Tibotec
and FDA Issue New Safety Warning for NNRTI Etravirine (Intelence) regarding Severe
Skin Rash and Hypersensitivity
 | Tibotec
Therapeutics, in cooperation with the U.S. Food and Drug Administration (FDA),
issued a Dear Healthcare Professional letter to relay important updated
safety information about the antiretroviral drug etravirine
(Intelence) regarding the risk of severe skin and hypersensitivity reactions.
|
|
By
Ronald Baker, PhD  | | Stevens-Johnson
syndrome is a serious allergic or hypersensitivity reaction. |
|
Specifically,
the existing Warning and Precaution section regarding Severe Skin Reactions has
been strengthened to reflect post-marketing reports of the following safety concerns. The
letter warns that etravirine should be immediately discontinued if signs and symptoms
of severe skin or hypersensitivity reactions develop.
Below is the text of
the revised information regarding severe skin and hypersensitivity reactions included
in the etravirine Prescribing Information: 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 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% 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. Discontinue
INTELENCE immediately if signs or symptoms of severe skin reactions or hypersensitivity
reactions develop (including, but not limited to, severe rash or rash accompanied
by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions,
conjunctivitis, facial edema, hepatitis, eosinophilia). Clinical status including
liver transaminases should be monitored and appropriate therapy initiated. Delay
in stopping INTELENCE treatment after the onset of severe rash may result in a
life-threatening reaction. In
addition, the following sections of the Prescribing Information have been updated
to include this new information: Highlights of Prescribing Information, Adverse
Reactions and Patient Counseling. Furthermore the "What are the possible
side effects of INTELENCE?" section of the patient Package Insert has also
been updated. Clinical
Trials Experience In
Phase 3 studies, the most frequently reported adverse drug reaction of at least
Grade 2 in severity was rash (9.0%). Stevens-Johnson syndrome, hypersensitivity
reaction, and erythema multiforme were reported in < 0.1% of subjects during
clinical development with INTELENCE. In general, in clinical trials, rash was
mild to moderate, occurred primarily in the second week of therapy, and was infrequent
after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. A
total of 2% of HIV-1 infected subjects in Phase 3 trials receiving INTELENCE discontinued
due to rash. Overall,
the cases referenced above within clinical and post-marketing experience illustrate
the importance of clinical vigilance and familiarity with the signs and symptoms
of severe skin rash and hypersensitivity reactions. Additionally they also underscore
the importance of immediate discontinuation of INTELENCE in cases where severe
rash or hypersensitivity reaction is suspected. About
INTELENCE (etravirine) Tablets
INTELENCE,
in combination with other antiretroviral agents (ARVs), is indicated for the treatment
of human immunodeficiency virus type 1 (HIV-1) infection in ARV treatment-experienced
adult patients who have evidence of viral replication and HIV-1 strains resistant
to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other ARVs. This
indication is based on Week 24 analyses from 2 randomized, double-blind, placebo-controlled
trials of INTELENCE. Both studies were conducted in clinically advanced, 3-class
ARV (NNRTI, N(t)RTI, protease inhibitor [PI]) treatment-experienced adults. The
following points should be considered when initiating therapy with INTELENCE:
 | Treatment
history and, when available, resistance testing, should guide the use of INTELENCE. | | The
use of other active ARVs with INTELENCE is associated with an increased likelihood
of treatment response. | | In
patients who have experienced virologic failure on an NNRTI-containing regimen,
do not use INTELENCE in combination with only N(t)RTIs. | | The
risks and benefits of INTELENCE have not been established in pediatric patients
or in treatment-naïve adult patients. |
Additional
Important Safety Information Warnings
& Precautions | Fat
Redistribution: Redistribution and/or accumulation of body fat have been observed
in patients receiving antiretroviral (ARV) therapy. The causal relationship, mechanism,
and long-term consequences of these events have not been established. | | Immune
reconstitution syndrome has been reported in patients treated with ARV therapy,
including INTELENCE |
Use
in Specific Populations | Hepatic
Impairment: INTELENCE should be used with caution in patients with severe hepatic
impairment (Child-Pugh Class C) as pharmacokinetics of INTELENCE have not been
evaluated in these patients. |
Adverse
Reactions | The
most common adverse events (>10%) of any intensity that occurred at a higher
rate than placebo were rash (16.9% vs. 9.3%) and nausea (13.9% vs. 11.1%). | | The
most common treatment-emergent adverse reactions (Grade 2-4) that occurred in
patients receiving an INTELENCE-containing regimen vs. placebo were rash (9.0%
vs. 3.1%), diarrhea (5.2% vs. 9.6%), nausea (4.7% vs. 3.5%), fatigue (3.3% vs.
4.0%), abdominal pain (3.0% vs. 2.5%), peripheral neuropathy (2.8% vs. 1.8%),
hypertension (2.8% vs. 2.2%), headache (2.7% vs. 4.1%), and vomiting (2.3% vs.
2.0%). |
Drug
Interactions | INTELENCE
should not be co-administered with the following ARVs: tipranavir/ritonavir, fosamprenavir/ritonavir,
atazanavir/ritonavir, full-dose ritonavir (600 mg bid), protease inhibitors administered
without ritonavir, and other NNRTIs. | | INTELENCE
should not be co-administered with carbamazepine, phenobarbital, phenytoin, rifampin,
rifapentine, rifabutin (when part of a regimen containing protease inhibitor/ritonavir)
or products containing St. John's wort (Hypericum perforatum). | | INTELENCE
and lopinavir/ritonavir should be co-administered with caution. | | Co-administration
of INTELENCE with other agents such as substrates, inhibitors, or inducers of
CYP3A4, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse events
profile of INTELENCE or the co-administered drug(s). This is not a complete list
of potential drug interactions |
Full
etravirine prescribing information is available online at http://www.intelence-info.com/intelence/assets/pdf/INTELENCE_PI.pdf 9/01/09 Sources Tibotec
Therapeutics. Dear
Healthcare Professional letter. August 2009. R
Klein and K Struble. New Intelence labeling: severe skin and hypersensitivity
reactions. FDA Update. August 26, 2009. |
