Abacavir (Page 2 of 8)

5.2 Lactic Acidosis and Severe Hepatomegaly With Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abavcavir. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with abacavir 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.

5.3 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir. 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.
Autoimmune disorders (such as Graves’disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

5.4 Myocardial Infarction

Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled, clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is 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, smoking).

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:
• Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].
• Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.2)].
• Immune reconstitution syndrome [see Warnings and Precautions (5.3)].
• Myocardial infarction [see Warnings and Precautions (5.4)].

6.1 Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Serious and Fatal Abacavir-associated Hypersensitivity Reactions
In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.
Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).
Additional Adverse Reactions with Use of Abacavir
Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 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 2Table 2. Treatment-emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024a) through 48 Weeks of Treatment.

Adverse Reaction Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325)
Dreams/sleep disordersDrug hypersensitivityHeadaches/migraineNauseaFatigue/malaiseDiarrheaRashesAbdominal pain/gastritis/gastrointestinal signs andsymptomsDepressive disordersDizzinessMusculoskeletal painBronchitisVomiting 10%9%7%7%7%7%6%6%6%6%6%4%2% 10%<1%b 11%11%10%6%12%8%6%6%5%5%9%

a This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.
b Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.
Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 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 3. Table 3. Treatment-emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment

Adverse Reaction Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264)
Nausea 19% 17%
Headache 13% 9%
Malaise and fatigue 12% 12%
Nausea and vomitingHypersensitivity reactionDiarrhea 10%8%7% 10%2%5%3%4%
Fever and/or chills 6%
Depressive disorders 6%
Musculoskeletal pain 5% 7%
Skin rashes 5% 4%
Ear/nose/throat infections 5% 4%
Viral respiratory infections 5% 5%
Anxiety 5% 3%
Renal signs/symptoms <1% 5%
Pain (non-site-specific) <1% 5%

Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.
Abacavir Once Daily Versus Abacavir Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with abacavir 600 mg once daily or abacavir 300 mg twice daily both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving abacavir once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving abacavir twice daily. However, subjects receiving abacavir 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received abacavir 300 mg twice daily. Five percent (5%) of subjects receiving abacavir 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving abacavir 300 mg twice daily. Two percent (2%) of subjects receiving abacavir 600 mg once daily had severe diarrhea while none of the subjects receiving abacavir 300 mg twice daily had this event.
Laboratory Abnormalities: Laboratory abnormalities (Grades 3 to 4) in therapy-naive adults during therapy with abacavir 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 4. Table 4. Laboratory Abnormalities (Grades 3 to 4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment

Grade 3/4 Laboratory Abnormalities Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325)
Elevated CPK (>4 X ULN) 8% 8%
Elevated ALT (>5 X ULN) 6% 6%
Elevated AST (>5 X ULN) 6% 5%
Hypertriglyceridemia (>750 mg/dL) 6% 5%
Hyperamylasemia (>2 X ULN) 4% 5%
Neutropenia (ANC <750/mm3) 2% 4%
Anemia (Hgb ≤6.9 gm/dL) <1% 2%
Thrombocytopenia (Platelets <50,000/mm3) 1% <1%
Leukopenia (WBC ≤1,500/mm3) <1% 2%

ULN = Upper limit of normal.
n = Number of subjects assessed.
Laboratory abnormalities in CNA3005 are listed in Table 5.Table 5. Treatment-Emergent Laboratory Abnormalities (Grades 3 to 4) in CNA3005

Grade 3/4 Laboratory Abnormalities Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264)
Elevated CPK (>4 x ULN) 18 (7%) 18 (7%)
ALT (>5.0 x ULN) 16 (6%) 16 (6%)
Neutropenia (<750/mm3) 13 (5%) 13 (5%)
Hypertriglyceridemia (>750 mg/dL) 5 (2%) 3 (1%)
Hyperamylasemia (>2.0 x ULN) 5 (2%) 1 (<1%)
Hyperglycemia (>13.9 mmol/L) 2 (<1%) 2 (<1%)
Anemia (Hgb ≤6.9 g/dL) 0 (0%) 3 (1%)

ULN = Upper limit of normal.
n = Number of subjects assessed.
The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.

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