Lamivudine and Zidovudine (Page 2 of 7)

5.6 Use With Interferon- and Ribavirin-Based Regimens


In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine tablet should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of lamivudine and zidovudine tablet 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 the complete prescribing information for interferon and ribavirin).
Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Co-administration of ribavirin and zidovudine is not advised.

5.7 Pancreatitis


Lamivudine and Zidovudine 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 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. 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 greater detail in other sections of the labeling:

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 (≥5% Frequency) in 4 Controlled Clinical Trials With lamivudine 300 mg/day and zidovudine 600 mg/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/day plus zidovudine 600 mg/daya
Test (Abnormal Level) Lamivudine plus Zidovudine % (n)
ULN = Upper limit of normal. ANC = Absolute neutrophil count. n = Number of patients assessed. * Frequencies of these laboratory abnormalities were higher in patients with mild laboratory abnormalities at baseline.

Neutropenia (ANC<750/mm3)

7.2% (237)

Anemia (Hgb<8 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 (>2.5x ULN)

0.8% (241)

Amylase (>2.0 x ULN)

4.2% (72)

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