ZIAGEN

1 INDICATIONS AND USAGE ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection. ZIAGEN, a nucleoside analogue human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. ( 1 )

2 DOSAGE AND ADMINISTRATION • Before initiating ZIAGEN, screen for the HLA-B*5701 allele. ( 2.1 ) • Adults: 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily. ( 2.2 ) • Pediatric Patients Aged 3 Months and Older: Administered either once or twice daily. Dose should be calculated on body weight (kg) and should not exceed 600 mg daily. ( 2.3 ) • Patients with Hepatic Impairment: Mild hepatic impairment – 200 mg twice daily. ( 2.4 ) 2.1 Screening for HLA-B*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 . Table 1. Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients a 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 a 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 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.

4 CONTRAINDICATIONS ZIAGEN 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 )]. • Presence of HLA-B*5701 allele. ( 4 ) • Prior hypersensitivity reaction to abacavir. ( 4 ) • Moderate or severe hepatic impairment. ( 4 )

Not available.

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 )] . • The most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. ( 6.1 ) • The most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 5%) in pediatric HIV-1 clinical trials were fever and/or chills, nausea and vomiting, skin rashes, and ear/nose/throat infections. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 ZIAGEN 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 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 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 a ) through 48 Weeks of Treatment 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. Adverse Reaction ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Dreams/sleep disorders 10% 10% Drug hypersensitivity 9% <1% b 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 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 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 ZIAGEN 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 ZIAGEN 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. ZIAGEN Once Daily versus ZIAGEN 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 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 CNA30021, were similar. For hypersensitivity reactions, subjects receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving ZIAGEN twice daily. However, subjects receiving ZIAGEN 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event. 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 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 ZIAGEN 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/mm 3 ) 2% 4% Anemia (Hgb ≤6.9 gm/dL) <1% 2% Thrombocytopenia (Platelets <50,000/mm 3 ) 1% <1% Leukopenia (WBC ≤1,500/mm 3 ) <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 ZIAGEN 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/mm 3 ) 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. 6.2 Clinical Trials Experience in Pediatric Subjects Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing) 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 ZIAGEN 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m 2 twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m 2 twice daily from CNA3006 are listed in Table 6 . Table 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills 9% 7% Nausea and vomiting 9% 2% Skin rashes 7% 1% Ear/nose/throat infections 5% 1% Pneumonia 4% 5% Headache 1% 5% Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving ZIAGEN (CNA3006) as compared with adult subjects (CNA30024). Other Adverse Events In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT. Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of ZIAGEN was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. 6.3 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of ZIAGEN. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures. Body as a Whole Redistribution/accumulation of body fat. Cardiovascular Myocardial infarction. Hepatic Lactic acidosis and hepatic steatosis [see Warnings and Precautions ( 5.2 )] . 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 [see Adverse Reactions ( 6.1 )] .