Lamivudine and Zidovudine (Page 2 of 6)

5.7 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.

5.8 Lipoatrophy

Treatment with zidovudine, a component of 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.

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 Diarrhea 33% 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 a

Test (Abnormal Level) EPIVIR plus RETROVIR % (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 subjects assessed. a Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.

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