Information for Healthcare Professionals: Abacavir (marketed as Ziagen) and Abacavir-Containing Medications
FDA ALERT [7/24/2008]: Serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701. Abacavir HSR is a multi-organ syndrome characterized by 2 or more clinical signs or symptoms that can include fever, rash, gastrointestinal symptoms, respiratory symptoms and constitutional symptoms.
FDA has reviewed data from 2 studies that support the recommendation for pre-therapy screening for the presence of the HLA-B*5701 allele and the selection of alternative therapy in positive subjects. Genetic tests for HLA-B*5701 are already available and all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications. Avoidance of abacavir therapy in HLA-B*5701 positive patients will significantly decrease the risk of developing clinically-suspected abacavir HSR. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only under exceptional circumstances when the potential benefit outweighs the risk.
Development of clinically-suspected abacavir HSR requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients negative for HLA-B*5701. This new safety information will be reflected in updated product labeling.
This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this when additional information or analyses become available.
To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program either online, by regular mail or by fax, using the contact information at the bottom of this sheet.
FDA has notified the maker of abacavir and abacavir-containing medications of the need to add information to the current Boxed Warning about the recommendation to test all patients for the HLA-B*5701 allele before starting or restarting therapy with abacavir or abacavir-containing medications. Patients who carry the HLA-B*5701 allele are at high risk for developing a hypersensitivity reaction. Avoiding abacavir-containing therapy in patients who carry the HLA-B*5701 allele has been found to reduce the risk of a potentially serious or fatal hypersensitivity reaction. The existing Medication Guide for abacavir has been updated to include this new safety information, and is considered a Risk Evaluation and Mitigation Strategy (REMS) under FDA's new authority to require REMS provided in Title IX of the FDA Amendments Act of 2007.
Recommendations and Information for Healthcare Professionals to Consider When Prescribing Abacavir:
- Healthcare professionals who prescribe abacavir (also known as Ziagen) or abacavir-containing medications should be fully aware of new prescribing information in the product label and in the revised Boxed Warning regarding HLA testing and abacavir HSR.
- Screening for the HLA-B*5701 allele is recommended for all patients prior to starting abacavir therapy. This approach has been found to decrease the risk of a hypersensitivity reaction.
- Patients who previously took abacavir and tolerated it have developed abacavir HSR upon restarting abacavir-containing therapy. Screening is 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 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.
- Discontinue abacavir therapy permanently if the patient becomes seriously ill and hypersensitivity cannot be ruled out, regardless of HLA-B*5701 status.
- Following a hypersensitivity reaction to abacavir, NEVER restart abacavir or any abacavir-containing product because severe symptoms can occur within hours and may include life-threatening hypotension and death.
Information for Patients to Consider if they are taking Abacavir:
- Some people are at greater risk for serious allergic reactions when first starting treatment with abacavir or with medications containing abacavir in a combination medicine. We can test for a risk factor for such reactions, which is called HLA-B*5701, before giving abacavir. Tests for HLA-B*5701 are readily available.
- If you test positive for HLA-B*5701, then your doctor will take that into account for your medical care.
- If you test negative for HLA-B*5701, you are at lower risk of a serious allergic reaction when taking abacavir, but it could still occur, and you still should be watchful.
- Even if you have previously taken abacavir without a reaction before but have never been tested for HLA-B*5701, you should still be tested before taking abacavir again.
- If you and your doctor decide that the benefits of starting abacavir outweigh possible risks, then you should watch for any sign described on the warning card. Abacavir HSR may include a combination of the following symptoms: fever, rash, generally ill feeling, extreme tiredness or achiness, gastrointestinal symptoms (nausea, vomiting, diarrhea or stomach pain), and respiratory symptoms (shortness of breath, cough or sore throat). If you develop a combination of any of the symptoms or signs of a reaction that are listed above, then you should contact your doctor immediately.
Abacavir HSR is a multi-organ syndrome characterized by 2 or more clinical signs or symptoms including fever, rash, gastrointestinal symptoms, respiratory symptoms and constitutional symptoms. Abacavir HSR usually develops early or within the first 6 weeks of initiation of therapy (median 11 days). However, due to wide array of symptoms and the common use of multiple medications in these patients, an early and definitive diagnosis of abacavir HSR may be difficult. FDA has reviewed data from two studies that demonstrate the risk of serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy is significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701. Pre-therapy testing for this allele and avoidance of abacavir-containing therapy in patients who carry the allele can significantly reduce the risk of developing abacavir HSR.
The first study (PREDICT-1) is a prospective, randomized, double-blind study evaluating the clinical utility of pre-therapy HLA-B*5701 screening compared to no screening on the incidence of abacavir HSR in patients who had never previously received abacavir. Clinically-suspected abacavir hypersensitivity reactions were reported in 7.8% (66/847) of subjects who received no HLA-B*5701 screening prior to abacavir treatment as compared to 3.4% (27/803) (p<0.0001) of subjects who underwent HLA-B*5701 and received abacavir only if they were negative. Data from PREDICT-1 estimates that 61% of HLA-B*5701 positive subjects will develop abacavir HSR during treatment with abacavir compared with 4.5% of HLA-B*5701 negative subjects. Screening HIV-1 infected subjects for the presence of HLA-B*5701 resulted in a reduction in incidence of clinically-suspected HSR of approximately 60% compared with current standard of care (no screening).
The second study (SHAPE) is a retrospective, case-control study designed to evaluate the sensitivity and specificity of the HLA-B*5701 allele with respect to abacavir HSR in black and white subjects in the United States. Subjects with clinically-suspected abacavir HSR were retrospectively tested for the presence of the HLA-B*5701 allele. Data from SHAPE supports the strong association between HLA-B*5701 and clinically-suspected abacavir HSR in both black and white subjects in the United States. The data from SHAPE supports pre-screening for the HLA-B*5701 allele in the broader US population to improve the safety profile of abacavir.
Mallal, S. et al. (2008) HLA-B*5701 Screening for Hypersensitivity to Abacavir. N Engl J Med. 358(6):568-579.
Hughes, C.A. et al. (2008) Abacavir Hypersensitivity Reaction: an Update. The Annals of Pharmacotherapy, 44:387-396.
Saag, M., et al. (2008) High Sensitivity of Human Leukocyte Antigen-B*5701 as a Marker for Immunologically Confirmed Abacavir Hypersensitivity in White and Black Patients. Clinical Infectious Diseases (CID), 46:1111-1118.