Abacavir , Lamivudine And Zidovudine

Description

11 DESCRIPTION Abacavir, lamivudine and zidovudine tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN ® ), lamivudine (also known as EPIVIR ® or 3TC), and zidovudine (also known as RETROVIR ® , azidothymidine, or ZDV) with inhibitory activity against HIV-1. Abacavir, lamivudine and zidovudine tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose, povidone, and yellow ferric oxide. The tablets are coated with a film opadry green that is made of FD&C blue no. 2, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow ferric oxide. 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 670.74 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white powder and soluble in water. 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, 0.2 hydrate. 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·0.2H 2 O and a molecular weight of 232.86 g per mol. It has the following structural formula: Lamivudine is a white to off-white solid and is soluble in water. 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 g per mol. It has the following...

What Is Abacavir , Lamivudine And Zidovudine Used For?

1 INDICATIONS AND USAGE Abacavir, lamivudine and zidovudine tablet, a combination of abacavir, lamivudine, and zidovudine, each nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.( 1 ) Abacavir, lamivudine and zidovudine tablet is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use: Limited data exist on the use of abacavir, lamivudine and zidovudine tablets alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see CLINICAL STUDIES ( 14 )] .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Before initiating abacavir, lamivudine and zidovudine tablets, screen for the HLA-B*5701 allele because abacavir, lamivudine and zidovudine tablet contains abacavir. ( 2.1 ) Adults and pediatric patients weighing at least 40 kg: 1 tablet twice daily. ( 2.2 ) Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir, lamivudine and zidovudine tablets are not recommended in patients requiring dosage adjustment or patients with hepatic impairment. ( 2.3 , 4 ) 2.1 Screening for HLA-B*5701 Allele prior to Starting Abacavir, Lamivudine and Zidovudine Tablets Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir, lamivudine and zidovudine tablets [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )] . 2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg The recommended dosage of abacavir, lamivudine and zidovudine tablet is one tablet taken orally twice daily with or without food. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir, lamivudine and zidovudine tablet is not recommended for: pediatric patients who weigh less than 40 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 mild hepatic impairment. Abacavir, lamivudine and zidovudine tablet is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS ( 4 ), USE IN SPECIFIC POPULATIONS ( 8.7 )] .

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The most commonly reported adverse reactions (incidence at least 10%) in clinical trials were nausea, headache, malaise and fatigue, and nausea and vomiting. ( 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: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )] . Hematologic toxicity, including neutropenia and anemia [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.2 )] . Symptomatic myopathy [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.3 )] . Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.4 )] . Exacerbations of hepatitis B [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.5 )] . 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 )] . Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS ( 5.7 )] . Lipoatrophy [see WARNINGS AND PRECAUTIONS ( 5.8 )] . Myocardial infarction [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 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, lamivudine and zidovudine 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, Lamivudine and Zidovudine Tablets Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1. Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment Adverse Reaction ZIAGEN ® plus Lamivudine / Zidovudine ( n = 262 ) Indinavir plus Lamivudine / Zidovudine ( n =...

Drug Interactions

7 DRUG INTERACTIONS Methadone: An increased methadone dose may be required in a small number of patients. ( 7.1 ) Riociguat: The riociguat dose may need to be reduced. ( 7.1 ) Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 7.2 ) Agents antagonistic with zidovudine: Concomitant use should be avoided. ( 7.3 ) Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.3 ) 7.1 Abacavir 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. 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). 7.2 Lamivudine 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 Zidovudine Agents Antagonistic with Zidovudine Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro : Stavudine Doxorubicin Nucleoside analogues, e.g., ribavirin Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration with the following drugs may increase the hematologic toxicity of zidovudine: Ganciclovir Interferon alfa Ribavirin Other bone marrow suppressive or cytotoxic agents

Contraindications

4 CONTRAINDICATIONS Presence of HLA-B*5701 allele. ( 4 ) Prior hypersensitivity reaction to abacavir, lamivudine, or zidovudine ( 4 ) Moderate or severe hepatic impairment. ( 4 , 8.7 ) Abacavir, lamivudine and zidovudine tablets are contraindicated in patients: who have the HLA-B*5701 allele [see WARNINGS AND PRECAUTIONS ( 5.1 )]. with prior hypersensitivity reaction to abacavir [see WARNINGS AND PRECAUTIONS ( 5.1 )], lamivudine, or zidovudine. with moderate or severe hepatic impairment [see USE IN SPECIFIC POPULATIONS ( 8.7 )] .

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir, lamivudine and zidovudine tablets 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, 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 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...

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving abacavir, lamivudine and zidovudine tablets.

Overdosage

10 OVERDOSAGE There is no known specific treatment for overdose with abacavir, lamivudine and zidovudine 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. Zidovudine Acute 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 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Abacavir, lamivudine and zidovudine is available as tablets. Each tablet contains 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green colored, oval shaped, biconvex, film-coated, debossed with "LU" on one side and "N51" on the other side. They are packaged as follows: Bottles of 60 Tablets NDC 68180-286-07 Bottles of 100 Tablets NDC 68180-286-01 Bottles of 500 Tablets NDC 68180-286-02 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].