WARNINGS AND PRECAUTIONS
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.
Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below.
Signs and Symptoms of Hypersensitivity: Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups.
Group 1: Fever
Group 2: Rash
Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)
Group 4: Constitutional (including generalized malaise, fatigue, or achiness)
Group 5: Respiratory (including dyspnea, cough, or pharyngitis).
Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently.
Hypersensitivity to abacavir was reported in approximately 8% of 2,670patients (n=206) in 9clinical trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9days; 89% appeared within the first 6weeks; 95% of patients reported symptoms from 2 or more of the5 groups listed above.
 Figure 1. Hypersensitivity-Related Symptoms Reported With ≥10% Frequency in Clinical Trials (n=206 Patients)
Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions. In one study, 4patients (11%) receiving ZIAGEN 600mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 patients receiving ZIAGEN 300mg twice daily.
Physical findings associated with hypersensitivity to abacavir in some patients include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.
Laboratory abnormalities associated with hypersensitivity to abacavir in some patients include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia.
Clinical Management of Hypersensitivity: Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
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.
If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of ZIAGEN or any other abacavir-containing product and that reintroduction of ZIAGEN or any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.
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.
Abacavir Hypersensitivity Reaction Registry: An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions and collection of information on each case. Physicians should register patients by calling 1-800-270-0425.
Lactic Acidosis/Severe Hepatomegaly With Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Myocardial Infarction
In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI).1 In a sponsor-conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking).
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5times the human exposure at the recommended dose based on AUC.
There are no adequate and well-controlled studies in pregnant women. ZIAGEN should be used during pregnancy only if the potential benefits outweigh the risk.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ZIAGEN, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
Although it is not known if abacavir is excreted in human milk, abacavir is secreted into the milk of lactating rats. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ZIAGEN.
Pediatric Use
The safety and effectiveness of ZIAGEN have been established in pediatric patients 3months to 13years of age. Use of ZIAGEN in these age groups is supported by pharmacokinetic studies and evidence from adequate and well-controlled studies of ZIAGEN in adults and pediatric patients [see Dosage and Administration (2.2), Clinical Pharmacology (12.3), Clinical Studies].
Geriatric Use
Clinical studies of ZIAGEN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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