Abacavir and Lamivudine

RECENT MAJOR CHANGES Dosage and Administration, Not Recommended Due to 12/2021 Lack of Dosage Adjustment ( 2.4 )

1 INDICATIONS AND USAGE Abacavir and lamivudine tablets, 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 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: • 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.

3 DOSAGE FORMS AND STRENGTHS Abacavir and lamivudine tablets, USP contain 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are Orange colored, modified capsule shaped, biconvex film coated tablets debossed with "I 60" on one side and plain on other side. Tablets: 600 mg of abacavir and 300 mg of lamivudine. ( 3 )

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

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 )]. • 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 )]. 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 Macleods Pharma USA, Inc., at 1-888-943-3210 or or 1-855-926-3384 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, 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 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment 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 Insomnia Depression/Depressed mood Headache/Migraine Fatigue/Malaise Dizziness/Vertigo Nausea Diarrhea a Rash Pyrexia Abdominal pain/gastritis Abnormal dreams Anxiety 9 % 7 % 7 % 7 % 6 % 6 % 5 % 5 % 5 % 5 % 4 % 4 % 3 % 7 % 9 % 7 % 6 % 8 % 6 % 6 % 6 % 5 % 3 % 5 % 5 % 5 % a Subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivit …

7 DRUG INTERACTIONS • Methadone: An increased methadone dose may be required in a small number of patients. ( 7.1 ) • Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 7.2 ) • Riociguat: The riociguat dose may need to be reduced. ( 7.3 ) 7.1 Methadone In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology ( 12.3 )]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. 7.2 Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology ( 12.3 )]. 7.3 Riociguat Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see Clinical Pharmacology ( 12.3 )] . The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).

8 USE IN SPECIFIC POPULATIONS Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for abacavir or lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose (see Data). Data Human Data: Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens. Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3) ] . Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily wit …

12.1 Mechanism of Action Abacavir and lamivudine tablet is an antiretroviral agent with activity against HIV-1 [see Microbiology ( 12.4 )].

Mechanism of Action Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

11 DESCRIPTION Abacavir and lamivudine Abacavir and lamivudine tablets USP contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1. Abacavir and lamivudine tablets USP are for oral administration. Each orange, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP, and the inactive ingredients magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablets are coated with a film (opadry orange YS-1-13065-A) that is made of FD&C yellow #6 aluminum lake, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide. Abacavir Sulfate The chemical name of abacavir sulfate is ( 1 S,cis) -4-[2-amino-6-(cyclopropylamino)-9 H -purin-9­-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C 14 H 18 N 6 O) 2 •H 2 SO 4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate USP is a white to off-white powder and soluble in water, slightly soluble in methanol and practically insoluble in ethyl acetate and in absolute alcohol. In vivo , abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir. Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2 ́,3 ́-dideoxy, 3 ́-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine USP is a white to off-white solid and is soluble in water. Abacavir Sulfate Structure Lamivudine Structure

10 OVERDOSAGE There is no known specific treatment for overdose with abacavir and lamivudine tablets. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. Abacavir: It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis. Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

16 HOW SUPPLIED/STORAGE AND HANDLING Abacavir and lamivudine tablets, USP is available as tablets. Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are orange, biconvex film-coated, modified capsule-shaped, and debossed with I 60 on one side with no markings on the reverse side. They are packaged as follows: Bottles of 30 tablets (NDC 33342-440-07). Carton of 30 tablets (5x6 unit dose) (NDC 33342-440-14). Carton of 60 tablets (10x6 unit dose) (NDC 33342-440-98). Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].