NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 CARCINOGENESIS MUTAGENESIS IMPAIRMENT OF FERTILITY. CarcinogenicityLamivudineLong-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.ZidovudineZidovudine was administered orally at dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on day 91 and then to 300 mg per kg per day on day 279.In mice, late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, squamous cell papilloma, and squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of middle-dose animal. No vaginal tumors were found at the lowest dose.In rats, late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every hours.It is not known how predictive the results of rodent carcinogenicity studies may be for humans.MutagenicityLamivudineLamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNULL synthesis in rat liver.ZidovudineZidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in cytogenetic study in rats given single dose.Impairment of FertilityLamivudineLamivudine did not affect male or female fertility in rats at dose associated with exposures approximately 130 times higher than the exposure in humans at the dose of 300 mg.ZidovudineZidovudine, administered to male and female rats at doses up to times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates.. 13.2 Animal Toxicology and/or Pharmacology. LamivudineReproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg per kg per day and 1,000 mg per kg per day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.ZidovudineOral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, dose of 3,000 mg per kg per day (very near the oral median lethal dose in rats of 3,683 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Lamivudine and Zidovudine tablets USP, containing 150 mg lamivudine and 300 mg zidovudine, are white to off white, scored, modified-capsule-shaped, film-coated tablets, debossed on both tablet faces, such that, when broken in half, LU and Y01 code is present on both halves of the tablet (LU on one face and Y01 on the opposite face of the tablet).They are available as follows:Bottles of 60s NDC 68180-284-07Store between and 30C (36 and 86F).

INDICATIONS & USAGE SECTION.


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

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Neutropenia and AnemiaInform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)].MyopathyInform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see WARNINGS AND PRECAUTIONS (5.2)].Lactic Acidosis/HepatomegalyInform patients that some HIV medicines, including lamivudine and zidovudine tablet, can cause rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see WARNINGS AND PRECAUTIONS (5.3)].Patients with Hepatitis or Co-infectionAdvise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see WARNINGS AND PRECAUTIONS (5.4)].Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see WARNINGS AND PRECAUTIONS (5.6)]. Related Products that are Not RecommendedInform patients that they should not take lamivudine and zidovudine tablets with ATRIPLA(R), COMPLERA(R), DUTREBIS(TM), EMTRIVA(R), EPIVIR(R), EPIVIR-HBV(R), EPZICOM(R), RETROVIR(R), STRIBILD(R), TRIUMEQ(R), TRIZIVIR(R), or TRUVADA(R) [see WARNINGS AND PRECAUTIONS (5.5)]. Drug InteractionsCaution patients about the use of other medications, including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of zidovudine [see DRUG INTERACTIONS (7.3)].Immune Reconstitution SyndromeIn some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS (5.8)]. Redistribution/Accumulation of Body FatInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS (5.9)].Information about HIV-1 InfectionLamivudine and zidovudine tablet is not cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV-1 RNULL have been associated with reduced risk of progression to AIDS and death.Advise patients to remain under the care of physician when using lamivudine and zidovudine tablets. Advise patients to take all HIV medications exactly as prescribed.Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment.Advise patients not to share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.Advise patients to always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.Instruct patients that if they miss dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.EPIVIR(R), RETROVIR(R), EPZICOM(R), TRIUMEQ(R), and TRIZIVIR(R) are registered trademarks of the ViiV Healthcare group of companies.(R)The other brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.Manufactured for:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United StatesMADE IN INDIA.Revised: June 2016 ID:246810.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Lamivudine and zidovudine tablet is an antiretroviral agent [see MICROBIOLOGY (12.4)].

MICROBIOLOGY SECTION.


12.4 Microbiology. Mechanism of ActionLamivudineLamivudine is 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 reverse transcriptase (RT) via DNULL chain termination after incorporation of the nucleotide analogue.ZidovudineZidovudine is synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNULL chain termination after incorporation of the nucleotide analogue.Antiviral ActivityLamivudine plus ZidovudineIn HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity.LamivudineThe antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. The EC50 values against HIV-2 isolates (n 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.ZidovudineThe antiviral activity of zidovudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM 0.27 mcg per mL) and 0.1 to microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.Neither lamivudine nor zidovudine were antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for EPIVIR(R) (lamivudine) and RETROVIR(R) (zidovudine).ResistanceIn subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.LamivudineLamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated subjects showed that the resistance was due to specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (M184V/I).ZidovudineHIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analog mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions.In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.Cross-resistanceCross-resistance has been observed among NRTIs. Cross-resistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine alone or in combination with zidovudine, isolates have emerged with substitution at codon 184, which confers resistance to lamivudine.TAM substitutions are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. Most commonly reported adverse reactions (incidence greater than or equal to 15%) in clinical trials 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 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 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 severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.3)]. Exacerbations of hepatitis [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.4)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis [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)]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS (5.8)]. Fat redistribution [see WARNINGS AND PRECAUTIONS (5.9)]. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Lamivudine plus Zidovudine Administered as Separate FormulationsIn randomized, controlled trials of EPIVIR(R) 300 mg per day plus RETROVIR(R) 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables and 2).Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Controlled Clinical Trials with EPIVIR(R) 300 mg per day and RETROVIR(R) 600 mg per dayAdverse ReactionEPIVIR(R) plus RETROVIR(R)(n 251)Body as 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 of the 2,613 adult subjects (0.3%) who received EPIVIR(R) 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 Controlled Clinical Trials of EPIVIR(R) 300 mg per day plus RETROVIR(R) 600 mg per dayFrequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline. ULN Upper limit of normal. ANC Absolute neutrophil count. = Number of patients assessed. Test(Abnormal Level)EPIVIR(R) plus RETROVIR(R)% (n)Neutropenia (ANC<750/mm3) 7.2% (237) Anemia (Hgb<8.0 g/dL) 2.9% (241) Thrombocytopenia (platelets<50,000/mm3) 0.4% (240) ALT (>5.0 ULN) 3.7% (241) AST (>5.0 ULN) 1.7% (241) Bilirubin (>2.5 ULN) 0.8% (241) Amylase (>2.0 ULN) 4.2% (72) 6.2 Postmarketing Experience. The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as WholeRedistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS (5.9)].Cardiovascular Cardiomyopathy.Endocrine and MetabolicGynecomastia, hyperglycemia.GastrointestinalOral mucosal pigmentation, stomatitis.GeneralVasculitis, weakness.Hemic and LymphaticAnemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly.Hepatic and PancreaticLactic acidosis and hepatic steatosis, pancreatitis, post-treatment exacerbations of hepatitis [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.3), (5.4), (5.7)].HypersensitivitySensitization reactions (including anaphylaxis), urticaria.MusculoskeletalMuscle weakness, CPK elevation, rhabdomyolysis.NervousParesthesia, peripheral neuropathy, seizures.RespiratoryAbnormal breath sounds/wheezing.SkinAlopecia, erythema multiforme, Stevens-Johnson syndrome.

BOXED WARNING SECTION.


WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS BSee full prescribing information for complete boxed warning.Hematologic Toxicity Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, component of lamivudine and zidovudine tablets. (5.1) Myopathy Symptomatic myopathy associated with prolonged use of zidovudine. (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.(5.3) Exacerbations of Hepatitis o Severe acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, component of lamivudine and zidovudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.4) WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS BHematologic ToxicityZidovudine, component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see WARNINGS AND PRECAUTIONS (5.1)].MyopathyProlonged use of zidovudine has been associated with symptomatic myopathy [see WARNINGS AND PRECAUTIONS (5.2)].Lactic Acidosis and Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS (5.3)].Exacerbations of Hepatitis BSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine and zidovudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis therapy may be warranted [see WARNINGS AND PRECAUTIONS (5.4)].

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Lamivudine and zidovudine tablet is an antiretroviral agent [see MICROBIOLOGY (12.4)].. 12.3 Pharmacokinetics. Pharmacokinetics in AdultsOne lamivudine and zidovudine tablet was bioequivalent to EPIVIR(R) tablet (150 mg) plus RETROVIR(R) tablet (300 mg) following single-dose administration to fasting healthy subjects (n 24).LamivudineFollowing oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).ZidovudineFollowing oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3.Table 3. Pharmacokinetic ParametersData presented as mean +- standard deviation except where noted. for Lamivudine and Zidovudine in AdultsParameterLamivudineZidovudineOral bioavailability (%) 86 +- 16 = 12 64 +- 10 = Apparent volume of distribution (L/kg) 1.3 +- 0.4 = 20 1.6 +- 0.6 = Plasma protein binding (%) <36 <38 CSF:plasma ratioMedian [range]. 0.12[0.04 to 0.47] = 38Children. 0.60[0.04 to 2.62] = 39Adults. Systemic clearance (L/h/kg) 0.33 +- 0.06 = 20 1.6 +- 0.6 = Renal clearance (L/h/kg) 0.22 +- 0.06 = 20 0.34 +- 0.05 = Elimination half-life (h)Approximate range. to 0.5 to Effect of Food on Absorption of lamivudine and zidovudine tabletsLamivudine and zidovudine tablets may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine tablets with food was similar when compared with fasting healthy subjects (n 24).Special PopulationsRenal ImpairmentLamivudine and zidovudine tablets: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).Hepatic ImpairmentLamivudine and zidovudine tablets: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).PregnancyLamivudine:Lamivudine pharmacokinetics were studied in 36 pregnant women during clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.Zidovudine:Zidovudine pharmacokinetics have been studied in Phase trial of women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.Although data are limited, methadone maintenance therapy in pregnant women did not appear to alter zidovudine pharmacokinetics.Geriatric PatientsThe pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age.GenderThere are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components.RaceLamivudineThere are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component.ZidovudineThe pharmacokinetics of zidovudine with respect to race have not been determined.Drug InteractionsNo drug interaction trials have been conducted using lamivudine and zidovudine tablets.Lamivudine and ZidovudineNo clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).Other interactionsInterferon AlfaThere was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects.RibavirinIn vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects [see WARNINGS AND PRECAUTIONS (5.5)].Table presents drug interaction information for the individual components of lamivudine and zidovudine tablets.Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCThis table is not all inclusive. Increase; Decrease; <-> no significant change; AUC area under the concentration versus time curve; CI confidence interval. Coadministered Drug and DoseDrug and DosenConcentrations ofLamivudine or ZidovudineConcentration of Coadministered DrugAUCVariabilityNelfinavir 750 mg every h 7 to 10 days Lamivudine single 150 mg 11 10% 95% CI:1% to 20% <-> Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily 5 days Lamivudine single 300 mg 14 43% 90% CI:32% to 55% <-> Atovaquone 750 mg every 12 with food Zidovudine 200 mg every8 14 31% Range 23% to 78%Estimated range of percent difference. <-> Clarithromycin 500 mg twice daily Zidovudine 100 mg every4 x days 12% Range34% to14% Not Reported Fluconazole 400 mg daily Zidovudine 200 mg every8 12 74% 95% CI:54% to 98% Not Reported Methadone 30 to 90 mg daily Zidovudine 200 mg every4 9 43% Range 16% to 64% <-> Nelfinavir 750 mg every h 7 to 10 days Zidovudine single 200 mg 11 35% Range 28% to 41% <-> Probenecid 500 mg every h 2 days Zidovudine mg/kg every h x3 days 106% Range 100% to 170% Not Assessed Rifampin 600 mg daily 14 days Zidovudine 200 mg every8 hx 14 days 47% 90% CI:41% to 53% Not Assessed Ritonavir 300 mg every h 4 days Zidovudine 200 mg every8 x days 25% 95% CI:15% to 34% <-> Valproic acid 250 mg or 500 mg every h 4 days Zidovudine 100 mg every8 x days 80% Range 64% to130% Not Assessed 12.4 Microbiology. Mechanism of ActionLamivudineLamivudine is 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 reverse transcriptase (RT) via DNULL chain termination after incorporation of the nucleotide analogue.ZidovudineZidovudine is synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNULL chain termination after incorporation of the nucleotide analogue.Antiviral ActivityLamivudine plus ZidovudineIn HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity.LamivudineThe antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. The EC50 values against HIV-2 isolates (n 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.ZidovudineThe antiviral activity of zidovudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM 0.27 mcg per mL) and 0.1 to microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.Neither lamivudine nor zidovudine were antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for EPIVIR(R) (lamivudine) and RETROVIR(R) (zidovudine).ResistanceIn subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.LamivudineLamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated subjects showed that the resistance was due to specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (M184V/I).ZidovudineHIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analog mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions.In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.Cross-resistanceCross-resistance has been observed among NRTIs. Cross-resistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine alone or in combination with zidovudine, isolates have emerged with substitution at codon 184, which confers resistance to lamivudine.TAM substitutions are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. One lamivudine and zidovudine tablet given twice daily is an alternative regimen to EPIVIR(R) tablets 150 mg twice daily plus RETROVIR(R) 600 mg per day in divided doses.. 14.1 Adults. The NUCB3007 (CAESAR) trial was conducted using EPIVIR(R) 150-mg tablets (150 mg twice daily) and RETROVIR(R) 100-mg capsules (2 100 mg times daily). CAESAR was multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR(R) or EPIVIR(R) plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. total of 1,816 HIV-1-infected adults with 25 to 250 (median 122) CD4 cells per mm3 at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 5.Table 5. Number of Subjects (%) with at Least HIV-1 Disease-progression Event or DeathEndpointCurrent Therapy(n 460)EPIVIR(R)plus Current Therapy(n 896)EPIVIR(R)plus NNRTIAn investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States. plus Current Therapy(n 460)HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) 14.2 Prevention of Maternal-Fetal HIV-1 Transmission. The utility of zidovudine alone for the prevention of maternal-fetal HIV-1 transmission was demonstrated in randomized, double-blind, placebo-controlled trial conducted inHIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm3 (median in the treated group: 560 cells per mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for weeks. The trial showed statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Lamivudine and zidovudine tablets are contraindicated in patients with previous hypersensitivity reaction to lamivudine or zidovudine. (4). Lamivudine and zidovudine tablet is contraindicated in patients with previous hypersensitivity reaction to lamivudine or zidovudine.

DESCRIPTION SECTION.


11 DESCRIPTION. Lamivudine and zidovudine tablets USP are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR(R)) and zidovudine (RETROVIR(R), 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, 300 mg of zidovudine, and the inactive ingredients dibasic calcium phosphate, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide.LamivudineThe 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 dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine. It has molecular formula of C8H11N3O3S 0.2H2O and molecular weight of 232.86. It has the following structural formula:Lamivudine is white to off-white solid with solubility of approximately 68 mg/mL in water at 20C. ZidovudineThe chemical name of zidovudine is 3-azido-3-deoxythymidine. It has molecular formula of C10H13N5O4 and molecular weight of 267.24. It has the following structural formula:Zidovudine is white to beige, odorless, crystalline solid with solubility of 20.1 mg/mL in water at 25C. lamivudine structure. zidovudine structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Adults and Adolescents weighing greater than or equal to 30 kg: tablet orally twice daily. (2.1) Pediatrics weighing greater than or equal to 30 kg: tablet orally twice daily. (2.2) Because lamivudine and zidovudine tablet is 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 tablets in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 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 solid oral dosage form is appropriate is tablet administered orally twice daily.Before prescribing lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets. If child is unable to reliably swallow lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed: EPIVIR(R) (lamivudine) oral solution and RETROVIR(R) (zidovudine) syrup.. 2.3 Not Recommended Due to Lack of Dosage Adjustment. Because lamivudine and zidovudine tablet is fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablet is 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.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Tablets: Scored 150 mg lamivudine and 300 mg zidovudine (3). Lamivudine and zidovudine tablets USP contain 150 mg of lamivudine and 300 mg of zidovudine. The tablets are white to off white, scored, modified-capsule-shaped, film-coated tablets, debossed on both tablet faces, such that, when broken in half, LU and Y01 code is present on both halves of the tablet (LU on one face and Y01 on the opposite face of the tablet).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Agents antagonistic with zidovudine: Concomitant use should be avoided (7.1) Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.1). 7.1 Zidovudine. Agents Antagonistic with ZidovudineConcomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro: Stavudine Doxorubicine Nucleoside analogues e.g., ribavirinHematologic/Bone Marrow Suppressive/Cytotoxic AgentsCoadministration with the following drugs may increase the hematologic toxicity of zidovudine: Ganciclovir Interferon alfa Ribavirin Other bone marrow suppressive or cytotoxic agents.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Clinical trials of lamivudine and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of lamivudine and zidovudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY (12.3)].

OVERDOSAGE SECTION.


10 OVERDOSAGE. There is no known specific treatment for overdose with lamivudine and zidovudine tablets. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.LamivudineBecause 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 lamivudine overdose event.ZidovudineAcute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have negligible effect on the removal of zidovudine, while elimination of its primary metabolite, azido-3-deoxy-5-O--D-glucopyranuronosylthymidine (GZDV), is enhanced.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. LAMIVUDINE AND ZIDOVUDINE TABLETS USPRx only150 mg/300 mgNDC 68180-284-07BOTTLE LABEL: 60 TABLETS. label-goa. label-pth.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Lamivudine and zidovudine tablet is not recommended for use in pediatric patients who weigh less than 30 kg because it is fixed-dose combination tablet that cannot be adjusted for this patient population [see DOSAGE AND ADMINISTRATION (2.2)].

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Pharmacokinetics in AdultsOne lamivudine and zidovudine tablet was bioequivalent to EPIVIR(R) tablet (150 mg) plus RETROVIR(R) tablet (300 mg) following single-dose administration to fasting healthy subjects (n 24).LamivudineFollowing oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).ZidovudineFollowing oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3.Table 3. Pharmacokinetic ParametersData presented as mean +- standard deviation except where noted. for Lamivudine and Zidovudine in AdultsParameterLamivudineZidovudineOral bioavailability (%) 86 +- 16 = 12 64 +- 10 = Apparent volume of distribution (L/kg) 1.3 +- 0.4 = 20 1.6 +- 0.6 = Plasma protein binding (%) <36 <38 CSF:plasma ratioMedian [range]. 0.12[0.04 to 0.47] = 38Children. 0.60[0.04 to 2.62] = 39Adults. Systemic clearance (L/h/kg) 0.33 +- 0.06 = 20 1.6 +- 0.6 = Renal clearance (L/h/kg) 0.22 +- 0.06 = 20 0.34 +- 0.05 = Elimination half-life (h)Approximate range. to 0.5 to Effect of Food on Absorption of lamivudine and zidovudine tabletsLamivudine and zidovudine tablets may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine tablets with food was similar when compared with fasting healthy subjects (n 24).Special PopulationsRenal ImpairmentLamivudine and zidovudine tablets: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).Hepatic ImpairmentLamivudine and zidovudine tablets: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).PregnancyLamivudine:Lamivudine pharmacokinetics were studied in 36 pregnant women during clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.Zidovudine:Zidovudine pharmacokinetics have been studied in Phase trial of women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.Although data are limited, methadone maintenance therapy in pregnant women did not appear to alter zidovudine pharmacokinetics.Geriatric PatientsThe pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age.GenderThere are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components.RaceLamivudineThere are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component.ZidovudineThe pharmacokinetics of zidovudine with respect to race have not been determined.Drug InteractionsNo drug interaction trials have been conducted using lamivudine and zidovudine tablets.Lamivudine and ZidovudineNo clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).Other interactionsInterferon AlfaThere was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects.RibavirinIn vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects [see WARNINGS AND PRECAUTIONS (5.5)].Table presents drug interaction information for the individual components of lamivudine and zidovudine tablets.Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCThis table is not all inclusive. Increase; Decrease; <-> no significant change; AUC area under the concentration versus time curve; CI confidence interval. Coadministered Drug and DoseDrug and DosenConcentrations ofLamivudine or ZidovudineConcentration of Coadministered DrugAUCVariabilityNelfinavir 750 mg every h 7 to 10 days Lamivudine single 150 mg 11 10% 95% CI:1% to 20% <-> Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily 5 days Lamivudine single 300 mg 14 43% 90% CI:32% to 55% <-> Atovaquone 750 mg every 12 with food Zidovudine 200 mg every8 14 31% Range 23% to 78%Estimated range of percent difference. <-> Clarithromycin 500 mg twice daily Zidovudine 100 mg every4 x days 12% Range34% to14% Not Reported Fluconazole 400 mg daily Zidovudine 200 mg every8 12 74% 95% CI:54% to 98% Not Reported Methadone 30 to 90 mg daily Zidovudine 200 mg every4 9 43% Range 16% to 64% <-> Nelfinavir 750 mg every h 7 to 10 days Zidovudine single 200 mg 11 35% Range 28% to 41% <-> Probenecid 500 mg every h 2 days Zidovudine mg/kg every h x3 days 106% Range 100% to 170% Not Assessed Rifampin 600 mg daily 14 days Zidovudine 200 mg every8 hx 14 days 47% 90% CI:41% to 53% Not Assessed Ritonavir 300 mg every h 4 days Zidovudine 200 mg every8 x days 25% 95% CI:15% to 34% <-> Valproic acid 250 mg or 500 mg every h 4 days Zidovudine 100 mg every8 x days 80% Range 64% to130% Not Assessed.

PREGNULLNCY SECTION.


8.1 Pregnancy. Pregnancy Category CPregnancy Exposure Registry:There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine tablets during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.Fetal Risk Summary:There are no adequate and well-controlled trials of lamivudine and zidovudine in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity and fetal malformations (zidovudine), and increased embryolethality (lamivudine). Lamivudine and zidovudine tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Clinical Considerations:Treatment of HIV during pregnancy optimizes the health of both mother and fetus. Clinical trial data reviewed by FDA demonstrate that maternal zidovudine treatment significantly reduces vertical transmission of HIV-1 infection to the fetus [see CLINICAL STUDIES (14.2)]. Published data suggest that combination antiretroviral regimens may reduce the rate of vertical transmission even further.Pharmacokinetics of lamivudine and zidovudine in pregnant women are similar to the pharmacokinetics in non-pregnant women. No dose adjustments are needed during pregnancy.In clinical trial, adverse events among HIV-1-infected women were not different among untreated women and women treated with zidovudine. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients (see Human data below).Data:Human DataLamivudine:Lamivudine pharmacokinetics were studied in pregnant women during 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 with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.Zidovudine:In randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug [see CLINICAL STUDIES (14.2)].Zidovudine pharmacokinetics were studied in Phase trial of women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.Animal DataLamivudine:Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see NONCLINICAL TOXICOLOGY (13.2)]. Zidovudine: Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg per day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose [see NONCLINICAL TOXICOLOGY (13.2)].

RECENT MAJOR CHANGES SECTION.


RECENT MAJOR CHANGES. Warnings and Precautions (5) 09/2015.

SPL UNCLASSIFIED SECTION.


WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS BHematologic ToxicityZidovudine, component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see WARNINGS AND PRECAUTIONS (5.1)].MyopathyProlonged use of zidovudine has been associated with symptomatic myopathy [see WARNINGS AND PRECAUTIONS (5.2)].Lactic Acidosis and Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS (5.3)].Exacerbations of Hepatitis BSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine and zidovudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis therapy may be warranted [see WARNINGS AND PRECAUTIONS (5.4)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. (8.2). 8.1 Pregnancy. Pregnancy Category CPregnancy Exposure Registry:There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine tablets during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.Fetal Risk Summary:There are no adequate and well-controlled trials of lamivudine and zidovudine in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity and fetal malformations (zidovudine), and increased embryolethality (lamivudine). Lamivudine and zidovudine tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Clinical Considerations:Treatment of HIV during pregnancy optimizes the health of both mother and fetus. Clinical trial data reviewed by FDA demonstrate that maternal zidovudine treatment significantly reduces vertical transmission of HIV-1 infection to the fetus [see CLINICAL STUDIES (14.2)]. Published data suggest that combination antiretroviral regimens may reduce the rate of vertical transmission even further.Pharmacokinetics of lamivudine and zidovudine in pregnant women are similar to the pharmacokinetics in non-pregnant women. No dose adjustments are needed during pregnancy.In clinical trial, adverse events among HIV-1-infected women were not different among untreated women and women treated with zidovudine. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients (see Human data below).Data:Human DataLamivudine:Lamivudine pharmacokinetics were studied in pregnant women during 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 with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.Zidovudine:In randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug [see CLINICAL STUDIES (14.2)].Zidovudine pharmacokinetics were studied in Phase trial of women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.Animal DataLamivudine:Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see NONCLINICAL TOXICOLOGY (13.2)]. Zidovudine: Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg per day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose [see NONCLINICAL TOXICOLOGY (13.2)].. 8.2 Lactation. The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed.. 8.4 Pediatric Use. Lamivudine and zidovudine tablet is not recommended for use in pediatric patients who weigh less than 30 kg because it is fixed-dose combination tablet that cannot be adjusted for this patient population [see DOSAGE AND ADMINISTRATION (2.2)].. 8.5 Geriatric Use. Clinical trials of lamivudine and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of lamivudine and zidovudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY (12.3)].. 8.6 Patients with Impaired Renal Function. Lamivudine and zidovudine tablet is not recommended for patients with creatinine clearance less than 50 mL per min because lamivudine and zidovudine tablet is fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of the lamivudine or zidovudine components of lamivudine and zidovudine tablet is required for patients with renal impairment then the individual components should be used [see DOSAGE AND ADMINISTRATION (2.3), CLINICAL PHARMACOLOGY (12.3)].. 8.7 Patients with Impaired Hepatic Function. Lamivudine and zidovudine tablet is fixed-dose combination and the dosage of the individual components cannot be adjusted. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Lamivudine and zidovudine tablets should not be administered with other lamivudine- or zidovudine-containing products or emtricitabine-containing products. (5.5) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue lamivudine and zidovudine tablets as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.6) Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. (5.6) Pancreatitis: Use with caution in patients with history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.7) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.8, 5.9). 5.1 Hematologic Toxicity/Bone Marrow Suppression. Zidovudine, component of lamivudine and zidovudine tablet, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and zidovudine tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 grams per dL [see ADVERSE REACTIONS (6.1)].Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine and zidovudine tablets. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.. 5.2 Myopathy. Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with lamivudine and zidovudine tablets.. 5.3 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. See full prescribing information for EPIVIR(R) (lamivudine) and RETROVIR(R) (zidovudine). Treatment with lamivudine and zidovudine tablets 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).. 5.4 Patients with Hepatitis Virus Co-infection. Post-treatment Exacerbations of HepatitisClinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR(R) (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.Emergence of Lamivudine-Resistant HBVSafety and efficacy of lamivudine have not been established for treatment of chronic hepatitis in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis virus. See full prescribing information for EPIVIR(R) (lamivudine).. 5.5 Related Products that are Not Recommended. Lamivudine and zidovudine tablet is fixed-dose combination of nucleoside analogue reverse transcriptase inhibitors (lamivudine and zidovudine). Concomitant administration of lamivudine and zidovudine tablets with other products containing lamivudine or zidovudine is not recommended. In addition, do not administer lamivudine and zidovudine tablets in combination with products containing emtricitabine.. 5.6 Use with Interferon- and Ribavirin-based Regimens. Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR(R) (lamivudine) and RETROVIR(R) (zidovudine). Discontinuation of lamivudine and zidovudine tablets should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and lamivudine and zidovudine tablets is not advised.. 5.7 Pancreatitis. Lamivudine and zidovudine tablets should be used with caution in patients with history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine and zidovudine tablet should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see ADVERSE REACTIONS (6.1)]. 5.8 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine tablets. 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 evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-BarrE 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.. 5.9 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. causal relationship has not been established.