AVANDAMET- rosiglitazone maleate and metformin hydrochloride tablet, film coated
GlaxoSmithKline LLC
WARNINGS
Rosiglitazone maleate: CONGESTIVE HEART FAILURE
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Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions ]. 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 of AVANDAMET must be considered.
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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. [See Contraindications , Warnings and Precautions .]
Metformin hydrochloride: LACTIC ACIDOSIS
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Lactic acidosis is rare, but serious complication that 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. [See Warnings and Precautions .]
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Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. [See Warnings and Precautions .]
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If acidosis is suspected, discontinue AVANDAMET and hospitalize the patient immediately [see Warnings and Precautions
Mechanism of Action
AVANDAMET: AVANDAMET combines antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type diabetes: Rosiglitazone, member of the thiazolidinedione class, and metformin, member of the biguanide class. Thiazolidinediones are insulin sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.
Rosiglitazone: Rosiglitazone improves glycemic control by improving insulin sensitivity. Rosiglitazone is highly selective and potent agonist for the peroxisome proliferator?activated receptor-gamma (PPAR?). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR? nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR?-responsive genes also participate in the regulation of fatty acid metabolism.
INDICATIONS AND USAGE
AVANDAMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.
Important Limitations of Use:
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Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, AVANDAMET should not be used in patients with type diabetes.
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Coadministration of AVANDAMET with insulin is not recommended [see Warnings and Precautions (5.2, 5.3)].
2 DOSAGE AND ADMINISTRATION
The dosage of antidiabetic therapy with AVANDAMET should be individualized on the basis of effectiveness and tolerability. The risk-benefit of initiating monotherapy versus dual therapy with AVANDAMET should be considered.
2.1 Starting Dose
AVANDAMET is generally given in divided doses with meals.
All patients should start the rosiglitazone component of AVANDAMET at the lowest recommended dose. Further increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention
To switch to AVANDAMET for patients currently treated with metformin, the usual starting dose of AVANDAMET is mg rosiglitazone (total daily dose) plus the dose of metformin already being taken (see Table 1).
To switch to AVANDAMET for patients currently treated with rosiglitazone, the usual starting dose of AVANDAMET is 1,000 mg metformin (total daily dose) plus the dose of rosiglitazone already being taken (see Table 1).
When switching from combination therapy of rosiglitazone plus metformin as separate tablets, the usual starting dose of AVANDAMET is the dose of rosiglitazone and metformin already being taken.
Maximum Dose
The maximum recommended total daily dose of AVANDAMET is mg rosiglitazone (taken as mg twice daily) and 2,000 mg metformin (taken as 1,000 mg twice daily)
DOSAGE FORMS AND STRENGTHS
Each film-coated oval tablet contains rosiglitazone as the maleate and metformin hydrochloride as follows:
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2 mg/500 mg pale pink, debossed with gsk on one side and 2/500 on the other
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4 mg/500 mg orange, debossed with gsk on one side and 4/500 on the other
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2 mg/1,000 mg yellow, debossed with gsk on one side and 2/1000 on the other
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4 mg/1,000 mg pink, debossed with gsk on one side and 4/1000 on the other
CONTRAINDICATIONS
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Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see Boxed Warning].
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Use in patients with renal disease or renal dysfunction [e.g., as suggested by serum creatinine levels ?1.5 mg/dL (males), ?1.4 mg/dL (females), or abnormal creatinine clearance], which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions ].
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Use in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
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Use in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. AVANDAMET should be temporarily discontinued in these patients. [See Warnings and Precautions .]
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Use in patients with history of hypersensitivity reaction to rosiglitazone or any of the product?s ingredients.
WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
Incidence and Management: Lactic acidosis is rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with AVANDAMET; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
Cardiac Failure
Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered
Major Adverse Cardiovascular Events
?Data from long-term, prospective, randomized, controlled clinical trials of rosiglitazone versus metformin or sulfonylureas, particularly cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components. meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo.
Edema
AVANDAMET should be used with caution in patients with edema
Hepatic Effects
Metformin: Since impaired hepatic function has been associated with some cases of lactic acidosis, AVANDAMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Rosiglitazone: Liver enzymes should be measured prior to the initiation of therapy with AVANDAMET in all patients and periodically thereafter per the clinical judgment of the healthcare professional
Macular Edema
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione
Fractures
Long-term trials (ADOPT and RECORD) show an increased incidence of bone fracture in patients, particularly female patients, taking rosiglitazone
Hematologic Effects
Decreases in mean hemoglobin and hematocrit occurred in dose-related fashion in adult patients treated with rosiglitazone
Vitamin B12 Levels
In controlled clinical trials of metformin of 29 weeks? duration, decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients
Ovulation
Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As result, these patients may be at an increased risk for pregnancy while taking AVANDAMET
Pregnancy
Pregnancy Category C
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
There are multiple medications available to treat type diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing particular diabetes medication for given patient.
Patients should be informed of the following:
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The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue AVANDAMET immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once patient is stabilized on any dose level of AVANDAMET, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
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Avoid excessive alcohol intake, either acute or chronic, while receiving AVANDAMET.
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AVANDAMET is not recommended for patients with symptomatic heart failure.
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A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo. Data from long-term clinical trials of rosiglitazone versus other antidiabetes agents (metformin or sulfonylureas), including cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components.
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AVANDAMET is not recommended for patients who are taking insulin.
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Management of type diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type diabetes but also in maintaining the efficacy of drug therapy.
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It is important to adhere to dietary instructions and to regularly have blood glucose, glycosylated hemoglobin (HbA1c), renal function, and hematologic parameters tested. It can take weeks to see reduction in blood glucose and to months to see the full effect of AVANDAMET.
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Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.
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Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDAMET should immediately report these symptoms to their physician.
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Therapy with AVANDAMET, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As result, these patients may be at an increased risk for pregnancy while taking AVANDAMET. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials so the frequency of this occurrence is not known.
