Abacavir and Lamivudine

1 INDICATIONS AND USAGE Abacavir and lamivudine tablet, a combination of abacavir and lamivudine, both nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. ( 1 ) 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 Before initiating abacavir and lamivudine tablets, screen for the HLA-B*5701 allele because abacavir and lamivudine tablets contains abacavir. ( 2.1 ) Adults: One tablet orally once daily. ( 2.2 ) Pediatric patients weighing at least 25 kg: One tablet daily. ( 2.3 ) Because abacavir and lamivudine tablets is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets is not recommended in patients with creatinine clearance less than 30 mL per minute or patients with hepatic impairment. ( 2.4 , 4 ) 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, 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 tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets are not recommended for: patients with creatinine clearance less than 30 mL per minute [see Use in Specific Populations ( 8.6 )] . patients with mild hepatic impairment. Abacavir and lamivudine tablets is 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.

4 CONTRAINDICATIONS Presence of HLA-B*5701 allele. ( 4 ) Prior hypersensitivity reaction to abacavir or lamivudine. ( 4 ) Moderate or severe hepatic impairment. ( 4 , 8.7 ) Abacavir and lamivudine tablets are 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 )] or lamivudine. with moderate or severe hepatic impairment [see Use in Specific Populations ( 8.7 )].

Not available.

6 ADVERSE REACTIONS The most commonly reported adverse reactions of at least moderate intensity (incidence greater than 5%) in an adult HIV-1 clinical trial were drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in greater detail in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions ( 5.1 )]. Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions ( 5.2 )]. Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.3 )]. Immune reconstitution syndrome [see Warnings and Precautions ( 5.4 )]. Myocardial infarction [see Warnings and Precautions ( 5.5 )]. 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, a component of abacavir and lamivudine tablets [ 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 and Lamivudine Tablets: Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with 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, are listed in Table 1. Table 1. 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 (CNA30021) through 48 Weeks of Treatment a 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. b CNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 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. Adverse Event ZIAGEN 600 mg q . d . plus EPIVIR plus Efavirenz ( n = 384 ) ZIAGEN 300 mg b . i . d . plus EPIVIR plus Efavirenz ( n = 386 ) Drug hypersensitivity a , b 9% 7% Insomnia 7% 9% Depression/Depressed mood 7% 7% Headache/Migraine 7% 6% Fatigue/Malaise 6% 8% Dizziness/Vertigo 6% 6% Nausea 5% 6% Diarrhea a 5% 6% Rash 5% 5% Pyrexia 5% 3% Abdominal pain/gastritis 4% 5% Abnormal dreams 4% 5% Anxiety 3% 5% Laboratory Abnormalities Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Other Adverse Events In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. 6.2 Clinical Trials Experience in Pediatric Subjects The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as abacavir and lamivudine tablets, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) 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. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see Adverse Reactions ( 6.1 )] . 6.3 Postmarketing Experience The following adverse reactions have been identified during postmarketing use. 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 exposure. Abacavir Cardiovascular: Myocardial infarction. 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 )] . Abacavir and Lamivudine Body as a Whole: Redistribution/accumulation of body fat . Digestive: Stomatitis. Endocrine and Metabolic: Hyperglycemia. General: Weakness. Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic: Lactic acidosis and hepatic steatosis [see Warnings And Precautions ( 5.3 )] , posttreatment exacerbation of hepatitis B [see Warnings And Precautions ( 5.2 )]. Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Muscle weakness, creatinine phosphokinase (CPK) elevation, rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.