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On July 6, 2004, the Division of Antiviral Drug Products approved a new dosing regimen for REYATAZ. In antiretroviral-experienced patients the new recommended dose is
REYATAZ 300 mg (two 150 mg capsules) once daily plus ritonavir 100 mg once daily taken taken with food.
For antiretroviral-naïve patients the recommended dose remains as REYATAZ 400 mg (two 200 mg capsules) once daily 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 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 an nucleocide reverse transcriptase inhibitor (NRTI).
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.
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 proportion 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)
- The number of baseline primary protease inhibitor mutations affects the virologic response of REYATAZ/ritonavir (See CLINICAL PHARMACOLOGY: Microbiology)
- There are no data regarding the use of REYATAZ/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, HIV RNA the response rate (< 400 copies/mL) was 75% for both REYATAZ/ritonavir (50/67) and lopinavir/ritonavir (50/67) 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% (14/34) and 43% (12/28) for REYATAZ/ritonavir and lopinavir/ritonavir, respectively. In patients with 5 or more baseline primary protease inhibitor mutations the response rates were 0% (0/9) and 23% (5/18) for REYATAZ/ritonavir and lopinavir/ritonavir, respectively.
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 the dose adjustment of REYATAZ/ritonavir/efavirenz 300/100/600 mg once daily applies to treatment-naïve subjects. Appropriate dosing recommendations for efavirenz and REYATAZ in treatment-experienced subjects have not been established.
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