LAMIVUDINE AND ZIDOVUDINE: Package Insert and Label Information

LAMIVUDINE AND ZIDOVUDINE- lamivudine and zidovudine tablet
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Lamivudine and zidovudine tablet, 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).

4 CONTRAINDICATIONS

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.

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 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, including lamivudine and zidovudine (components of 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 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

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).

5.5 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 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.

5.6 Pancreatitis

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 tablets should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see ADVERSE REACTIONS (6.1)].

5.7 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.

5.8 Lipoatrophy

Treatment with zidovudine, a component of lamivudine and zidovudine tablet, 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.

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 (5.5)].

• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see WARNINGS AND PRECAUTIONS (5.5)].

• Pancreatitis [see WARNINGS AND PRECAUTIONS (5.6)].

• Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS (5.7)].

• Lipoatrophy [see WARNINGS AND PRECAUTIONS (5.8)].

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 (Tables 1 and 2).

Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in 4 Controlled Clinical Trials with EPIVIR^® 300 mg per day and RETROVIR^® 600 mg per day

Adverse Reaction	EPIVIR ® plus RETROVIR ® ( n = 251 )
Body as a whole
Headache	35%
Malaise & fatigue	27%
Fever or chills	10%
Digestive
Nausea	33%
Diarrhea	18%
Nausea & vomiting	13%
Anorexia and/or decreased appetite	10%
Abdominal pain	9%
Abdominal cramps	6%
Dyspepsia	5%
Nervous system
Neuropathy	12%
Insomnia & other sleep disorders	11%
Dizziness	10%
Depressive disorders	9%
Respiratory
Nasal signs & symptoms	20%
Cough	18%
Skin
Skin rashes	9%
Musculoskeletal
Musculoskeletal pain	12%
Myalgia	8%
Arthralgia	5%

Pancreatitis was observed in 9 of the 2,613 adult subjects (0.3%) who received EPIVIR^® in controlled clinical trials [see WARNINGS AND PRECAUTIONS (5.6)].

Selected laboratory abnormalities observed during therapy are listed in Table 2.

Table 2. Frequencies of Selected Laboratory Abnormalities among Adults in 4 Controlled Clinical Trials of EPIVIR^® 300 mg per day plus RETROVIR^® 600 mg per day *

ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
n = Number of subjects assessed.
* Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.
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)