Drug Facts
Composition & Profile
Identifiers & Packaging
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].; 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 68180-286-07 ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE TABLETS 300 mg 150 mg 300 mg TABLETS Rx only Bottle Label: 60 Tablets NDC 68180-286-07 ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE TABLETS 300 mg 150 mg 300 mg TABLETS Rx only Carton Label: 60 Tablets
- 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].
- 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 68180-286-07 ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE TABLETS 300 mg 150 mg 300 mg TABLETS Rx only Bottle Label: 60 Tablets NDC 68180-286-07 ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE TABLETS 300 mg 150 mg 300 mg TABLETS Rx only Carton Label: 60 Tablets
Overview
Abacavir, lamivudine and zidovudine tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN ® ), lamivudine (also known as EPIVIR ® or 3TC), and zidovudine (also known as RETROVIR ® , azidothymidine, or ZDV) with inhibitory activity against HIV-1. Abacavir, lamivudine and zidovudine tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose, povidone, and yellow ferric oxide. The tablets are coated with a film opadry green that is made of FD&C blue no. 2, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow ferric oxide. Abacavir Sulfate The chemical name of abacavir sulfate is (1 S,cis )-4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S , 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C 14 H 18 N 6 O) 2 ·H 2 SO 4 and a molecular weight of 670.74 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white powder and soluble in water. Dosages are expressed in terms of abacavir. Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, 0.2 hydrate. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S·0.2H 2 O and a molecular weight of 232.86 g per mol. It has the following structural formula: Lamivudine is a white to off-white solid and is soluble in water. Zidovudine The chemical name of zidovudine is 3'-azido-3'-deoxythymidine. It has a molecular formula of C 10 H 13 N 5 O 4 and a molecular weight of 267.24 g per mol. It has the following structural formula: Zidovudine is a white to yellowish powder with a solubility of 20.1 mg/mL in water at 25°C. Abacavir Sulfate Lamivudine Zidovudine
Indications & Usage
Abacavir, lamivudine and zidovudine tablet, a combination of abacavir, lamivudine, and zidovudine, each nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.( 1 ) Abacavir, lamivudine and zidovudine tablet is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use: Limited data exist on the use of abacavir, lamivudine and zidovudine tablets alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see CLINICAL STUDIES ( 14 )] .
Dosage & Administration
Before initiating abacavir, lamivudine and zidovudine tablets, screen for the HLA-B*5701 allele because abacavir, lamivudine and zidovudine tablet contains abacavir. ( 2.1 ) Adults and pediatric patients weighing at least 40 kg: 1 tablet twice daily. ( 2.2 ) Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir, lamivudine and zidovudine tablets are not recommended in patients requiring dosage adjustment or patients with hepatic impairment. ( 2.3 , 4 ) 2.1 Screening for HLA-B*5701 Allele prior to Starting Abacavir, Lamivudine and Zidovudine Tablets Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir, lamivudine and zidovudine tablets [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )] . 2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg The recommended dosage of abacavir, lamivudine and zidovudine tablet is one tablet taken orally twice daily with or without food. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because abacavir, lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir, lamivudine and zidovudine tablet is not recommended for: pediatric patients who weigh less than 40 kg [see USE IN SPECIFIC POPULATIONS ( 8.4 )]. patients with creatinine clearance less than 50 mL per minute [see USE IN SPECIFIC POPULATIONS ( 8.6 )]. patients with mild hepatic impairment. Abacavir, lamivudine and zidovudine tablet is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS ( 4 ), USE IN SPECIFIC POPULATIONS ( 8.7 )] .
Warnings & Precautions
Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue abacavir, lamivudine and zidovudine tablets as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.6 ) Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. ( 5.6 ) Immune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. ( 5. 7, 5.8 ) 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 mm 3 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 )].
Boxed Warning
HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. ( 5.1 ) Hypersensitivity to abacavir is a multi-organ clinical syndrome. ( 5.1 ) Patients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. ( 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. ( 4 ) Discontinue abacavir, lamivudine and zidovudine tablets as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue abacavir, lamivudine and zidovudine tablets if hypersensitivity cannot be ruled out, even when other diagnoses are possible. ( 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. ( 5.1 ) Hematologic Toxicity Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of abacavir, lamivudine and zidovudine tablets . ( 5.2 ) Myopathy Symptomatic myopathy associated with prolonged use of zidovudine. ( 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). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. ( 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 human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of abacavir, lamivudine and zidovudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.5 ) 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 )] .
Contraindications
Presence of HLA-B*5701 allele. ( 4 ) Prior hypersensitivity reaction to abacavir, lamivudine, or zidovudine ( 4 ) Moderate or severe hepatic impairment. ( 4 , 8.7 ) Abacavir, lamivudine and zidovudine tablets are contraindicated in patients: who have the HLA-B*5701 allele [see WARNINGS AND PRECAUTIONS ( 5.1 )]. with prior hypersensitivity reaction to abacavir [see WARNINGS AND PRECAUTIONS ( 5.1 )], lamivudine, or zidovudine. with moderate or severe hepatic impairment [see USE IN SPECIFIC POPULATIONS ( 8.7 )] .
Adverse Reactions
The most commonly reported adverse reactions (incidence at least 10%) in clinical trials were nausea, headache, malaise and fatigue, and nausea and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )] . Hematologic toxicity, including neutropenia and anemia [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.2 )] . Symptomatic myopathy [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.3 )] . Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.4 )] . Exacerbations of hepatitis B [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.5 )] . Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see WARNINGS AND PRECAUTIONS ( 5.6 )] . Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see WARNINGS AND PRECAUTIONS ( 5.6 )] . Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS ( 5.7 )] . Lipoatrophy [see WARNINGS AND PRECAUTIONS ( 5.8 )] . Myocardial infarction [see WARNINGS AND PRECAUTIONS ( 5.9 )] . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious and Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir, lamivudine and zidovudine tablets [see BOXED WARNING , WARNINGS AND PRECAUTIONS ( 5.1 )]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Additional Adverse Reactions with Use of Abacavir, Lamivudine and Zidovudine Tablets Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1. Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment Adverse Reaction ZIAGEN ® plus Lamivudine / Zidovudine ( n = 262 ) Indinavir plus Lamivudine / Zidovudine ( n = 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/mm 3 ) 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.
Drug Interactions
Methadone: An increased methadone dose may be required in a small number of patients. ( 7.1 ) Riociguat: The riociguat dose may need to be reduced. ( 7.1 ) Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 7.2 ) Agents antagonistic with zidovudine: Concomitant use should be avoided. ( 7.3 ) Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.3 ) 7.1 Abacavir Methadone In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN ® twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY ( 12.3 )] . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. Riociguat Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [ see Clinical Pharmacology ( 12.3 ) ]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat). 7.2 Lamivudine Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see CLINICAL PHARMACOLOGY ( 12.3 )] . 7.3 Zidovudine Agents Antagonistic with Zidovudine Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro : Stavudine Doxorubicin Nucleoside analogues, e.g., ribavirin Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration with the following drugs may increase the hematologic toxicity of zidovudine: Ganciclovir Interferon alfa Ribavirin Other bone marrow suppressive or cytotoxic agents
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