COMBIVIR

COMBIVIR- lamivudine and zidovudine tablet, film coated
ViiV Healthcare Company

WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B

Zidovudine, a component of COMBIVIR (lamivudine and zidovudine) tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV1) disease [see Warnings and Precautions (5.1)].

Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)].

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of COMBIVIR). Discontinue COMBIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)].

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV1 and have discontinued lamivudine, which is one component of COMBIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue COMBIVIR and are coinfected with HIV1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE

COMBIVIR, a combination of 2 nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Adults and Adolescents

The recommended dosage of COMBIVIR in HIV‑1‑infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily.

2.2 Recommended Dosage for Pediatric Patients

The recommended dosage of scored COMBIVIR tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily.

Before prescribing COMBIVIR tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a COMBIVIR tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) oral solution and RETROVIR (zidovudine) syrup.

2.3 Not Recommended Due to Lack of Dosage Adjustment

Because COMBIVIR is a fixed‑dose tablet and cannot be dose adjusted, COMBIVIR is not recommended for:

pediatric patients weighing less than 30 kg [see Use in Specific Populations (8.4)].
patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)].
patients with hepatic impairment [see Use in Specific Populations (8.7)].
patients experiencing dose‑limiting adverse reactions.

Liquid and solid oral formulations of the individual components of COMBIVIR are available for these populations.

3 DOSAGE FORMS AND STRENGTHS

COMBIVIR tablets contain 150 mg of lamivudine and 300 mg of zidovudine. The tablets are white, scored, film‑coated, modified capsule‑shaped tablets, debossed on both tablet faces, such that when broken in half, the full “GX FC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet).

4 CONTRAINDICATIONS

COMBIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine.

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of COMBIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV‑1 disease. COMBIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 grams per dL [see Adverse Reactions (6.1)].

Frequent blood counts are strongly recommended in patients with advanced HIV‑1 disease who are treated with COMBIVIR. Periodic blood counts are recommended for other HIV‑1‑infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

5.2 Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV‑1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with COMBIVIR.

5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of COMBIVIR). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Treatment with COMBIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.4 Patients with Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment.

Emergence of LamivudineResistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV–1-infected subjects who have received lamivudine‑containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).

5.5 Use with Interferon- and Ribavirin–Based Regimens

Patients receiving interferon alfa with or without ribavirin and COMBIVIR should be closely monitored for treatment‑associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for RETROVIR (zidovudine). Discontinuation of COMBIVIR 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 full 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 COMBIVIR is not advised.

5.6 Pancreatitis

COMBIVIR should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with COMBIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].

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