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-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.
Treatment with zidovudine, a component of lamivudine and zidovudine, 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.
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)].
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 FormulationsIn 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).
|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 (5.6)]. Selected laboratory abnormalities observed during therapy are listed in Table 2.
|Test(Abnormal Level)||EPIVIR plus RETROVIR% (n)|
|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.|
|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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