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New pediatric dosage form and label changes for Reyataz (atazanavir)

On June 2, 2014, FDA approved a new dosage form, Reyataz (atazanavir) oral powder for use in combination with other antiretroviral agents for the treatment of HIV-1, in patients over 3 months of age and between 10kg to < 25 kg. The first part of this announcement summarizes the changes relevant to the oral formulation and use in pediatric patients. The second part summarizes other general changes to the label.
Oral Powder or Use in Pediatric Patients Label Changes:

  • The DOSAGE AND ADMINISTRATION was updated to include information on the oral powder formulation

REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 10 kg or who weigh 25 kg or more.

Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients
REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 10 kg and less than 25 kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. The table below displays the recommended dosage of REYATAZ oral powder and ritonavir.


Table:                         Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 10 kg and less than 25 kg)a

Body Weight

Daily Dosage of REYATAZ
Oral Powder

Daily Dosage of Ritonavir Oral Solution

10 kg to less than 15 kg

200 mg (4 packets)b

80 mg

15 kg to less than 25 kg

250 mg (5 packets)b

80 mg

a   The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministratrion of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).
b   Each packet contains 50 mg of REYATAZ.
Instructions for Mixing REYATAZ Oral Powder

  • It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.
  • Determine the number of packets (4 or 5 packets) that are needed.
  • Prior to mixing, tap the packet to settle the powder. Use a clean pair of scissors to cut each packet along the dotted line.
  • Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.

     
  • Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.

     
  • Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.
  • Administer ritonavir immediately following REYATAZ powder administration.
  • Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation (may leave the mixture at room temperature during this one hour period). Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.
  • Dosage of REYATAZ Capsules in Pediatric Patients subsection was also modified as follows

The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients 6 years of age to less than 18 years of age) is based on body weight.


Table :    Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)a,b

Body weight

REYATAZ Daily Dosage

Ritonavir Daily Dosage

Treatment-Naive and Treatment-Experiencedc

Less than 15 kg

Capsules not recommended

N/A

15 kg to less than 20 kg

150 mg

100 mg

20 kg to less than 40 kg

200 mg

100 mg

At least 40 kg

300 mg

100 mg

Treatment-Naive, at least 13 years old and cannot tolerate ritonavirc

At least 40 kg

400 mg

N/A

a   Administer REYATAZ capsules and ritonavir simultaneously with food.
b  The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).
c  In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir.

  • A WARNING AND PRECAUTION was added regarding patients with phenylketonuria.  Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.
  • The ADVERSE REACTION section was updated as follows:

Adverse Reactions in Pediatric Patients: REYATAZ Oral Powder
The data described below reflect exposure to REYATAZ oral powder in 89 subjects weighing from 10 kg to less than 25 kg, including 65 patients exposed for 48 weeks. These data are from two pooled open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric patients (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 15 months to less than 7.5 years of age. In these studies 53% were female and 47% were male. All patients received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric patients taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric patients weighing 10 kg to less than 25 kg taking REYATAZ oral powder were increased amylase (19%), neutropenia (12%), increased SGPT/ALT (5%), elevation of total bilirubin (2.6 times ULN, 12%), increased lipase (5%), and decreased hemoglobin (3%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Section 8.4 Pediatric Use was revised as follows:
REYATAZ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients 3 months of age and older weighing at least 10 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus (a bilirubin-induced brain dysfunction). All REYATAZ contraindications, warnings, and precautions apply to pediatric patients.

The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 10 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397. The safety profile in pediatric patients was generally similar to that observed in adults

  • Section 12 Clinical Pharmacology was updated to include data with the powder formulation as follows:

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the powder formulation are summarized in Table 18 by weight ranges that correspond to the recommended doses.


Table 18:    Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in HIV-Infected Pediatric Patients

Body Weight
(range in kg) [n]

atazanavir/ritonavir
Dose (mg)

Cmax ng/mL
Geometric Mean (CV%)

AUC ng•h/mL
Geometric Mean (CV%)

Cmin ng/mL
Geometric Mean (CV%)

10 to <15 [18]

200/80

5197 (53%)

50305 (67%)

572 (111%)

15 to <25 [31]

250/80

5386 (47%)

55525 (46%)

678 (69%)

  • Section 12.4 was updated to include clinical virology data from the pediatric trials as follows:

Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451(PRINCE II): No treatment-emergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other PIs arose in the viruses from one subject each (L19I/R, M36M/I, H69K/R, and I72I/V). None of these viruses acquired phenotypic resistance to ATV, ATV/RTV, or any NNRTI or NRTI. In AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/I, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold change: 1.74, using a commercial investigational assay with an ATV cutoff of 2.2 fold change). Secondary PI substitutions also arose in the viruses of one subject each, including V11V/I, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61/E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from three subjects developed M184V in the reverse transcriptase, and all three exhibited phenotypic resistance to emtricitabine and lamivudine.

  • Section 14.3 was updated to include clinical trial data from pediatric trials with the oral powder.

Pediatric Trials with REYATAZ Oral Powder
Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.

  • AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
  • AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age

In these studies 134 patients (73 antiretroviral-naive and 61 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.

For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.

Sixty-five (65) patients from both studies weighing 10 kg to less than 25 kg treated with REYATAZ oral powder with ritonavir were evaluated. Patients 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution, and patients 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <400 copies/mL at Week 48 were 78% (32/41) and 71% (17/24), respectively in patients who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively in patients who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy was 412 cells/mm3 (10.5%) in antiretroviral-naive patients and 228 cells/mm3 (6%) in antiretroviral-experienced patients who received REYATAZ oral powder with ritonavir.

Other general Label Changes:
DOSAGE AND ADMINISTRATION

  • Section 2.2 Dosage in Adult Patients and 2.5 Dosage Adjustment in Pregnant Patients was revised to present a more streamlined recommended Reyataz and ritonavir dosage in adults

The table below displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.


Table:                         Recommended REYATAZ and Ritonavir Dosage in Adultsa

 

REYATAZ Once Daily
Dosage

Ritonavir Once Daily
Dosage

Treatment-Naive Adult Patients

recommended regimen

300 mg

100 mg

unable to tolerate ritonavir

400 mg

N/A

in combination with efavirenz

400 mg

100 mg

Treatment-Experienced Adult Patients

recommended regimen

300 mg

100 mg

in combination with both H2RA and tenofovir

400 mg

100 mg

a See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir, and didanosine).

Dosage Adjustments in Pregnant Patients
The table below includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults).


Table :                        Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa

 

REYATAZ
Once Daily
Dosage

Ritonavir
Once Daily
Dosage

Treatment-Naive and Treatment-Experienced

Recommended Regimen

300 mg

100 mg

Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovirb

In combination with either H2RA or tenofovir

400 mg

100 mg

a  See Drug Interactions (7) for instructions concerning coadministration of acid reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir and didanosine).
b  REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with both tenofovir and H2RA.

  • Section 2.6 Renal Impairment section was revised as follows:

Renal Impairment
For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Use in Specific Populations (8.7).]

Nevirapine was added to the list of contraindicated medications.

You may view the entire revised label at Drugs@FDA (Reyataz).

REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection for patients 3 months and older weighing at least 10 kg, distributed by Bristol Myers Squibb.

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