Combivir
lamivudine and zidovudine · Tablet, Film Coated · Oral
Uses
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. 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 )
Dosage and administration
• 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 ) 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.
Dosage forms and strengths
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). Tablets: Scored 150 mg lamivudine and 300 mg zidovudine ( 3 )
Contraindications
4 CONTRAINDICATIONS 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 )
Warnings and precautions
• 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 ) 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 [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 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). 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 )]. 5.7 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. 5.8 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.
Side effects
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 . 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 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/mm 3 ) 7.2% (237) Anemia (Hgb <8.0 g/dL) 2.9% (241) Thrombocytopenia (platelets <50,000/mm 3 ) 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. 6.2 Postmarketing Experience 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.
Drug interactions
• Agents antagonistic with zidovudine: Concomitant use should be avoided. ( 7.1 )
• Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.1 )
• Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 7.2 ) 7.1 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 [see Clinical Pharmacology ( 12.3 )] .
Use in specific populations
• Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COMBIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data) . In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data). Data Human Data: Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8). Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens. A randomized, double-blind, placebo-controlled trial was conducted in HIV–1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COMBIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data) . In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data). Data Human Data: Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8). Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens. A randomized, double-blind, placebo-controlled trial was conducted in HIV–1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo.
Pediatric use
8.4 Pediatric Use COMBIVIR is not recommended for use in pediatric patients who weigh less than 30 kg because it is a fixed‑dose combination tablet that cannot be adjusted for this patient population [see Dosage and Administration ( 2.2 )].
Geriatric use
8.5 Geriatric Use Clinical trials of COMBIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of COMBIVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] .
Overdosage
There is no known specific treatment for overdose with COMBIVIR. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Lamivudine Because a negligible amount of lamivudine was removed via (4‑hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. Zidovudine Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3′-azido-3′-deoxy-5′- O -β- D -glucopyranuronosylthymidine (GZDV), is enhanced.
Description
11 DESCRIPTION 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
Mechanism of action
12.1 Mechanism of Action COMBIVIR is an antiretroviral agent [see Microbiology ( 12.4 )] .
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING COMBIVIR tablets, containing 150 mg lamivudine and 300 mg zidovudine, are white, scored, film‑coated, modified‑capsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full “GXFC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet). They are available as follows: 60 Tablets/Bottle (NDC 49702-202-18). Store between 2° and 30°C (36° and 86°F).
Patient information
Neutropenia and Anemia Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV‑1 disease [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Myopathy Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV‑1 disease, have been associated with prolonged use of zidovudine [see Warnings and Precautions ( 5.2 )] . Lactic Acidosis/Hepatomegaly with Steatosis Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking COMBIVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions ( 5.3 )] . Patients with Hepatitis B or C Co-infection Advise patients co‑infected with HIV‑1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions ( 5.4 )] . Inform patients with HIV‑1/HCV co-infection that 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 [see Warnings and Precautions ( 5.5 )]. Drug Interactions Advise patients that other medications may interact with COMBIVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of COMBIVIR [see Drug Interactions ( 7.1 )] . Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when COMBIVIR is started [see Warnings and Precautions ( 5.7 )]. Lipoatrophy Advise patients that loss of subcutaneous fat may occur in patients receiving COMBIVIR and that they will be regularly assessed during therapy [see Warnings and Precautions ( 5.8 )] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COMBIVIR during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations ( 8.2 )] . Missed Dose Instruct patients that if they miss a dose of COMBIVIR, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration ( 2 )] . Trademarks are owned by or licensed to the ViiV Healthcare group of companies. Manufactured for: ViiV Healthcare Durham, NC 27701 ©2023 ViiV Healthcare group of companies or its licensor. CMB:11PI
Label text from the FDA structured product label by ViiV Healthcare Company (revised Aug 22, 2023). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Lamivudine in 1 product
- Zidovudine in 1 product
Combivir NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 49702-202 | Lamivudine 150 mg/1; Zidovudine 300 mg/1 Tablet, Film Coated | ViiV Healthcare Company | NDA |
Frequently asked questions
What is Combivir used for?
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. 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 )
What are the side effects of Combivir?
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 )] . •… See the full label for the complete list.
Who makes Combivir?
Combivir is listed by 1 labeler in the FDA NDC directory, including ViiV Healthcare Company.