Important note: Information in this article was accurate in 2004. The state of the art may have changed since the publication date. 
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Food and Drug Administration - July 7, 2004
Richard Klein, Kimberly Struble
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-na ve 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.
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:
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.
Table 1: HIV RNA Response by Number and Type of Baseline PI Mutation, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis |
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Virologic Response = HIV RNA <400 copies/mLb |
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Number and Type of Baseline PI Mutationsa |
ATV/RTV (n=110) |
LPV/RTV (n=113) |
3 or more primary PI mutations including: c |
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D30N |
75% (6/8) |
50% (3/6) |
M36I |
20% (3/15) |
33% (6/18) |
M46I/L/V |
24% (4/17) |
23% (5/22) |
I54V/L/T/M/A |
31% (5/16) |
31% (5/16) |
A71V/T/I |
34% (10/29) |
39% (12/31) |
G73S/A/C |
14% (1/7) |
43% (3/7) |
V77I |
47% (7/15) |
44% (7/16) |
V82A/F/T/S/I |
29% (6/21) |
27% (7/26) |
I84V |
13% (1/8) |
33% (2/6) |
N88D |
63% (5/8) |
67% (4/6) |
L90M |
10% (2/21) |
44% (11/25) |
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Number of baseline primary PI mutationsa |
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All patients, as-treated |
58% (64/110) |
59% (67/113) |
0-2 PI mutations |
75% (50/67) |
75% (50/67) |
3-4 PI mutations |
41% (14/34) |
43% (12/28) |
5 or more PI mutations |
0% (0/9) |
28% (5/18) |
a Primary mutations include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.b Results should be interpreted with caution because the subgroups were small.c There were insufficient data (n<3) for PI mutations V32I, I47V, G48V, I50V, and F53L. |
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Table 2: Baseline Phenotype by Outcome, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis |
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Virologic Response = HIV RNA <400 copies/mLb |
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Baseline Phenotypea |
ATV/RTV (n=111) |
LPV/RTV (n=111) |
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0-2 |
71% (55/78) |
70% (56/80) |
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>2-5 |
53% (8/15) |
44% (4/9) |
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>5-10 |
13% (1/8) |
33% (3/9) |
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>10 |
10% (1/10) |
23% (3/13) |
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a Fold change in in vitro susceptibility relative to the wild-type reference.b Results should be interpreted with caution because the subgroups were small. |
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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.
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.
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-na ve subjects. Appropriate dosing recommendations for efavirenz and REYATAZ in treatment-experienced subjects have not been established.
040707
FD040703
SOURCE: Food and Drug Administration (FDA).
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