2.1 Screening for HLAB*5701 Allele prior to Starting ZIAGEN

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

2.2 Recommended Dosage for Adult Patients

The recommended dosage of ZIAGEN 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 ZIAGEN oral solution 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.

ZIAGEN 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 ZIAGEN tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN tablets for HIV-1-infected pediatric patients is presented in Table 1.

aData 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)].

2.4 Recommended Dosage for Patients with Hepatic Impairment

The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child‑Pugh Class A) is 200 mg twice daily. To enable dose reduction, ZIAGEN 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, ZIAGEN is contraindicated in these patients.

5.1 Hypersensitivity Reactions

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

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All patients should be screened for the HLA‑B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA‑B*5701 allele assessment.

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ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑B*5701-positive patients.

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Before starting ZIAGEN, review medical history for prior exposure to any abacavir-containing product. NE VER restart ZIA GEN or any other abacavir‑containing product following a hypersensitivity reaction to abacavir, regardless of HLA‑B*5701 status.

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To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue ZIAGEN 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).

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If a hypersensitivity reaction cannot be ruled out, do not restart ZIAGEN or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death can occur within hours.

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If a hypersensitivity reaction is ruled out, patients may restart ZIAGEN. 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 ZIAGEN or any other abacavir-containing product is recommended only if medical care can be readily accessed.

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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. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. 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).

5.3 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 eva luation 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 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.

5.5 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).

5.6 Related Products that are Not Recommended

ZIAGEN is one of multiple abacavir-containing products. Concomitant administration of ZIAGEN with other products containing abacavir is not recommended.