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Recent Major Changes Section
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WARNINGS See full prescribing information for complete boxed warning. Rosiglitazone maleate: CONGESTIVE HEART FAILURE AND MYOCARDIAL INFARCTION Thiazolidinediones, including rosiglitazone, cause or exacerbate heart failure in some patients (5.2). After initiation of AVANDAMET, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction must be considered. (5.2) AVANDAMET is not recommended in patients with symptomatic heart failure. Initiation of AVANDAMET in patients with established NYHA Class III or IV heart failure is contraindicated. (4, 5.2) A meta-analysis of 52 clinical trials (mean duration 6 months; 16,995 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with a statistically significant increased risk of myocardial infarction. Three other trials (mean duration 46 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, showed a statistically non-significant increased risk of myocardial infarction and a statistically non-significant decreased risk of death. There have been no clinical trials directly comparing cardiovascular risk of rosiglitazone and ACTOS ® (pioglitazone, another thiazolidinedione), but in a separate trial, pioglitazone (when compared to placebo) did not show an increased risk of myocardial infarction or death. (5.3) Metformin hydrochloride: LACTIC ACIDOSIS Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment and acute congestive heart failure. (5.1) Symptoms include malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. (5.1) If acidosis is suspected, discontinue AVANDAMET and hospitalize the patient immediately. (5.1)
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AVANDAMET is a combination antidiabetic product containing a thiazolidinedione and a biguanide. After consultation with a healthcare professional who has considered and advised the patient of the risks and benefits of rosiglitazone, this drug is indicated as an adjunct to diet and exercise to improve glycemic control when treatment with both rosiglitazone and metformin is appropriate in adults with type 2 diabetes mellitus who either are: already taking rosiglitazone, or not already taking rosiglitazone and are unable to achieve glycemic control on other diabetes medications and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS) or pioglitazone-containing products (ACTOPLUS MET ® , ACTOPLUS MET XR ® , DUETACT ® ) for medical reasons. (1) Other Important Limitations of Use: Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. (1) Coadministration with insulin is not recommended. (1, 5.2, 5.3)
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2 Dosage And Administration
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Individualize the starting dose based on the patient’s current regimen. (2.1) Dose increases should be accompanied by careful monitoring for adverse events related to fluid retention. (2.1) Give in divided doses with meals with gradual dose escalation to reduce the gastrointestinal side effects. (2.2) Do not exceed the maximum recommended daily dose of 8 mg rosiglitazone and 2,000 mg metformin. (2.3) Do not initiate if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels. (2.4)
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3 Dosage Forms And Strengths
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Oval, film-coated tablets containing rosiglitazone/metformin hydrochloride: 2 mg/500 mg, 4 mg/500 mg, 2 mg/1,000 mg, and 4 mg/1,000 mg (3)
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Initiation in patients with established NYHA Class III or IV heart failure. (4) Use in significant renal disease or renal dysfunction. (4) Use in acute or chronic metabolic acidosis. (4) Use in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. (4, 5.1)
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5 Warnings And Precautions
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Fluid retention, which may exacerbate or lead to heart failure, may occur. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk of other cardiovascular effects. (5.2) Increased risk of myocardial infarction has been observed in a meta-analysis of 52 clinical trials of rosiglitazone (incidence rate 0.4% versus 0.3%). (5.3) Coadministration with insulin is not recommended. (1, 5.2, 5.3) Assess renal function before starting therapy and at least annually. (5.1) Avoid use in patients with evidence of hepatic disease. (2.4, 5.1) Warn patients against excessive alcohol intake. (5.1) Promptly evaluate patients who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis. (5.1) Dose-related edema (5.4), weight gain (5.5), and anemia (5.9) may occur. Macular edema has been reported. (5.7) Increased incidence of bone fracture. (5.8) Measure hematologic parameters annually. (5.9)
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The most common adverse reactions (≥10%) include nausea/vomiting, diarrhea, headache, and dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Med-Health Pharma, LLC at 1-877-896-6654 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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Inhibitors of CYP2C8 (e.g., gemfibrozil) may increase rosiglitazone levels. (7.1) Inducers of CYP2C8 (e.g., rifampin) may decrease rosiglitazone levels. (7.1) Cationic drugs eliminated by renal tubular secretion; use with caution. (7.2)
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8 Use In Specific Populations
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Do not use during pregnancy. No human or animal data. (8.1) Safety and effectiveness in children under 18 years have not been established. (8.4) Because reduced renal function is associated with increasing age, use with caution in elderly patients. (8.5)
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Created by
fda_medical_bot
on
1/7/2012
