LAMIVUDINE and ZIDOVUDINE (Page 2 of 7)

5.7 Pancreatitis

Lamivudine and Zidovudine Tablet 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 tablet. 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 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 lamivudine 300 mg per day plus zidovudine 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (see Tables 1 and 2). Table 1. Selected Clinical Adverse Reactions (Greater than or equal to 5% Frequency) in 4 Controlled Clinical Trials With lamivudine 300 mg per day and zidovudine 600 mg per day

Adverse Reaction Lamivudine plus Zidovudine (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 patients (0.3%) who received lamivudine in controlled clinical trials
[see Warnings and Precautions ( 5.7)].

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 Lamivudine 300 mg per day plus Zidovudine 600 mg per day a

Test (Abnormal Level) Lamivudine plus Zidovudine % (n)
Neutropenia (ANC<750/mm 3) 7.2% (237)
Anemia (Hgb<8 g/dL) 2.9% (241)
Thrombocytopenia (platelets-<50,000/mm 3) 0.4% (240)
ALT (>5 x ULN) 3.7% (241)
AST (>5 x ULN) 1.7% (241)
Bilirubin (>2.5x ULN) 0.8% (241)
Amylase (>2 x ULN) 4.2% (72)

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.
n = Number of patients assessed. a Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.

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