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FDA Reports Higher Abacavir Hypersensitivity, 8% vs 5%
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"Increased Rate and Severity of Abacavir-associated Hypersensitivity Reaction in Randomized Controlled Clinical Trials"
The FDA resented this study in poster 835 at the 12th CROI in which a higher rate of abacavir hypersensitivity was found than had previously been thought (8% vs 5%). As a result, the FDA changed the abacavir label. The FDA suggested that since abacavir will be used once daily a further study should be performed using this dose.
Hypersensitivity reaction (HSR) is a well-known, serious, and potentially fatal adverse event associated with abacavir (ABC) use. The labeled rate of HSR has been 5% since the accelerated approval of ABC in 1998, and is based on an earlier, less inclusive definition of HSR. We noted a higher incidence of HSR (8%) during the review of pivotal clinical trial data that lead to ABCŐs traditional approval in 2004 (based on data from New Drug Application (NDA) 20-977/20-978), prompting us to review HSR data from other well-controlled trials.
We reviewed the traditional approval NDA database on HSR, describing data only from those clinical trials that were randomized and controlled where ABC twice-daily dosing was used in at least 1 arm. We also examined HSR events using FisherŐs exact analysis in 1 available randomized clinical trial comparing ABC twice daily with ABC once daily both in combination with other drugs.
We reviewed HSR data from 9 randomized clinical trials as part of NDA 20-977/978: APV30001, APV30002, APV30003, CNA30024, ESS40001, ESS40002, ESS40003, ESS40006, and ESS40009. ABC was used as part of triple combination ART in all 9 trials. The trials enrolled patients from November 1999 to February 2002; 4 enrolled treatment-na•ve subjects, and the remainder enrolled treatment-experienced subjects or both. The trial lengths varied from 16 to 96 weeks (median 48 weeks). All nine trials used the current definition of HSR (a multi-organ clinical syndrome) and a detailed data collection module. There were n = 206 HSR in n = 2670 total exposed to ABC or 8%, with a range of 2 to 9%. In the 1 ABC twice-daily vs once-daily trial (CNA30021, n = 770, part of NDA 21-652), 7% on twice-daily and 9% on once-daily arms had documented HSR at week 48 (p = 0.28). Of the subjects who experienced HSR, severe HSR was reported in 2% (n = 8) of twice-daily vs 5% (n = 19) of once-daily subjects (p < 0.02). No deaths were attributed to ABC HSR.
When the most current HSR definition and a formal module were used to diagnose HSR, the reported rate was 8% compared to the previous labeled rate of 5%. Although the overall HSR rate was similar between twice-daily and once-daily dosing in a single randomized clinical trial, there were more cases of severe HSR with the once-daily dosing. Based on the results of our review, we changed the ABC label to reflect the higher HSR rate of 8% and included wording to describe the increased cases of severe HSR reported in the once-daily dosing arm. Further studies are needed to address the increased severity of HSR with ABC once daily.
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