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New Dosing Regimen for Ritonavir-Boosted Atazanavir in Treatment-Experienced Patients; Revisions Made to Packaging Insert

July 7, 2004

On July 6, 2004, the Division of Antiviral Drug Products approved a new dosing regimen for Reyataz. In antiretroviral-experienced patients the recommended dose is Reyataz 300 mg (two 150 mg capsules) once daily plus ritonavir 100 mg once daily taken with food.

For antiretroviral-naive patients the recommended dose remains as Reyataz 400 mg (two 200 mg capsules) once daily taken with food.

The data to support the new dosing regimen came from study AI424-045, a study of patients who had failed at least two regimens containing medications from the three ARV drug classes available at the time of enrollment. This 48-week trial to evaluated the efficacy and safety of Reyataz 300 mg + ritonavir 100 mg once daily or Reyataz 400 mg + saquinavir 1200 mg once daily compared to lopinavir/ritonavir 400/100 mg twice daily each with tenofovir and a nucleoside reverse transcriptase inhibitor in treatment-experienced patients.

Reyataz/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. The HIV RNA change from baseline was -1.58 log10 copies/mL for Reyataz/ritonavir and -1.70 log10 copies/mL for lopinavir/ritonavir.

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Study AI424-045 was not large enough to reach a definitive conclusion that Reyataz/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measures of proportions below the HIV RNA lower limit of detection. The proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at week 48 was 55% and 38% for Reyataz/ritonavir and 57% and 45% for lopinavir/ritonavir, respectively.

The major revisions to the package insert are summarized below.


Indications and Usage

Information that should be considered when initiating therapy with Reyataz was added as follows. This data pertains to Reyataz/ritonavir.

The following points should be considered when initiating therapy with Reyataz:

  • In antiretroviral-experienced patients with prior virologic failure, coadministration of Reyataz with ritonavir is recommended.

  • In Study AI424-045 Reyataz/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that Reyataz/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection. (See description of clinical studies above.)

  • The number of baseline primary protease inhibitor mutations affects the virologic response of Reyataz/ritonavir. (See Clinical Pharmacology: Microbiology below.)

  • There are no data regarding the use of Reyataz and ritonavir in therapy-naive patients.


Clinical Pharmacology

Microbiology

  • A table was included to provide information regarding HIV RNA response at week 48 by number and type of baseline protease inhibitor mutations and baseline phenotype in treatment-experienced subjects (study AI424-045). In summary, the HIV RNA response rates (< 400 copies/mL) were 75% for both Reyataz/ritonavir and lopinavir/ritonavir in patients with 0-2 baseline primary protease inhibitor mutations. In patients with 3-4 baseline primary protease inhibitor mutations the response rates were 41% and 43% for Reyataz/ritonavir and lopinavir/ritonavir, respectively. In patients with 5 or more baseline primary protease inhibitor mutations the response rates were 0% and 28% for Reyataz/ritonavir and lopinavir/ritonavir, respectively.


Table 1: HIV RNA Response by Number and Type of Baseline PI Mutation, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
 Virologic Response = HIV RNA <400 copies/mL2
Number and Type of Baseline PI Mutations1ATV/RTV

(n=110)

LPV/RTV

(n=113)

3 or more primary PI mutations including:3  
D30N75% (6/8)50% (3/6)
M36I20% (3/15)33% (6/18)
M46I/L/V24% (4/17)23% (5/22)
I54V/L/T/M/A31% (5/16)31% (5/16)
A71V/T/I34% (10/29)39% (12/31)
G73S/A/C14% (1/7)43% (3/7)
V77I47% (7/15)44% (7/16)
V82A/F/T/S/I29% (6/21)27% (7/26)
I84V13% (1/8)33% (2/6)
N88D63% (5/8)67% (4/6)
L90M10% (2/21)44% (11/25)
Number of baseline primary PI mutations1
All patients, as-treated58% (64/110)59% (67/113)
0-2 PI mutations75% (50/67)75% (50/67)
3-4 PI mutations41% (14/34)43% (12/28)
5 or more PI mutations0% (0/9)28% (5/18)

  1. Primary mutations include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.

  2. Results should be interpreted with caution because the subgroups were small.

  3. There were insufficient data (n<3) for PI mutations V32I, I47V, G48V, I50V, and F53L.


Table 2: Baseline Phenotype by Outcome, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
 Virologic Response = HIV RNA <400 copies/mL2
Baseline Phenotype1ATV/RTV

(n=111)

LPV/RTV

(n=111)

0-271% (55/78)70% (56/80)
>2-553% (8/15)44% (4/9)
>5-1013% (1/8)33% (3/9)
>1010% (1/10)23% (3/13)

  1. Fold change in in vitro susceptibility relative to the wild-type reference.

  2. Results should be interpreted with caution because the subgroups were small.


Warnings

PR Interval Prolongation

  • The following statement was added: There have been rare reports of second-degree AV block and other conduction abnormalities and no reports of third-degree AV block.

  • Information regarding reports of first-degree AV block from Study 045 was added.


Precautions

  • A subsection regarding rash was included to state that the incidence of rash in controlled clinical trials (n=1597) was 21%. The median time to onset of rash was 8 weeks after initiation of Reyataz and the median duration of rash was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Dosing with Reyataz was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical studies was 0.4%. Reyataz should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving Reyataz.


Drug Interactions

  • A change to the clinical comment for the interaction between efavirenz and Reyataz was made to distinguish that the dose adjustment of Reyataz/ritonavir/efavirenz 300/100/600 mg once daily applies to treatment-naive subjects. Appropriate dosing recommendations for efavirenz and Reyataz in treatment-experienced subjects have not been established.


  
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This article was provided by U.S. Food and Drug Administration. Visit the FDA's website to find out more about their activities and publications.
 
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