ABACAVIR, LAMIVUDINE AND ZIDOVUDINE- abacavir , lamivudine and zidovudine tablet

ABACAVIR, LAMIVUDINE AND ZIDOVUDINE by

Drug Labeling and Warnings

ABACAVIR, LAMIVUDINE AND ZIDOVUDINE by is a Prescription medication manufactured, distributed, or labeled by Lupin Pharmaceuticals, Inc., LUPIN LIMITED. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B

    Hypersensitivity Reactions

    Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of abacavir, lamivudine and zidovudine tablets. Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see WARNINGS AND PRECAUTIONS (5.1)].

    Abacavir, lamivudine and zidovudine tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1)]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir, lamivudine and zidovudine tablets or reinitiation of therapy with abacavir, lamivudine and zidovudine tablets, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir, lamivudine and zidovudine tablets immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1)].

    Following a hypersensitivity reaction to abacavir, lamivudine and zidovudine tablets, NEVER restart abacavir, lamivudine and zidovudine tablets or any other abacavir-containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND PRECAUTIONS (5.1)].

    Hematologic Toxicity

    Zidovudine, a component of abacavir, 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 (5.2)].

    Myopathy

    Prolonged use of zidovudine has been associated with symptomatic myopathy [see WARNINGS AND PRECAUTIONS (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, including abacavir, lamivudine, and zidovudine (components of abacavir, lamivudine and zidovudine tablets). Discontinue abacavir, lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS (5.4)].

    Exacerbations of Hepatitis B

    Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, a component of abacavir, 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 abacavir, lamivudine and zidovudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS (5.5)].

  • 1 INDICATIONS AND USAGE

    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)] .
  • 2 DOSAGE AND ADMINISTRATION

    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)] .
  • 3 DOSAGE FORMS AND STRENGTHS

    Abacavir, lamivudine and zidovudine tablets contain 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.

  • 4 CONTRAINDICATIONS

    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)] .
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions

    Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir, lamivudine and zidovudine tablets. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see ADVERSE REACTIONS (6.1)]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

    Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:

    • All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir, lamivudine and zidovudine tablets or reinitiation of therapy with abacavir, lamivudine and zidovudine tablets, unless patients have a previously documented HLA-B*5701 allele assessment.
    • Abacavir, lamivudine, and zidovudine tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.
    • Before starting abacavir, lamivudine and zidovudine tablets, review medical history for prior exposure to any abacavir-containing product. NEVER restart abacavir, lamivudine and zidovudine tablets or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
    • To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir, lamivudine and zidovudine tablets immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
    • If a hypersensitivity reaction cannot be ruled out, do not restart abacavir, lamivudine and zidovudine tablets or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.
    • If a hypersensitivity reaction is ruled out, patients may restart abacavir, lamivudine and zidovudine tablets. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir, lamivudine and zidovudine tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed.
    • A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.

    5.2 Hematologic Toxicity/Bone Marrow Suppression

    Zidovudine, a component of abacavir, lamivudine and zidovudine tablet, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Abacavir, 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 abacavir, 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.

    5.3 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 abacavir, lamivudine and zidovudine tablets.

    5.4 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, including abacavir, lamivudine and zidovudine (components of abacavir, lamivudine and zidovudine tablets). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN® (abacavir), EPIVIR® (lamivudine), and RETROVIR® (zidovudine). Treatment with abacavir, 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).

    5.5 Patients with Hepatitis B Virus Co-infection

    Posttreatment Exacerbations of Hepatitis

    Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR® (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 HBV

    Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B 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 B virus. See full prescribing information for EPIVIR® (lamivudine).

    5.6 Use with Interferon- and Ribavirin-Based Regimens

     Patients receiving interferon alfa with or without ribavirin and abacavir, lamivudine and zidovudine tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for RETROVIR® (zidovudine). Discontinuation of abacavir, 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 abacavir, lamivudine and zidovudine tablet is not advised.

    5.7 Immune Reconstitution Syndrome

    Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir, 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-BarrÉ 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.

    5.8 Lipoatrophy

    Treatment with zidovudine, a component of abacavir, lamivudine and zidovudine tablets, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

    5.9 Myocardial Infarction

    Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.

    As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

    5.10 Therapy-Experienced Patients

    In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy- experienced patients [see Microbiology (12.4)].

  • 6 ADVERSE REACTIONS

    The following adverse reactions are discussed in other sections of the labeling:

    • Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)] .
    • 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 [seeBOXED 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=264)
    Nausea
    		19%
    		17%
    Headache
    		13%
    		9%
    Malaise and fatigue
    		12%
    		12%
    Nausea and vomiting
    		10%
    		10%
    Hypersensitivity reaction
    		8%
    		2%
    Diarrhea
    		7%
    		5%
    Fever and/or chills
    		6%
    		3%
    Depressive disorders
    		6%
    		4%
    Musculoskeletal pain
    		5%
    		7%
    Skin rashes
    		5%
    		4%
    Ear/nose/throat infections
    		5%
    		4%
    Viral respiratory infections
    		5%
    		5%
    Anxiety
    		5%
    		3%
    Renal signs/symptoms
    		<1%
    		5%
    Pain (non-site-specific)
    		<1%
    		5%

    Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.

    Laboratory Abnormalities

    Laboratory abnormalities in CNA3005 are listed in Table 2.

    Table 2. Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in CNA3005

    ULN = Upper limit of normal.

    n = Number of subjects assessed.
    Laboratory Parameter
    		ZIAGEN® plus Lamivudine/Zidovudine
    (n = 262)
    		Indinavir plus Lamivudine/Zidovudine
    (n = 264)
    Elevated CPK (>4 x ULN)
    		18 (7%)
    		18 (7%)
    ALT (>5.0 x ULN)
    		16 (6%)
    		16 (6%)
    Neutropenia (<750/mm3)
    		13 (5%)
    		13 (5%)
    Hypertriglyceridemia (>750 mg/dL)
    		5 (2%)
    		3 (1%)
    Hyperamylasemia (>2.0 x ULN)
    		5 (2%)
    		1 (<1%)
    Hyperglycemia (>13.9 mmol/L)
    		2 (<1%)
    		2 (<1%)
    Anemia (Hgb ≤6.9 g/dL)
    		0 (0%)
    		3 (1%)

    Other Adverse Events

    In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

     

    Abacavir

    Cardiovascular:

    Myocardial infarction.

     

    Skin:

    Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see ADVERSE REACTIONS (6.1)].

     

    Abacavir, Lamivudine, and/or Zidovudine

    Body as a Whole:

    Redistribution/accumulation of body fat.

     

    Cardiovascular:

    Cardiomyopathy.

     

    Digestive:

    Stomatitis.

     

    Endocrine and Metabolic:

    Gynecomastia.

     

    Gastrointestinal:

    Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.

     

    General:

    Vasculitis, weakness.

     

    Hemic and Lymphatic:

    Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.

     

    Hepatic:

    Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS (5.4)], elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS (5.5)].

     

    Hypersensitivity:

    Sensitization reactions (including anaphylaxis), urticaria.

     

    Musculoskeletal:

    Arthralgia, myalgia, muscle weakness, rhabdomyolysis.

     

    Nervous:

    Dizziness, paresthesia, peripheral neuropathy, seizures.

     

    Psychiatric:

    Insomnia and other sleep disorders.

     

    Respiratory:

    Abnormal breath sounds/wheezing.

     

    Skin:

    Alopecia, erythema multiforme, Stevens-Johnson syndrome.

     

     

  • 7 DRUG INTERACTIONS

    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.

    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
  • 8 USE IN SPECIFIC POPULATIONS

    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 rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 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:

    Abacavir

    Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens.

    Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see CLINICAL PHARMACOLOGY (12.3)].

    Lamivudine

    Based on prospective reports to the APR of 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 trials assessed pharmacokinetics in 16 women at 36 weeks' gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks' gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks' gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

    Zidovudine

    Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine 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 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens.

    A 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. Of the 363 neonates that were evaluated, 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 full prescribing information for RETROVIR® (zidovudine) and COMBIVIR® (lamivudine and zidovudine).

    Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see CLINICAL PHARMACOLOGY (12.3)].

    There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. 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. The clinical relevance of transient elevations in serum lactate is unknown.

    Animal Data:

    Abacavir

    Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.

    Lamivudine

    Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

    Zidovudine

    A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

    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.

    8.4 Pediatric Use

    Abacavir, lamivudine and zidovudine tablet is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations [see DOSAGE AND ADMINISTRATION (2.3)].

    Therapy-Experienced Pediatric Trial

    A randomized, double-blind trial, CNA3006, compared ZIAGEN® plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir.

    8.5 Geriatric Use

    Clinical trials of abacavir, 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 abacavir, 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

    Abacavir, lamivudine and zidovudine tablet is not recommended for patients with creatinine clearance less than 50 mL per min because abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of abacavir, 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

    Abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of abacavir, lamivudine and zidovudine tablet, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see CLINICAL PHARMACOLOGY (12.3)].

    The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, abacavir, lamivudine and zidovudine tablets are contraindicated in these patients [see CONTRAINDICATIONS (4)].

    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.

  • 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.

  • 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 (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-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 (C14H18N6O)2·H2SO4 and a molecular weight of 670.74 g per mol. It has the following structural formula:

    Abacavir Sulfate

    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 C8H11N3O3S·0.2H2O and a molecular weight of 232.86 g per mol. It has the following structural formula:

    Lamivudine

    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 C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula:

    Zidovudine

    Zidovudine is a white to yellowish powder with a solubility of 20.1 mg/mL in water at 25°C.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Abacavir, lamivudine and zidovudine tablet is an antiretroviral agent [see Microbiology (12.4)].

    12.3 Pharmacokinetics

    Pharmacokinetics in Adults

    In a single-dose, 3-way crossover bioavailability trial of 1 abacavir, lamivudine and zidovudine tablet versus 1 ZIAGEN® tablet (300 mg), 1 EPIVIR® tablet (150 mg), plus 1 RETROVIR® tablet (300 mg) administered simultaneously in healthy subjects (n = 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all 3 components. One abacavir, lamivudine and zidovudine tablet was bioequivalent to 1 ZIAGEN® tablet (300 mg), 1 EPIVIR® tablet (150 mg), plus 1 RETROVIR® tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

    Abacavir:

    Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0 to 12 h) was 6.02 ± 1.73 mcghour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.

    Lamivudine:

    Following 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 a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

    Zidovudine:

    Following 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 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. A second metabolite, 3′-amino-3′  deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

    In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

    The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.

    Table 3. Pharmacokinetic Parameters* for Abacavir, Lamivudine, and Zidovudine in Adults
    Parameter
    		Abacavir
    		Lamivudine
    		Zidovudine
  • * Data presented as mean ± standard deviation except where noted.
  • † Approximate range.
    		•
    Oral bioavailability (%)
    		86 ± 25
    		n = 6
    		86 ± 16
    		n = 12
    		64 ± 10
    		n = 5
    Apparent volume of distribution (L/kg)
    		0.86 ± 0.15
    		n = 6
    		1.3 ± 0.4
    		n = 20
    		1.6 ± 0.6
    		n = 8
    Systemic clearance (L/h/kg)
    		0.80 ± 0.24
    		n = 6
    		0.33 ± 0.06
    		n = 20
    		1.6 ± 0.6
    		n = 6
    Renal clearance (L/h/kg)
    		0.007 ± 0.008
    		n = 6
    		0.22 ± 0.06
    		n = 20
    		0.34 ± 0.05
    		n = 9
    Elimination half-life (h)
    		1.45 ± 0.32
    		n = 20
    		5 to 7†
    		0.5 to 3†

    Effect of Food on Absorption of Abacavir, Lamivudine and Zidovudine Tablets

    Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of abacavir, lamivudine and zidovudine tablets with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) [see DOSAGE AND ADMINISTRATION (2.2)].

     

    Specific Populations

    Patients with Renal Impairment: 

    Abacavir, Lamivudine and Zidovudine Tablets 

    The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).

     

    Patients with Hepatic Impairment: 

    Abacavir, Lamivudine and Zidovudine Tablets 

    The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).

     

    Pregnant Women: 

    Abacavir 

    Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

     

    Lamivudine

    Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 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 a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant 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 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

     

    Geriatric Patients: 

    The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.

     

    Male and Female Patients:

    There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.

     

    Racial Groups: 

    Abacavir and Lamivudine 

    There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components.

     

    Zidovudine

    The pharmacokinetics of zidovudine with respect to race have not been determined.

     

    Drug Interaction Studies:

    The drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using abacavir, lamivudine and zidovudine tablets. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine.

     

    Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents:

    Abacavir and lamivudine do not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9, or CYP2D6), therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.

     

    Effect of Other Agents on the Pharmacokinetics of Abacavir, Lamivudine, or Zidovudine:

    Abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.

     

    Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.

     

    Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

     

    Glucuronyl Transferase:

    Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

     

    Ethanol:

    Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

     

    Interferon Alfa:

    There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

     

    Methadone:

    In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see DRUG INTERACTIONS (7.1)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.

     

    Ribavirin:

    In 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 a multi-drug regimen to HIV-1/HCV co-infected subjects [see WARNINGS AND PRECAUTIONS (5.6)].

     

    Sorbitol (Excipient):

    Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC (0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.

     

    The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.

     

    Table 4. Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUC*

    ↑= Increase; ↓= Decrease; ↔= No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.


  • * See DRUG INTERACTIONS (7) for additional information on drug interactions.
  • † The drug-drug interaction was only evaluated in males.
  • ‡ Estimated range of percent difference.
    		•
    Coadministered 
    Drug and Dose
    		Drug and Dose
    		n
    		Concentrations of Abacavir, Lamivudine, or Zidovudine
    		Concentration of Coadministered Drug



    		AUC
    		Variability

    Ethanol
    0.7 g/kg
    		Abacavir single
    600 mg
    		24
    		↑41%
    		90% CI:
    35% to 48%
    		↔†
    Nelfinavir
    750 mg every 8 h x 7 to 10 days
    		Lamivudine single
    150 mg
    		11
    		↑10%
    		95% CI:
    1% to 20%
    		↔
    Trimethoprim 160 mg/ Sulfamethoxazole 
    800 mg daily x 5 days
    		Lamivudine single
    300 mg
    		14
    		↑43%
    		90% CI:
    32% to 55%
    		↔
    Atovaquone
    750 mg every 12 h with food
    		Zidovudine
    200 mg every
    8 h
    		14
    		↑31%
    		Range: 23% to 78%‡
    		↔
    Clarithromycin 500 mg twice daily
    		Zidovudine
    100 mg every
    4 h x 7 days
    		4
    		↓12%
    		Range:
    ↓34% to ↑14%
    		Not Reported
    Fluconazole 400 mg daily
    		Zidovudine
    200 mg every
    8 h
    		12
    		↑74%
    		95% CI:
    54% to 98%
    		Not Reported
    Methadone 30 to 90 mg daily
    		Zidovudine
    200 mg every
    4 h
    		9
    		↑43%
    		Range:
    16% to 64%‡
    		↔
    Nelfinavir 750 mg every 8 h x 7 to 10 days
    		Zidovudine
    single
    200 mg
    		11
    		↓35%
    		Range:
    28% to 41%
    		↔
    Probenecid 500 mg every 6 h x
    2 days
    		Zidovudine
    2 mg/kg every
    8 h x 3 days
    		3
    		↑106%
    		Range:
    100% to 170% c
    		Not Assessed
    Rifampin
       600 mg daily x
       14 days
    		Zidovudine
    200 mg every
    8 h x 14 days
    		8
    		↓47%
    		90% CI:
    41% to 53%
    		Not Assessed
    Ritonavir
       300 mg every 6 h x 4
       days
    		Zidovudine
    200 mg every 8 h x 4 days
    		9
    		↓25%
    		95% CI:
    15% to 34%
    		↔
    Valproic acid
       250 mg or 500 mg
       every 8 h x 4 days
    		Zidovudine
    100 mg every 8 h x
    4 days
    		6
    		↑80%
    		Range:
    64% to 130%‡
    		Not Assesed

    12.4 Microbiology

    Mechanism of Action

    Abacavir:

    Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

    Lamivudine: 

    Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

    Zidovudine:

    Zidovudine is a 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 DNA chain termination after incorporation of the nucleotide analogue.

    Antiviral Activity

    Abacavir:

    The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 + 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM.

    Lamivudine: 

    The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and 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: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A - G and group O viruses (n = 3 except n = 2 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.

    Zidovudine: 

    The antiviral activity of zidovudine against HIV-1 was assessed in a 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 9 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 abacavir, lamivudine, nor zidovudine was 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 ZIAGEN® (abacavir), EPIVIR® (lamivudine), RETROVIR® (zidovudine).

    Resistance

    HIV-1 isolates with reduced susceptibility to abacavir, lamivudine, or zidovudine have been selected in cell culture and were also recovered from subjects treated with abacavir, lamivudine, and zidovudine, or the combinations of the individual components.

    Abacavir and Lamivudine: 

    HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions, K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.

    Zidovudine:

    Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analogue 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 a 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-Resistance

    Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with TAM substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

    TAMs are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir. Cross-resistance between lamivudine and zidovudine has not been reported.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity

    Abacavir: 

    Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats.  These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.

    Lamivudine: 

    Long-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.

    Zidovudine: 

    Zidovudine was administered orally at 3 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, 7 late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

    In rats, 2 late-appearing (after 20 months), non-metastasizing 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 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

    It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

    Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg-per-kg-per-day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

    Mutagenicity

    Abacavir: 

    Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

    Lamivudine: 

    Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

    Zidovudine: 

    Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

    Impairment of Fertility

    Abacavir:

    Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.

    Lamivudine:

    Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.

    Zidovudine:

    Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

    13.2 Animal Toxicology and/or Pharmacology

    Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.

  • 14 CLINICAL STUDIES

    The following trial was conducted with the individual components of abacavir, lamivudine and zidovudine tablet [see CLINICAL PHARMACOLOGY (12.3)].

    CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN® (300 mg twice daily) plus COMBIVIR® (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR® twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median pretreatment CD4+ cell count was 360 cells per mm3, and median plasma HIV-1 RNA was 4.8 log10 copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR®Test) through 48 weeks of treatment are summarized in Table 5.

    Table 5. Outcomes of Randomized Treatment through Week 48 (CNA3005)
    Outcome
    		ZIAGEN® plus 
    Lamivudine/Zidovudine 
    (n = 262)
    		Indinavir plus 
    Lamivudine/Zidovudine 
    (n = 265)
  • * Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL.
  • † Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48.
  • ‡ Includes consent withdrawn, lost to follow-up, protocol violations, those with missing data, clinical progression, and other.
    		•
    Responder*
    		49%
    		50%
    Virologic failure†
    		31%
    		28%
    Discontinued due to adverse reactions
    		10%
    		12%
    Discontinued due to other reasons‡
    		11%
    		10%

    Treatment response by plasma HIV-1 RNA strata is shown in Table 6.

    Table 6. Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005)
    Screening HIV-1 RNA
    (copies/mL)
    		ZIAGEN® plus
    Lamivudine/Zidovudine
    (n = 262)
    		Indinavir plus
    Lamivudine/Zidovudine
    (n = 265)

    		<400 copies/mL
    		n
    		<400 copies/mL
    		n
    ≥10,000 to ≤100,000
    		50%
    		166
    		48%
    		165
    >100,000
    		48%
    		96
    		52%
    		100

    In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir.

    Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm3 was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.

  • 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].

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Hypersensitivity Reaction

    Inform patients:

    • that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of abacavir, lamivudine and zidovudine tablet, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir, lamivudine and zidovudine tablets. The complete text of the Medication Guide is reprinted at the end of this document.
    • to carry the Warning Card with them.
    • how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS (5.1), MEDICATION GUIDE] .
    • that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking abacavir, lamivudine and zidovudine tablet.
    • that a hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir, lamivudine and zidovudine tablet is not immediately discontinued.
    • to not restart abacavir, lamivudine and zidovudine tablet or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
    • that if they have a hypersensitivity reaction, they should dispose of any unused abacavir, lamivudine and zidovudine tablet to avoid restarting abacavir.
    • that a hypersensitivity reaction is usually reversible if it is detected promptly and abacavir, lamivudine and zidovudine tablet is stopped right away.
    • that if they have interrupted abacavir, lamivudine and zidovudine tablet for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
    • to not restart abacavir, lamivudine and zidovudine tablet or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

    Neutropenia and Anemia

    Inform 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 (5.2)].

    Myopathy

    Inform 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 (5.3)].

    Lactic Acidosis/Hepatomegaly with Steatosis

    Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking abacavir, lamivudine and zidovudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see WARNINGS AND PRECAUTIONS (5.4)].

    Patients with Hepatitis B or C Co-infection

    Advise 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 healthcare provider [see WARNINGS AND PRECAUTIONS (5.5)].

    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)].

    Drug Interactions

    Advise patients that other medications may interact with abacavir, lamivudine and zidovudine tablets and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of abacavir, lamivudine and zidovudine tablets [see DRUG INTERACTIONS (7.3)]. 

    Immune Reconstitution Syndrome

    Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when abacavir, lamivudine and zidovudine tablets are started [see WARNINGS AND PRECAUTIONS (5.7)].

    Lipoatrophy

    Advise patients that loss of subcutaneous fat may occur in patients receiving abacavir, lamivudine and zidovudine tablets and that they will be regularly assessed during therapy [see WARNINGS AND PRECAUTIONS (5.8)].

    Pregnancy Registry

    Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir, lamivudine and zidovudine tablets during pregnancy [see USE IN SPECIFIC POPULATIONS (8.1)].

    Lactation

    Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see USE IN SPECIFIC POPULATIONS (8.2)].

    Missed Dose

    Instruct patients that if they miss a dose of abacavir, lamivudine and zidovudine tablets, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see DOSAGE AND ADMINISTRATION (2)].

    Availability of Medication Guide

    Instruct patients to read the Medication Guide before starting abacavir, lamivudine and zidovudine tablets and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

    The 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 21202

    United States

    Manufactured by:

    Lupin Limited

    Pithampur (M.P.) - 454 775

    India

    Revised: August 2019                                                                                   ID#: 261194

  • MEDICATION GUIDE

    MEDICATION GUIDE

    Abacavir, Lamivudine and Zidovudine Tablets

    (a-BAK-a-vir , la-MIV-ue-deen, zye-DOE-vue-deen)

    What is the most important information I should know about abacavir, lamivudine and zidovudine tablets?

    Abacavir, lamivudine and zidovudine tablets can cause serious side effects, including:

    • Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with abacavir, lamivudine and zidovudine tablets and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.

    If you get a symptom from 2 or more of the following groups while taking abacavir, lamivudine  and zidovudine tablets, call your healthcare provider right away to find out if you should stop taking abacavir, lamivudine and zidovudine tablets.


    		Symptom(s)
    Group 1 
    		Fever 
    Group 2 
    		Rash 
    Group 3 
    		Nausea, vomiting, diarrhea, abdominal (stomach area) pain 
    Group 4 
    		Generally ill feeling, extreme tiredness, or achiness 
    Group 5 
    		Shortness of breath, cough, sore throat 

    A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times.

    If you stop abacavir, lamivudine and zidovudine tablets because of an allergic reaction, never take abacavir, lamivudine and zidovudine tablets or any other abacavir-containing medicine (EPZICOM®, TRIUMEQ®, or ZIAGEN®) again.

    • If you have an allergic reaction, dispose of any unused abacavir, lamivudine and zidovudine tablets. Ask your pharmacist how to properly dispose of medicines.
    • If you take abacavir, lamivudine and zidovudine tablets or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death .
    • If you stop abacavir, lamivudine and zidovudine tablets for any other reason, even for a few days, and you are not allergic to abacavir, lamivudine and zidovudine tablets, talk with your healthcare provider before taking it again. Taking abacavir, lamivudine and zidovudine tablets again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.

    If your healthcare provider tells you that you can take abacavir, lamivudine and zidovudine tablets again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.

    • Blood problems . Zidovudine (RETROVIR®), one of the medicines in abacavir, lamivudine and zidovudine tablets, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). These blood cell problems are especially likely to happen in people with advanced human immunodeficiency virus type 1 (HIV-1) disease or AIDS. Your healthcare provider should check your blood cell counts regularly during treatment with abacavir, lamivudine and zidovudine tablets.
    • Muscle pain or weakness (myopathy) can happen during treatment with abacavir, lamivudine and zidovudine tablets. Zidovudine (RETROVIR®), one of the medicines in abacavir, lamivudine and zidovudine tablets, can cause muscle pain or weakness when used for a long time.
    • Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take abacavir, lamivudine and zidovudine tablets. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:
      • feel very weak or tired
      • unusual (not normal) muscle pain
      • trouble breathing
      • stomach pain with nausea and vomiting
      • feel cold, especially in your arms and legs
      • feel dizzy or light-headed
      • have a fast or irregular heartbeat
    • Serious liver problems can happen in people who take abacavir, lamivudine and zidovudine tablets. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
      • your skin or the white part of your eyes turns yellow (jaundice)
      • dark or "tea-colored" urine
      • light colored stools (bowel movements)
      • loss of appetite for several days or longer
      • nausea
      • pain, aching, or tenderness on the right side of your stomach area

    You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).

     

    • Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking abacavir, lamivudine and zidovudine tablets. A "flare-up" is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease is serious and may lead to death.
      • Do not run out of abacavir, lamivudine and zidovudine tablets. Refill your prescription or talk to your healthcare provider before your abacavir, lamivudine and zidovudine tablets are all gone.
      • Do not stop abacavir, lamivudine and zidovudine tablets without first talking to your healthcare provider.
      • If you stop taking abacavir, lamivudine and zidovudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.
    • Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with abacavir, lamivudine and zidovudine tablets and become harder to treat (resistant).
    • Use with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines, and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking abacavir, lamivudine and zidovudine tablets and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms.

    What are abacavir, lamivudine and zidovudine tablets?

    Abacavir, lamivudine and zidovudine tablet is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used alone or with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Abacavir, lamivudine and zidovudine tablet contains 3 prescription medicines, abacavir (ZIAGEN®), lamivudine (EPIVIR®) and zidovudine (RETROVIR®).

    Abacavir, lamivudine and zidovudine tablets should not be used in children weighing less than 88 pounds (40 kg).

    Do not take abacavir, lamivudine and zidovudine tablets if you:

     

    • have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with abacavir, lamivudine and zidovudine tablets.
    • are allergic to abacavir or any of the ingredients in abacavir, lamivudine and zidovudine tablets. See the end of this Medication Guide for a complete list of ingredients in abacavir, lamivudine and zidovudine tablets.
    • have liver problems.

    What should I tell my healthcare provider before taking abacavir, lamivudine and zidovudine tablets?

    Before you take abacavir, lamivudine and zidovudine tablets, tell your healthcare provider if you:

    • have been tested and know whether or not you have a particular gene variation called HLA-B*5701.
    • have or have had liver problems, including hepatitis B or C virus infection.
    • have kidney problems.
    • have low blood cell counts (bone marrow problem). Ask your healthcare provider if you are not sure.
    • have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
    • drink alcohol or take medicines that contain alcohol.
    • are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.

    Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

    • are breastfeeding or plan to breastfeed. Do not breastfeed if you take abacavir, lamivudine and zidovudine tablets.
      • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.

    Some medicines interact with abacavir, lamivudine and zidovudine tablets. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with abacavir, lamivudine and zidovudine tablets.

    Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take abacavir, lamivudine and zidovudine tablets with other medicines.

    How should I take abacavir, lamivudine and zidovudine tablets?

    • Take abacavir, lamivudine and zidovudine tablets exactly as your healthcare provider tells you to take it.
    • If you miss a dose of abacavir, lamivudine and zidovudine tablets, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.
    • Stay under the care of a healthcare provider during treatment with abacavir, lamivudine and zidovudine tablets.
    • Abacavir, lamivudine and zidovudine tablets may be taken with or without food.
    • Tell your healthcare provider if you or your child has trouble swallowing abacavir, lamivudine and zidovudine tablets.
    • Do not run out of abacavir, lamivudine and zidovudine tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.
    • If you take too much abacavir, lamivudine and zidovudine tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

    What are the possible side effects of abacavir, lamivudine and zidovudine tablets?

    • Abacavir, lamivudine and zidovudine tablets can cause serious side effects including :
    • See "What is the most important information I should know about abacavir, lamivudine and zidovudine tablets?"
    • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking abacavir, lamivudine and zidovudine tablets.
    • Loss of body fat can happen in people who take HIV-1 medicines that contain zidovudine. This loss of fat may occur in the legs, arms, buttocks, and face. The loss of fat may be permanent and long-term health effects are not known.
    • Heart attack (myocardial infarction). Some HIV-1 medicines including abacavir, lamivudine and zidovudine tablets may increase your risk of heart attack.

    The most common side effects of abacavir, lamivudine and zidovudine tablets include:

    • nausea
    • headache
    • weakness or tiredness
    • vomiting

    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

    These are not all the possible side effects of abacavir, lamivudine and zidovudine tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store abacavir, lamivudine and zidovudine tablets?

    • Store abacavir, lamivudine and zidovudine tablets at 59°F to 86°F (15°C to 30°C).

    Keep abacavir, lamivudine and zidovudine tablets and all medicines out of the reach of children.

     

    General information for safe and effective use of abacavir, lamivudine and zidovudine tablets.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use abacavir, lamivudine and zidovudine tablets for a condition for which it was not prescribed. Do not give abacavir, lamivudine and zidovudine tablets to other people, even if they have the same symptoms that you have. It may harm them.

     

    You can ask your healthcare provider or pharmacist for the information about abacavir, lamivudine and zidovudine tablets that is written for health professionals.

     

    For more information go to www.lupinpharmaceuticals.com or call 1-800-399-2561.

     

    What are the ingredients in abacavir, lamivudine and zidovudine tablets?

    Active ingredients: abacavir, lamivudine and zidovudine

     

    Inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, and yellow ferric oxide.

     

    Tablet film coating contains: opadry green made of FD&C blue no. 2, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow ferric oxide.

     

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

     

    The 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 21202

    United States

     

    Manufactured by:

    Lupin Limited

    Pithampur (M.P.) - 454 775

    India

     

    Revised: September 2018                                                                 ID#: 256360

     

  • PRINCIPAL DISPLAY PANEL

    ABACAVIR, LAMIVUDINE AND ZIDOVUDINE TABLETS

    300 mg 150 mg 300 mg

    Rx only

    NDC: 68180-286-07

    Notice to Authorized Dispenser:

    Dispense drug product with Medication Guide and Warning Card from the carton.

    Each tablet contains abacavir sulfate USP equivalent to 300 mg of abacavir, 150 mg of lamivudine USP, and 300 mg of zidovudine USP.

    Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

    See prescribing information for dosage information.

    Manufactured for:

    Lupin Pharmaceuticals, Inc.

    Baltimore, Maryland 21202

    United States

    Manufactured by:

    Lupin Limited

    Pithampur (M.P.) - 454 775

    INDIA

    NDC: <a href=/NDC/68180-286-07>68180-286-07</a> ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE TABLETS 300 mg 150 mg 300 mg TABLETS Rx only Bottle Label: 60 Tablets
    NDC: <a href=/NDC/68180-286-07>68180-286-07</a> ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE TABLETS 300 mg 150 mg 300 mg TABLETS Rx only Carton Label: 60 Tablets
  • INGREDIENTS AND APPEARANCE
    ABACAVIR, LAMIVUDINE AND ZIDOVUDINE 
    abacavir , lamivudine and zidovudine tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 68180-286
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LAMIVUDINE (UNII: 2T8Q726O95) (LAMIVUDINE - UNII:2T8Q726O95) LAMIVUDINE150 mg
    ZIDOVUDINE (UNII: 4B9XT59T7S) (ZIDOVUDINE - UNII:4B9XT59T7S) ZIDOVUDINE300 mg
    ABACAVIR SULFATE (UNII: J220T4J9Q2) (ABACAVIR - UNII:WR2TIP26VS) ABACAVIR300 mg
    Inactive Ingredients
    Ingredient NameStrength
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    POLYVINYL ALCOHOL, UNSPECIFIED (UNII: 532B59J990)  
    POVIDONE (UNII: FZ989GH94E)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    ColorBLUE (blue-green) Scoreno score
    ShapeOVAL (oval-shaped) Size22mm
    FlavorImprint Code LU;N51
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 68180-286-071 in 1 CARTON12/17/2013
    160 in 1 BOTTLE; Type 0: Not a Combination Product
    2NDC: 68180-286-021 in 1 CARTON12/17/2013
    2500 in 1 BOTTLE; Type 0: Not a Combination Product
    3NDC: 68180-286-011 in 1 CARTON12/17/2013
    3100 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20291212/17/2013
    Labeler - Lupin Pharmaceuticals, Inc. (089153071)
    Registrant - LUPIN LIMITED (675923163)
    Establishment
    NameAddressID/FEIBusiness Operations
    LUPIN LIMITED863645527MANUFACTURE(68180-286)
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