Abacavir and Lamivudine: Package Insert and Label Information

ABACAVIR AND LAMIVUDINE- abacavir sulfate and lamivudine tablet, film coated
AvKARE, Inc.

WARNING: HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of abacavir and lamivudine tablets. 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 and lamivudine tablets are 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 and lamivudine tablets or reinitiation of therapy with abacavir and lamivudine tablets, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir and lamivudine 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 and lamivudine tablets, NEVER restart abacavir and lamivudine 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)].

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 and other antiretrovirals. Discontinue abacavir and lamivudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions ( 5.2)].

Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, which is a component of abacavir and lamivudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue abacavir and lamivudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions ( 5.3)] .

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Screening for HLA-B*5701 Allele Prior to Starting Abacavir and Lamivudine Tablets

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

2.2 Recommended Dosage for Adult Patients

The recommended dosage of abacavir and lamivudine tablets for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food.

2.3 Recommended Dosage for Pediatric Patients

The recommended oral dose of abacavir and lamivudine tablets for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see Clinical Studies ( 14.2)]. Before prescribing abacavir and lamivudine tablets tablets, pediatric patients should be assessed for the ability to swallow tablets.

2.4 Not Recommended Due to Lack of Dosage Adjustment

Because abacavir and lamivudine tablets is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets is not recommended for:

  1. patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations ( 8.6)].
  2. patients with mild hepatic impairment. Abacavir and lamivudine tablets are contraindicated in patients with moderate or severe hepatic impairment [see Contraindications ( 4), Use in Specific Populations ( 8.7)] .

Use of EPIVIR ® (lamivudine) oral solution or tablets and ZIAGEN ® (abacavir) oral solution may be considered.

3 DOSAGE FORMS AND STRENGTHS

Abacavir and lamivudine tablets USP contain 600 mg of abacavir as abacavir sulfate, USP and 300 mg of lamivudine, USP. The tablets are yellow, film-coated, convex, capsule-shaped tablet debossed with “5382” on one side of the tablet and “TV” on the other side.

4 CONTRAINDICATIONS

Abacavir and lamivudine tablets are contraindicated in patients:Abacavir and lamivudine tablets are contraindicated in patients:

  1. who have the HLA-B*5701 allele [see Warnings and Precautions ( 5.1)]. who have the HLA-B*5701 allele [see Warnings and Precautions ( 5.1)].
  2. with prior hypersensitivity reaction to abacavir [see Warnings and Precautions ( 5.1)] or lamivudine. with prior hypersensitivity reaction to abacavir [see Warnings and Precautions ( 5.1)] or lamivudine.
  3. with moderate or severe hepatic impairment [see Use in Specific Populations ( 8.7)]. with moderate or severe hepatic impairment [see Use in Specific Populations ( 8.7)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine tablets. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (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:

  1. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine tablets or reinitiation of therapy with abacavir and lamivudine tablets, unless patients have a previously documented HLA-B*5701 allele assessment.
  2. Abacavir and lamivudine tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.
  3. Before starting abacavir and lamivudine tablets, review medical history for prior exposure to any abacavir- containing product. NEVER restart abacavir and lamivudine tablets or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
  4. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir and lamivudine 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).
  5. If a hypersensitivity reaction cannot be ruled out, do not restart abacavir and lamivudine tablets or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.
  6. If a hypersensitivity reaction is ruled out, patients may restart abacavir and lamivudine 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 and lamivudine tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed.
  7. 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 and other antiretrovirals. See full prescribing information for ZIAGEN ® (abacavir) and EPIVIR ® (lamivudine). Treatment with abacavir and lamivudine 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 elevations).

5.3 Patients with Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR® (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence of Lamivudine-resistant HBV
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR® (lamivudine).

5.4 Use with Interferon- and Ribavirin-based Regimens

Patients receiving interferon alfa with or without ribavirin and abacavir and lamivudine tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR® (lamivudine). Discontinuation of abacavir and lamivudine tablets should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir and lamivudine tablets. 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.

5.6 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.

5.7 Myocardial Infarction

In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI 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, smoking).

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

  1. Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions ( 5.1)] .
  2. Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions ( 5.2)] .
  3. Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions ( 5.3)] .
  4. Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions ( 5.4)] .
  5. Immune reconstitution syndrome [see Warnings and Precautions ( 5.5)] .
  6. Fat redistribution [see Warnings and Precautions ( 5.6)] .
  7. Myocardial infarction [see Warnings and Precautions ( 5.7)] .

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