On February 27, 2013, FDA approved changes to the Intelence (etravirine) label to include revisions to the Warnings and Precautions, Adverse Reactions, and Postmarketing Experience sections to include information regarding drug rash with eosinophilia and systemic symptoms (DRESS), to update Adverse Reaction section with information regarding the occurrence of rash in men vs. women and pediatric patients and to add drug interaction information for artemether/lumefantrine and telaprevir. The specific changes are outlined below.
Section 5 Warnings and Precautions
5.1 Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE® compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving INTELENCE® discontinued from Phase 3 trials due to rash [see Adverse Reactions (6)]. Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females [see Adverse Reactions (6)].
Section 6 Adverse Reactions
6.1 Clinical Trial Experience: Adults
The incidence of rash was higher in women compared to men in the INTELENCE® arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men).
6.2 Clinical Trials Experience: Pediatric Subjects (6 years to less than 18 years of age)
Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males); discontinuations due to rash were reported in 4% of subjects (4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.
6.3 Postmarketing Experience
Immune System Disorders: Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported.
Section 7 Drug Interactions
Antimalarials: artemether/lumefantrine – No change in etravirine exposures. Decrease in artemether, dihydroartemisinin and lumefantrine exposures. Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®.
Hepatitis C Virus (HCV) Direct-Acting Antivirals:telaprevir – No change in etravirine exposures. Decrease in telaprevir exposures. There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®.
Section 12 Clinical Pharmacology was also updated to include the results from these drug interaction trials. The complete revised label will be available soon at Drugs@FDA.
Intelence is a product of Janssen Pharmaceuticals.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Special Health Issues
Food and Drug Administration
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