LAMIVUDINE AND ZIDOVUDINE: Package Insert and Label Information
LAMIVUDINE AND ZIDOVUDINE- lamivudine and zidovudine tablet
WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B
Zidovudine, a component of lamivudine and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see WARNINGS AND PRECAUTIONS (5.1)].
Prolonged use of zidovudine has been associated with symptomatic myopathy [see WARNINGS AND PRECAUTIONS (5.2)].
Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue lamivudine and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS (5.3)].
Exacerbations of Hepatitis 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 tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and zidovudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS (5.4)].
1 INDICATIONS AND USAGE
Lamivudine and zidovudine tablets, a combination of 2 nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage for Adults and Adolescents
The recommended dosage of lamivudine and zidovudine tablets in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily.
2.2 Recommended Dosage for Pediatric Patients
The recommended dosage of scored lamivudine and zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally 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® (lamivudine) oral solution and RETROVIR® (zidovudine) syrup.
2.3 Not Recommended Due to Lack of Dosage Adjustment
Because lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablet is not recommended for:
• Pediatric patients weighing less than 30 kg [see USE IN SPECIFIC POPULATIONS (8.4)].
• Patients with creatinine clearance less than 50 mL per minute [see USE IN SPECIFIC POPULATIONS (8.6)].
• Patients with hepatic impairment [see USE IN SPECIFIC POPULATIONS (8.7)].
• Patients experiencing dose-limiting adverse reactions.
Liquid and solid oral formulations of the individual components of lamivudine and zidovudine tablets are available for these populations.
3 DOSAGE FORMS AND STRENGTHS
Lamivudine and zidovudine tablets USP contain 150 mg of lamivudine and 300 mg of zidovudine. The tablets are white to off white, scored, modified-capsule-shaped, film-coated tablets, debossed on both tablet faces, such that, when broken in half, “LU” and “Y01” code is present on both halves of the tablet (“LU” on one face and “Y01” on the opposite face of the tablet).
Lamivudine and zidovudine tablet is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine.
5 WARNINGS AND PRECAUTIONS
5.1 Hematologic Toxicity/Bone Marrow Suppression
Zidovudine, a component of lamivudine and zidovudine tablet, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine and zidovudine tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 grams per dL [see ADVERSE REACTIONS (6.1)].
Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine and zidovudine tablets. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.
Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with lamivudine and zidovudine tablets.
5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for EPIVIR® (lamivudine) and RETROVIR® (zidovudine). Treatment with lamivudine and zidovudine tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
5.4 Patients with Hepatitis B Virus Co-infection
Post-treatment 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).
5.5 Related Products that are Not Recommended
Lamivudine and zidovudine tablet is a fixed-dose combination of 2 nucleoside analogue reverse transcriptase inhibitors (lamivudine and zidovudine). Concomitant administration of lamivudine and zidovudine tablets with other products containing lamivudine or zidovudine is not recommended. In addition, do not administer lamivudine and zidovudine tablets in combination with products containing emtricitabine.
5.6 Use with Interferon- and Ribavirin-based Regimens
Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR® (lamivudine) and RETROVIR® (zidovudine). Discontinuation of lamivudine and zidovudine tablets should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).
Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and lamivudine and zidovudine tablets is not advised.
Lamivudine and zidovudine tablets 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 tablet should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see ADVERSE REACTIONS (6.1)].
5.8 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine and zidovudine tablets. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-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.
5.9 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.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
• Hematologic toxicity, including neutropenia and anemia [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)].
• Symptomatic myopathy [see Boxed WARNING, WARNINGS AND PRECAUTIONS (5.2)].
• Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.3)].
• Exacerbations of hepatitis 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)].
• Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS (5.8)].
• Fat redistribution [see WARNINGS AND PRECAUTIONS (5.9)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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.
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).
|Adverse Reaction||EPIVIR ® plus RETROVIR ® ( n = 251 )|
|Body as a whole|
|Malaise & fatigue||27%|
|Fever or chills||10%|
|Nausea & vomiting||13%|
|Anorexia and/or decreased appetite||10%|
|Insomnia & other sleep disorders||11%|
|Nasal signs & symptoms||20%|
Pancreatitis was observed in 9 of the 2,613 adult subjects (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.
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
n = Number of patients assessed.
|Test ( Abnormal Level )||EPIVIR ® plus RETROVIR ®% ( n )|
|Neutropenia (ANC<750/mm3)||7.2% (237)|
|Anemia (Hgb<8.0 g/dL)||2.9% (241)|
|Thrombocytopenia (platelets<50,000/mm3)||0.4% (240)|
|ALT (>5.0 x ULN)||3.7% (241)|
|AST (>5.0 x ULN)||1.7% (241)|
|Bilirubin (>2.5 x ULN)||0.8% (241)|
|Amylase (>2.0 x ULN)||4.2% (72)|
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