İHALE DÜNYASI
İHALE DÜNYASI
SECTION Lamivudine and Zidovudine: Lamivudine and Zidovudine tablets USP are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV-1. Lamivudine and Zidovudine tablets USP are for oral administration. Each film-coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C 8H 11N 3O 3S and a molecular weight of 229.3. It has the following structural formula: Meets USP Dissolution Test 2 image description
INDICATIONS & USAGE SECTION Lamivudine and Zidovudine tablets USP, a combination of two nucleoside analogues, are indicated in combination with other antiretrovirals for the treatment of HIV-1 infection.
DOSAGE & ADMINISTRATION SECTION 2.1 Adults and Adolescents Weighing ?30 kg The recommended oral dose of lamivudine and zidovudine tablets in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) twice daily. 2.2 Pediatric Patients The recommended oral dosage of scored lamivudine and zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered twice daily. Before prescribing lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed: EPIVIR (R) (lamivudine) oral solution and RETROVIR (R) (zidovudine) syrup. 2.3 Patients Requiring Dosage Adjustment Because lamivudine and zidovudine is a fixed-dose combination tablet, it should not be prescribed for pediatric patients weighing less than 30 kg or patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 50 mL/min), patients with hepatic impairment, or patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of lamivudine and zidovudine are available for these populations.
SECTION Lamivudine and Zidovudine tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the product.
SECTION The following adverse reactions are discussed in greater detail in other sections of the labeling: Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.1)]. Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)]. Lactic acidosis and hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3)]. Acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.4)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.6)]. Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)]. Pancreatitis [see Warnings and Precautions (5.7)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Lamivudine Plus Zidovudine Administered As Separate Formulations: In 4 randomized, controlled trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables 1 and 2). Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received EPIVIR in controlled clinical trials [see Warnings and Precautions (5.7)]. Selected laboratory abnormalities observed during therapy are listed in Table 2. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of EPIVIR, RETROVIR, and/or lamivudine and zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EPIVIR, RETROVIR, and/or lamivudine and zidovudine. Body as a Whole:Redistribution/accumulation of body fat [see Warnings and Precautions (5.9)]. Cardiovascular:Cardiomyopathy. Endocrine and Metabolic:Gynecomastia, hyperglycemia. Gastrointestinal:Oral mucosal pigmentation, stomatitis. General:Vasculitis, weakness. Hemic and Lymphatic:Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic and Pancreatic:Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.7)]. Hypersensitivity:Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal:Muscle weakness, CPK elevation, rhabdomyolysis. Nervous:Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome. image description image description image description
SECTION 5.1 Hemotologic Toxicity/Bone Marrow Suppression Zidovudine, a component of lamivudine and zidovudine, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm 3 or hemoglobin less than 9.5 g/dL [see Adverse Reactions (6.1)]. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine and zidovudine. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption maybe needed. 5.2 Myopathy Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with lamivudine and zidovudine. 5.3 Lactic Acidosis/Hepatomegaly With Steatosis Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering lamivudine and zidovudine to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with lamivudine and zidovudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.4 Patients With HIV-1 and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of hepatitis B viral DNA (HBV DNA). Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. Important Differences Among Lamivudine-Containinq Products: Lamivudine and Zidovudine tablets contain a higher dose of the same active ingredient (lamivudine) than EPIVIR-HBV (R) (lamivudine) tablets and oral solution. EPIVIR-HBV was developed for treating chronic hepatitis B. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. Emergence of Lamivudine-Resistant HBV: In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. 5.5 Use With Other, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing Products Lamivudine and Zidovudine is a fixed-dose combination of lamivudine and zidovudine. Lamivudine and Zidovudine should not be administered concomitantly with other lamivudine- or zidovudine-containing products including EPIVIR (R) (lamivudine) tablets and oral solution, EPIVIR-HBV tablets and oral solution, RETROVIR (R) (zidovudine) tablets, capsules, syrup, and IV Infusion, EPZICOM (R) (abacavir sulfate and lamivudine) tablets, or TRIZIVIR (R) (abacavir sulfate, lamivudine, and zidovudine) tablets; or emtricitabine-containing products, including ATRIPLA (R) (efavirenz, emtricitabine, and tenofovir), EMTRIVA (R) (emtricitabine), TRUVADA (R) (emtricitabine and tenofovir) or COMPLERA TM (rilpivirine/emtricitabine/tenofovir). 5.6 Use With Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], 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. Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of lamivudine and zidovudine 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 the complete 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 zidovudine is not advised. 5.7 Pancreatitis Lamivudine and Zidovudine should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine and zidovudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)]. 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.9 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. --- BOXED WARNING: BOXED WARNING SECTION WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B Hematologic Toxicity: Zidovudine, one of the 2 active ingredients in lamivudine and zidovudine tablets , has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease [see Warnings and Precautions (5.1)]. Myopathy: Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)]. Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)]. 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, which is one component of lamivudine and zidovudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)].
SECTION No drug interaction studies have been conducted using lamivudine and zidovudine tablets [see Clinical Pharmacology (12.3)]. 7.1 Antiretroviral Agents Lamivudine: Zalcitabine: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine and zidovudine in combination with zalcitabine is not recommended. Zidovudine: Stavudine: Concomitant use of lamivudine and zidovudine with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro. Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided. 7.2 Doxorubicin Zidovudine: Concomitant use of lamivudine and zidovudine with doxorubicin should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro. 7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Zidovudine: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. 7.4 Interferon- and Ribavirin-Based Regimens Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3)]. 7.5 Trimethoprim/Sulfamethoxazole (TMP/SMX) Lamivudine: No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.