Hypersensitivity Reaction: Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). In one study, once-daily dosing of ZIAGEN was associated with more severe hypersensitivity reactions (see WARNINGS and PRECAUTIONS: INFORMATION FOR PATIENTS).

Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a ≥ 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 5.

Table 5. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, ≥ 5% Frequency) in Therapy-Naive Adults (CNA30024^*) Through 48 Weeks of Treatment

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a ≥ 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 6.

Table 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, ≥ 5% Frequency) in Therapy-Naive Adults (CNA3005) Through 48 Weeks of Treatment

Five patients receiving ZIAGEN in Study CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.

ZIAGEN Once Daily versus ZIAGEN Twice Daily (Study CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a ≥ 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from Study CNA30021 were similar. (For hypersensitivity reactions, patients receiving ZIAGEN once daily showed a rate of 9% in comparison to a rate of 7% for patients receiving ZIAGEN twice daily.) However, patients receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared to patients who received ZIAGEN 300 mg twice daily. Five percent (5%) of patients receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared to 2% of patients receiving ZIAGEN 300 mg twice daily. Two percent (2%) of patients receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the patients receiving ZIAGEN 300 mg twice daily had this event.

Therapy-Experienced Pediatric Patients: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a ≥ 5% frequency during therapy with ZIAGEN 8 mg/kg twice daily, lamivudine 4 mg/kg twice daily, and zidovudine 180 mg/m² twice daily compared with lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m² twice daily from CNA3006 are listed in Table 7.

Table 7. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, ≥ 5% Frequency) in Therapy-Experienced Pediatric Patients (CNA3006) Through 16 Weeks of Treatment

Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 8.

Table 8. Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) Through 48 Weeks of Treatment

Laboratory abnormalities in study CNA3005 are listed in Table 9.

Table 9. Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in Study CNA3005

In a study of therapy-experienced pediatric patients (CNA3006), laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a study of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric patients receiving ZIAGEN (CNA3006) as compared to adult patients (CNA30024).

The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in Study CNA30021.

Other Adverse Events: In addition to adverse reactions in Tables 5, 6, 7, 8, and 9, other adverse events observed in the expanded access program were pancreatitis and increased GGT.

Observed During Clinical Practice: In addition to adverse reactions reported from clinical trials, the following events have been identified during use of abacavir in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to abacavir, or a combination of these factors.

Body as a Whole: Redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).

Hepatic: Lactic acidosis and hepatic steatosis (see WARNINGS and PRECAUTIONS).

Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.

There have also been reports of erythema multiforme with abacavir use.

Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir.

Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure (see CLINICAL PHARMACOLOGY: Drug Interactions).

The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%).This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

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