b and Strength to Administer

3.5 kg to less than 5 kg

100 mg

two 50 mg capsules

5 kg to less than 7.5 kg

150 mg

three 50 mg capsules

7.5 kg to less than 15 kg

200 mg

one 200 mg capsule

15 kg to less than 20 kg

250 mg

one 200 mg + one 50 mg capsule

20 kg to less than 25 kg

300 mg

one 200 mg + two 50 mg capsules

25 kg to less than 32.5 kg

350 mg

one 200 mg + three 50 mg capsules

32.5 kg to less than 40 kg

400 mg

two 200 mg capsules

at least 40 kg

600 mg

one 600 mg tablet OR
three 200 mg capsules

a Capsules can be administered intact or as sprinkles
b Tablets must not be crushed

2.3 Capsule Sprinkle Method of Administration
For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons (10 mL) of reconstituted room temperature infant formula in a medicine cup by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the SUSTIVA-food or  formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining SUSTIVA residue, and administered to the patient. The SUSTIVA-food or  formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of SUSTIVA.

The Warnings and Precautions Section 5.7 Rash was updated to include information regarding pediatric patients as follows:
Rash was reported in 59 of 182 pediatric patients (32%) treated with SUSTIVA. Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with SUSTIVA in pediatric patients should be considered.

Section 6 Adverse Reactions was updated to include clinical trial experience in pediatric patients
Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received SUSTIVA in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash.

Section 8.4 Pediatric Use was updated as follows:
The safety, pharmacokinetic profile, and virologic and immunologic responses of SUSTIVA were evaluated in antiretroviral-naive and  experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults.
Use of SUSTIVA in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of SUSTIVA have not been evaluated in this age group and there is a risk of developing HIV resistance if SUSTIVA is underdosed. See Dosage and Administration (2.2) for dosing recommendations for pediatric patients.

Section 12.3 Pharmacokinetics was also updated to include pharmacokinetic parameters for Sustiva at steady state in pediatrics. Of note the data is predicted by a population pharmacokinetic model by weight ranges that correspond to the recommended doses.

Also the effect of food on oral absorption was included as follows:
Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.

Section 14 Clinical Studies was updated as follows:
14.2  Pediatric Patients
Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with SUSTIVA. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA

Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with SUSTIVA. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA

Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with SUSTIVA. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA

Sustiva is a Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI), and is a product of Bristol Myers Squibb.

The complete revised labeling will be posted soon on 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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Information in this article was accurate in May 3, 2013. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.