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. (1)

• •Adults and Adolescents weighing greater than or equal to 30 kg: 1 tablet orally twice daily. (2.1)
• •Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily. (2.2)
• •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)

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.

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.

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.

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

COMBIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine. (4)

• •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. (5.5)
• •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. (5.5)
• •Pancreatitis: Use with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.6)
• •Immune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. (5.7, 5.8)

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.

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, 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.

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).

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.

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)].

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.

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.

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)].

• •Most commonly reported adverse reactions (incidence greater than or equal to 15%) in clinical trials of combination lamivudine and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Formulations

In 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).

Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in 4 Controlled Clinical Trials with EPIVIR 300 mg per Day and RETROVIR 600 mg per Day

Adverse Reaction	EPIVIR plus RETROVIR (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 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.

Table 2. Frequencies of Selected Laboratory Abnormalities among Adults in 4 Controlled Clinical Trials of EPIVIR 300 mg per Day plus RETROVIR 600 mg per Day^a

Test (Abnormal Level)	EPIVIR plus RETROVIR % (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 subjects assessed.
a Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.

The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole

Redistribution/accumulation of body fat [see Warnings and Precautions (5.8)].

Cardiovascular

Cardiomyopathy.

Endocrine and Metabolic

Gynecomastia, hyperglycemia.

Gastrointestinal

Oral mucosal pigmentation, stomatitis.

General

Vasculitis, weakness.

Hemic and Lymphatic

Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and Pancreatic

Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.6)].

Hypersensitivity

Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal

Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous

Paresthesia, peripheral neuropathy, seizures.

Respiratory

Abnormal breath sounds/wheezing.

Skin

Alopecia, erythema multiforme, Stevens‑Johnson syndrome.