Manufacturer: GlaxoSmithKline, Research Triangle Park, NC

Indication: As an adjunct to diet and exercise, this combination drug is indicated for the treatment of type 2 diabetes.

Drug Class: Medication rosiglitazone maleate, which acts directly to increase insulin sensitivity and to decrease insulin resistance, a major underlying cause of type 2 diabetes, is used in combination with an effective oral antidiabetic therapeutic agent, met-formin HCl, to control blood sugar (glucose).

Uniqueness of Drug: The drug combines two leading diabetes medications in one convenient tablet. This combination of drugs is characterized by two different mechanisms of action and offers the opportunity to help diabetic patients manage type 2 diabetes for a longer period of time and more effectively compared with previous agents.

Precautions: Lactic acidosis is a rare but serious metabolic complication that can occur as a result of metformin canadian accumulation during treatment with the combination of rosiglitazone maleate and metformin HCl. Lactic acidosis is characterized by elevated blood lactate levels (above 5 mmol/ml), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate-to-pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels greater than 5 mcg/ml are generally found. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency.

When lactic acidosis develops, death occurs in 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiological conditions, including diabetes mellitus, and whenever significant tissue hypoperfusion and hypoxemia are present.

Patients with congestive heart failure who require pharmacological management, particularly patients with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and with the patient’s age.

Unless the creatinine clearance demonstrates that renal function is not impaired, treatment with the drug combination should not be initiated in patients older than age 80, because these patients are more susceptible to the development of lactic acidosis. The drug combination should be promptly withheld from patients with any condition associated with hypoxemia, dehydration, or sepsis.

The drug combination should be avoided in patients with evidence of hepatic disease. Patients should be cautioned against excessive intake of alcohol, because alcohol potentiates the effects of metformin HCl on lactate metabolism. The drug combination should be temporarily discontinued before any intravascular radiocontrast study and any surgical procedure.

Once a patient is stabilized on any dose of the drug combination, gastrointestinal symptoms that are common during initiation of therapy are unlikely to be drug-related. Gastrointestinal symp­toms that occur later are sometimes a result of lactic acidosis or other serious disease.

Dosage and Administration: The dose of a rosiglitazone maleate/metformin HCl tablet should be based on the patient’s current doses of both of these agents. The dosage with the combination antidiabetic tablet should be individualized according to the effectiveness and tolerability but should not exceed the maximum recommended daily dose of 8 mg of rosiglitazone maleate/2,000 mg of metformin HCl. The combination should be given in divided doses with meals, with the dose gradually escalated. This strategy reduces gastrointestinal side effects (largely caused) and permits the physician to determine the minimum effective dose for each patient. Sufficient time should be given to assess adequacy of the therapeutic response. The fasting plasma glucose level should be used to determine the therapeutic response to the drug combination.

If glycemic control is not adequate in one to two weeks after an increase in metformin dosage, or if control is not adequate in eight to 12 weeks after an increase in rosiglitazone dosage, dosage titration is recommended.

If glycemic control is inadequate with metformin mono-therapy, the usual starting dose of rosiglitazone maleate/met-formin HCl is 4 mg of rosiglitazone (total daily dose) plus the dose of metformin HCl already being taken.

If blood glucose levels are inadequately controlled with rosigli-tazone monotherapy, the usual starting dose of rosiglitazone maleate/metformin HCl is 1,000 mg of metformin (total daily dose) plus the dose of rosiglitazone already being taken.

When a switch is made to the combination therapy of rosigli-tazone maleate plus metformin HCl, the usual starting dose of the combination is the dose of rosiglitazone and metformin already being taken as separate tablets.

If additional glycemic control is needed, the daily dose of rosiglitazone maleate/metformin HCl may be increased by increments of 4 mg of rosiglitazone and/or 500 mg of metformin, up to the maximum recommended total daily dose of 8 mg of rosiglitazone maleate/2,000 mg of metformin HCl.

P&T Committee Considerations: Rosiglitazone maleate targets insulin resistance, an underlying cause of type 2 diabetes, whereas metformin HCl works to reduce the amount of blood sugar (glucose) produced by the liver. The two medications, when used in combination, target core metabolic defects to help achieve better blood glucose control than metformin alone. These properties make this medication an important option for patients with type 2 diabetes.

When blood glucose concentrations are elevated over an extended period, serious complications can result, including cardiovascular disease, kidney damage, and blindness. To reach normal blood glucose concentrations in patients with type 2 diabetes, it may be necessary to use a combination of therapies that treat the disease more effectively. Therefore, it is recommended that maleate/metformin HCl tablets be placed on the formulary to treat highly resistant type 2 diabetes.

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