Lamivudine and Zidovudine (Page 2 of 7)

5.5 Use With Other, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing Products

Lamivudine and zidovudine tablets are a fixed-dose combination of lamivudine and zidovudine. Lamivudine and zidovudine tablets should not be administered concomitantly with other lamivudine- or zidovudine-containing products including EPIVIR (lamivudine) Tablets and Oral Solution, EPIVIR-HBV Tablets and Oral Solution, RETROVIR® (zidovudine) Tablets, Capsules, Syrup, and IV Infusion, EPZICOM® (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR® (abacavir sulfate, lamivudine, and zidovudine) Tablets; or emtricitabine-containing products, including ATRIPLA® (efavirenz, emtricitabine, and tenofovir), EMTRIVA® (emtricitabine), TRUVADA® (emtricitabine and tenofovir) or COMPLERA™ (rilpivirine/emtricitabine/tenofovir).

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 tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. 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 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. Coadministration of ribavirin and zidovudine is not advised.

5.7 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) ].

5.8 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.

5.9 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:

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 hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3)].

Acute 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) ].

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 EPIVIR (lamivudine) 300 mg per day plus RETROVIR (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 EPIVIR (Lamivudine) 300 mg/day and RETROVIR (Zidovudine) 600 mg/day
Adverse Reaction EPIVIR (Lamivudine) plus RETROVIR (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 EPIVIR (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 EPIVIR (Lamivudine) 300 mg/day Plus RETROVIR (Zidovudine) 600 mg/day *
*
Frequencies of these laboratory abnormalities were higher in patients with mild laboratory abnormalities at baseline.
Test (Abnormal Level) EPIVIR (Lamivudine) plus RETROVIR (Zidovudine) % (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)

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

n = Number of patients assessed.

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