Abacavir: Package Insert and Label Information

ABACAVIR- abacavir sulfate tablet, film coated
Cipla USA Inc.

WARNING HYPERSENSITIVITY REACTIONS

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir sulfate.

Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see Warnings and Precautions (5.1)].

Abacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir or reinitiation of therapy with abacavir, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir tablets immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)].

Following a hypersensitivity reaction to abacavir, NEVER restart abacavir tablets or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Abacavir tablets USP 300 mg, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

2 DOSAGE AND ADMINISTRATION

2.1 Screening for HLA-B*5701 Allele prior to Starting Abacavir tablets

Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir tablets [see Boxed Warning, Warnings and Precautions (5.1)].

2.2 Recommended Dosage for Adults Patients

The recommended dosage of abacavir sulfate for adults is 600 mg daily, administered orally as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.

2.3 Recommended Dosage for Pediatric Patients

The recommended dosage of abacavir sulfate in HIV-1-infected pediatric patients aged 3 months and older is 8 mg per kg orally twice daily or 16 mg per kg orally once-daily (up to a maximum of 600 mg daily) in combination with other antiretroviral agents.

Abacavir tablet is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing abacavir tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow abacavir tablets, the oral solution formulation should be prescribed. The recommended oral dosage of abacavir tablets for HIV-1-infected pediatric patients is presented in Table 1.

Table 1. Dosing Recommendations for Abacavir Scored Tablets in Pediatric Patients
*
Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies (14.2)].
Weight (kg) Once-Daily Dosing Regimen * Twice-Daily Dosing Regimen
AM Dose PM Dose Total Daily Dose
14 to <20 1 tablet (300 mg) ½ tablet (150 mg) ½ tablet (150 mg) 300 mg
≥20 to <25 1½ tablets (450 mg) ½ tablet (150 mg) 1 tablet (300 mg) 450 mg
≥25 2 tablets (600 mg) 1 tablet (300 mg) 1 tablet (300 mg) 600 mg

2.4 Recommended Dosage for Patients with Hepatic Impairment

The recommended dose of abacavir sulfate in patients with mild hepatic impairment (Child-Pugh Class A) is 200 mg twice daily. To enable dose reduction, abacavir oral solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, abacavir sulfate is contraindicated in these patients.

3 DOSAGE FORMS AND STRENGTHS

Abacavir tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow coloured, capsule shaped, biconvex, film coated, having scoreline on both sides with “5” and “14” debossed on either side of scoreline on one side.

4 CONTRAINDICATIONS

Abacavir tablet is contraindicated in patients:

  • who have the HLA-B*5701 allele [see Warnings and Precautions (5.1)].
  • with prior hypersensitivity reaction to abacavir [see Warnings and Precautions (5.1)].
  • with moderate or severe hepatic impairment [see Use in Specific Populations (8.6)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir sulfate. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir sulfate (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir sulfate:

  • All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir tablets or reinitiation of therapy with abacavir tablets, unless patients have a previously documented HLA-B*5701 allele assessment.
  • Abacavir tablet is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.
  • Before starting abacavir tablets, review medical history for prior exposure to any abacavir-containing product. NEVER restart abacavir tablets or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
  • To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir tablets immediately if a hypersensitivity reaction is suspected, 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).
  • If a hypersensitivity reaction cannot be ruled out, do not restart abacavir tablets or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours.
  • If a hypersensitivity reaction is ruled out, patients may restart abacavir tablets. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed.
  • A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.

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 abacavir. 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 tablets 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 elevation

5.3 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir sulfate. 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-Barre 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 sulfate

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 sulfate 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 2.

Table 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024*) through 48 Weeks of Treatment
*
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.
Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding
Adverse Reaction Abacavir sulfate plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325)
Dreams/sleep disorders 10% 10%
Drug hypersensitivity 9% <1%
Headaches/migraine 7% 11%
Nausea 7% 11%
Fatigue/malaise 7% 10%
Diarrhea 7% 6%
Rashes 6% 12%
Abdominal pain/gastritis/ gastrointestinal signs and symptoms 6% 8%
Depressive disorders 6% 6%
Dizziness 6% 6%
Musculoskeletal pain 6% 5%
Bronchitis 4% 5%
Vomiting 2% 9%

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 sulfate 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 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment
Adverse Reaction Abacavir sulfate plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264)
Nausea 19% 17%
Headache 13% 9%
Malaise and fatigue 12% 12%
Nausea and vomiting 10% 10%
Hypersensitivity reaction 8% 2%
Diarrhea 7% 5%
Fever and/or chills 6% 3%
Depressive disorders 6% 4%
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 sulfate 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 sulfate Once Daily versus Abacavir sulfate 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 sulfate 600 mg once daily or abacavir sulfate 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 sulfate once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving abacavir sulfate twice daily. However, subjects receiving abacavir sulfate 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received abacavir sulfate 300 mg twice daily. Five percent (5%) of subjects receiving abacavir sulfate 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving abacavir sulfate 300 mg twice daily. Two percent (2%) of subjects receiving abacavir sulfate 600 mg once daily had severe diarrhea while none of the subjects receiving abacavir sulfate 300 mg twice daily had this event.

Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with abacavir sulfate 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 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment

ULN = Upper limit of normal

n = Number of subjects assessed.

Grade 3/4 Laboratory Abnormalities Abacavir sulfate 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%

Laboratory abnormalities in CNA3005 are listed in Table 5.

Table 5. Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005

ULN = Upper limit of normal

n = Number of subjects assessed.

Grade 3/4 Laboratory Abnormalities Abacavir sulfate 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%)

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

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