Lamivudine and Zidovudine

Boxed Warning 04/2018 Warnings and Precautions, Lactic Acidosis and Severe 04/2018 Hepatomegaly with Steatosis (5.3) Warnings and Precautions, Lipoatrophy (5.8) 04/2018

1 INDICATIONS AND USAGE Lamivudine and Zidovudine tablets, a combination of 2 nucleoside analogues, are indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Lamivudine and zidovudine tablets, a combination of 2 nucleoside analogue reverse transcriptase inhibitors, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1)

2 DOSAGE AND ADMINISTRATION • Adults and Adolescents weighing greater than or equal to 30 kg: 1 tablet orally twice daily. ( 2.1 ) • Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily. ( 2.2 ) • Because lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablet is not recommended in patients requiring dosage adjustment or with hepatic impairment or experiencing dose-limiting adverse reactions. ( 2.3 , 4 ) 2.1 Recommended Dosage for Adults and Adolescents The recommended dosage of lamivudine and zidovudine tablet in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily. 2.2 Recommended Dosage for Pediatric Patients The recommended dosage of scored lamivudine and zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily. Before prescribing lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) oral solution and RETROVIR (zidovudine) syrup. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because lamivudine and zidovudine is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablets are not recommended for: • pediatric patients weighing less than 30 kg [see Use in Specific Populations ( 8.4 )]. • patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations ( 8.6 )]. • patients with hepatic impairment [see Use in Specific Populations ( 8.7 )]. • patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of lamivudine and zidovudine tablets are available for these populations.

3 DOSAGE FORMS AND STRENGTHS Lamivudine and Zidovudine Tablets USP , containing 150 mg lamivudine and 300 mg zidovudine, are white to off-white, modified capsule shaped, biconvex, film-coated tablets with deep breakline in between ‘C’ and ‘60’ on one side and deep breakline on the other side. Tablets: Scored 150 mg lamivudine and 300 mg zidovudine (3)

4 CONTRAINDICATIONS Lamivudine and Zidovudine Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the product. Lamivudine and Zidovudine Tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome). (4)

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hematologic toxicity, including neutropenia and anemia [see Boxed Warning , Warnings and Precautions (5.1) ]. Symptomatic myopathy [see Boxed Warning , Warnings and Precautions (5.2) ]. Lactic acidosis and hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.3) ]. Acute exacerbations of hepatitis B [see Boxed Warning , Warnings and Precautions (5.4) ]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.6) ]. Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6) ]. Pancreatitis [see Warnings and Precautions (5.7) ]. Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult and pediatric HIV-1 clinical studies of combination lamivudine and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Exelan Pharmaceuticals, Inc., 1-855-295-7455 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Lamivudine Plus Zidovudine Administered As Separate Formulations: In 4 randomized, controlled trials of lamivudine 300 mg per day plus zidovudine 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables 1 and 2). Table 1. Selected Clinical Adverse Reactions (≥5% Frequency) in 4 Controlled Clinical Trials With lamivudine 300 mg/day and zidovudine 600 mg/day Adverse Reaction Lamivudine plus Zidovudine (n = 251) Body as a whole Headache 35% Malaise & fatigue 27% Fever or chills 10% Digestive Nausea 33% Diarrhea 18% Nausea & vomiting 13% Anorexia and/or decreased appetite 10% Abdominal pain 9% Abdominal cramps 6% Dyspepsia 5% Nervous system Neuropathy 12% Insomnia & other sleep disorders 11% Dizziness 10% Depressive disorders 9% Respiratory Nasal signs & symptoms 20% Cough 18% Skin Skin rashes 9% Musculoskeletal Musculoskeletal pain 12% Myalgia 8% Arthralgia 5% Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received lamivudine in controlled clinical trials [see Warnings and Precautions (5.7) ]. Selected laboratory abnormalities observed during therapy are listed in Table 2. Table 2. Frequencies of Selected Laboratory Abnormalities Among Adults in 4 Controlled Clinical Trials of lamivudine 300 mg/day plus zidovudine 600 mg/day a Test (Abnormal Level) Lamivudine plus Zidovudine % (n) ULN = Upper limit of normal. ANC = Absolute neutrophil count. n = Number of patients assessed. * Frequencies of these laboratory abnormalities were higher in patients with mild laboratory abnormalities at baseline. Neutropenia (ANC5.0 x ULN) 3.7% (241) AST (>5.0 x ULN) 1.7% (241) Bilirubin (>2.5x ULN) 0.8% (241) Amylase (>2.0 x ULN) 4.2% (72) 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of lamivudine, zidovudine, and/or lamivudine and zidovudine tablet. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine, zidovudine, and/or lamivudine and zidovudine tablet. Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.9) ]. Cardiovascular: Cardiomyopathy. Endocrine and Metabolic: Gynecomastia, hyperglycemia. Gastrointestinal: Oral mucosal pigmentation, s …

7 DRUG INTERACTIONS No drug interaction studies have been conducted using lamivudine and zidovudine tablets [see Clinical Pharmacology (12.3) ]. Concomitant use with the following drugs should be avoided: stavudine (7.1) , zalcitabine (7.1) , doxorubicin. (7.2) Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.3) 7.1 Antiretroviral Agents Lamivudine: Zalcitabine: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine and zidovudine tablet in combination with zalcitabine is not recommended. Zidovudine: Stavudine: Concomitant use of lamivudine and zidovudine tablet with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro . Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided. 7.2 Doxorubicin Zidovudine: Concomitant use of lamivudine and zidovudine tablet with doxorubicin should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro . 7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Zidovudine: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. 7.4 Interferon- and Ribavirin-Based Regimens Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-l/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ]. 7.5 Trimethoprim/Sulfamethoxazole (TMP/SMX) Lamivudine: No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

8 USE IN SPECIFIC POPULATIONS • Lactation: Women infected with HIV should be instructed not to breastfeed due to the 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 lamivudine and zidovudine 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 lamivudine or zidovudine 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. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data). In animal reproduction studies, 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. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data). Data Human Data: Lamivudine : Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first 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 a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 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 trial 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 …

12.1 Mechanism of Action Lamivudine and Zidovudine Tablet is an antiviral agent [see Clinical Pharmacology (12.4) ].

11 DESCRIPTION Lamivudine and Zidovudine tablets, USP are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV-1. Lamivudine and Zidovudine tablets, USP are for oral administration. Each film-coated tablet contains 150 mg of lamivudine, USP, 300 mg of zidovudine, USP, and the inactive ingredients microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and opadry white (hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide). Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidine-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 0 3 S and a molecular weight of 229.26. It has the following structural formula: Lamivudine USP is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C. Zidovudine The chemical name of zidovudine is 3'-azido-3'-deoxythymidine. It has a molecular formula of C 10 H 13 N 5 O 4 and a molecular weight of 267.24. It has the following structural formula: Zidovudine USP is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg/mL in water at 25°C. Meets USP Dissolution Test 2. lamivudinestructure zedovudinechemicalstructure

10 OVERDOSAGE Lamivudine and Zidovudine Tablet: There is no known antidote for lamivudine and zidovudine tablet. Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. 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. Zidovudine: Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and 1 report of a grand mal seizure. Hematologic changes were transient. All patients recovered. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3’-azido-3’-deoxy-5’- O -β- D -glucopyranuronosylthymidine (GZDV), is enhanced.

16 HOW SUPPLIED/STORAGE AND HANDLING Lamivudine and Zidovudine Tablets USP, containing 150 mg lamivudine and 300 mg zidovudine, are white to off-white, modified capsule shaped, biconvex, film-coated tablets with deep breakline in between ‘C’ and ‘60’ on one side and deep breakline on the other side. They are available as follows: Bottles of 60 NDC 65862-036-60 Cartons of 60 (6 x 10) Unit-dose Tablets NDC 65862-036-10 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].