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U.S. Department of Health and Human Services

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Important safety-related label update for Ziagen (abacavir sulfate)

On July 18, 2008, FDA approved changes to the package insert for Ziagen (abacavir sulfate) highlighting information about the association of the HLA-B*5701 allele (a part of a gene) and hypersensitivity reactions (HSR) caused by abacavir-containing therapy.

Abacavir is associated with serious and sometimes fatal HSR. Abacavir HSR is a multi-organ syndrome characterized by 2 or more clinical signs or symptoms including fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea or abdominal pain), respiratory symptoms (dyspnea, cough or pharyngitis) and constitutional symptoms (generalized malaise, fatigue or myalgia). Occurrence of abacavir HSR requires immediate and permanent discontinuation of abacavir therapy.

The label change recommends screening patients for the HLA-B*5701 allele prior to initiating or reinitiating abacavir-containing therapy. Prospective screening for HLA-B*5701 and selection of alternative therapy for subjects who carry this allele will reduce the incidence of abacavir hypersensitivity (HSR) reaction and improve the safety profile of this drug.

The product label for abacavir has been updated to include the following new information:

WARNING: Risk of hypersensitivity Reactions, Lactic Acidosis

Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.
Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reaction

Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.

HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

When therapy with ZIAGEN has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of ZIAGEN or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of ZIAGEN to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of ZIAGEN.

If hypersensitivity cannot be ruled out, DO NOT reintroduce ZIAGEN or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

Risk Factor: HLA-B*5701 Allele: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.

CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.

Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.

Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.

In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

The following new information has been added to the Medication Guide:

Under What is the most important information I should know about ZIAGEN? 
Serious Allergic Reaction to Abacavir. ZIAGEN contains abacavir (also contained in EPZICOM(R) and TRIZIVIR(R)). Patients taking ZIAGEN may have a serious allergic reaction (hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701 than if you do not. Your doctor can determine with a blood test if you have this gene variation. If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your doctor right away to determine if you should stop taking this medicine.

Under Who should not take ZIAGEN?
Before starting ZIAGEN, tell your doctor about all of your medical conditions, including if you:
have been tested and know whether or not you have a particular gene variation called HLA-B*5701.

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You can find the complete revised label on the FDA web site at Drugs@FDA, entering "Ziagen," clicking on the NDA number, and following the link to the product label.

Labeling for the abacavir-containing combination products marketed as Trizivir and Epzicom will be updated through labeling supplements in the near future.

The labeling changes described here are predicated on data from two studies. CNA106030 (PREDICT-1), a prospective, randomized, double-blind study, evaluated the clinical utility of pre-therapy HLA-B*5701 screening compared to no screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive, HIV-1 infected subjects. ABC107442 (SHAPE), a retrospective, case-control study was designed to evaluate the sensitivity and specificity of the HLA-B*5701 allele with respect to abacavir HSR within the racial groups of black and white subjects in the United States. These studies support the recommendation for pre-therapy screening for patients carrying the HLA-B*5701 allele and selection of alternative therapy in positive subjects. Avoidance of abacavir therapy in HLA-B*5701 positive patients will significantly decrease the risk of developing clinical abacavir hypersensitivity.

Abacavir HSR generally develops within the first 6 weeks of initiation of therapy (median 11 days) in the majority of subjects who are affected. However, due to the wide range of clinical signs and symptoms that may signify the development of abacavir HSR, and confounding multiple antiretroviral and prophylactic medications, definitive diagnosis can sometimes be difficult. Earlier studies suggested a genetic basis relating to the development of abacavir HSR.

The Medication Guide and Warning Card that provide information about signs and symptoms of hypersensitivity reactions is dispensed with every new prescription and refill, and an Abacavir Hypersensitivity Registry has been established to encourage providers to register patients by calling a "1-800" number listed in the product label to allow FDA to monitor post marketing cases of abacavir hypersensitivity.

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral indicated in combination with other antiretroviral agents for treatment of HIV-1 infection in adult and pediatric patients, manufactured by Glaxo SmithKline.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration