COMBIVIR tablets are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV‑1. COMBIVIR tablets are for oral administration. Each film‑coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (‑)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (‑)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off‑white crystalline solid and is soluble in water. Zidovudine The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C 10 H 13 N 5 O 4 and a molecular weight of 267.24 g per mol. It has the following structural formula: Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C. lamivudine chemical structure zidovudine chemical structure

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. COMBIVIR, a combination of 2 nucleoside analogue reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection.

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). Tablets: Scored 150 mg lamivudine and 300 mg zidovudine

• Adults and Adolescents weighing greater than or equal to 30 kg: 1 tablet orally twice daily. • Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily. • Because COMBIVIR is a fixed‑dose tablet and cannot be dose adjusted, COMBIVIR is not recommended in patients requiring dosage adjustment or with hepatic impairment or experiencing dose‑limiting adverse reactions. ( 2.3 , 4 ) 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

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

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 . • patients with creatinine clearance less than 50 mL per minute . • patients with hepatic impairment . • patients experiencing dose‑limiting adverse reactions. Liquid and solid oral formulations of the individual components of COMBIVIR are available for these populations.

• Hepatic decompensation, some fatal, has occurred in HIV‑1/HCV co‑infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue COMBIVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. • 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. • Pancreatitis: Use with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. • Immune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. 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 mm 3 or hemoglobin less than 9.5 grams per dL . 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

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

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

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 Lamivudine ‑ Resistant 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)

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) . 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

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

Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including COMBIVIR. 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

Lipoatrophy Treatment with zidovudine, a component of COMBIVIR, 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.

• Agents antagonistic with zidovudine: Concomitant use should be avoided. • Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. • Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration

Zidovudine Agents Antagonistic with Zidovudine Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro: • Stavudine • Doxorubicine • Nucleoside analogues, e.g., ribavirin Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration with the following drugs may increase the hematologic toxicity of zidovudine: • Ganciclovir • Interferon alfa • Ribavirin • Other bone marrow suppressive or cytotoxic agents 7.2 Lamivudine Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines .