Pharmacy & Therapeutics - September 2008 - (Page 551)

Pharmaceutical Approval Update Repaglinide Plus Metformin HCl Tablets (PrandiMet) Manufacturer: Novo Nordisk, Inc., Princeton, N.J. Indication: The combination of repaglinide (Prandin, Novo Nordisk) and metformin (Glucophage, Bristol-Myers Squibb) is used as an adjunct to diet and exercise to improve glycemic control in patients with type-2 diabetes who are already being treated with a meglitimide and metformin or who have not achieved adequate glycemic control with either component alone. Important limitations of use. PrandiMet is not indicated for patients with type-1 diabetes or with diabetic ketoacidosis, because it is not effective in these settings. Drug Class: Each tablet contains two oral antihyperglycemic drugs used in the management of type-2 diabetes. The concomitant use of both agents was previously approved based on clinical trials of patients with type-2 diabetes whose glucose levels were inadequately controlled with exercise, diet, and metformin HCl alone. The chemical formula of repaglinide is S(+)2-ethoxy-4(2((3methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid. Repaglinide is chemically unrelated to the oral sulfonylurea insulin secretagogues. It is freely soluble in methanol and ethanol. The pKa of repaglinide in acid is 3.9, and the pKa in amine is 6.0. Metformin HCl (N,N-dimethylimidodicarbonimidic diamide HCl) is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. It is a white to offwhite crystalline compound with a molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. Its pKa is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. Uniqueness of Product: Only 57% of people with diabetes in the U.S. are meeting recommended blood glucose levels— a glycosylated hemoglobin value (HbA1c) of 7% or below). Many patients need more than one medication to control type2 diabetes. Combining the insulin secretagogue repaglinide (Prandin) with the sensitizer metformin conveniently addresses three abnormalities of type-2 diabetes: impaired insulin secretion, insulin resistance, and excessive hepatic glucose production. In trials, the addition of repaglinide to metformin significantly improved HbA1c and fasting plasma glucose levels from baseline, compared with repaglinide or metformin alone. Boxed Warning: Lactic acidosis is a rare but serious complication that can occur after metformin accumulation. The risk increases with sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure (CHF). The onset of lactic acidosis often is subtle and is accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and abdominal distress. Laborator y abnormalities include low pH, an increased anion gap, and elevated levels of lactate in the blood. If acidosis is suspected, repaglinide plus metformin should be discontinued and the patient should be hospitalized immediately. Warnings and Precautions with Metformin: Lactic acidosis. Lactic acidosis is a rare but serious metabolic complication that can occur after metformin accumulation during treatment with PrandiMet. When it occurs, it is fatal in approximately 50% of patients. Lactic acidosis may also occur in association with pathophysiological conditions, including diabetes mellitus and significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (above 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 above 5 mcg/mL are generally present. The reported incidence of lactic acidosis in patients receiving metformin is low (0.03 cases per 1,000 patient-years of exposure, with approximately 0.015 fatal cases per 1,000 patient-years of exposure). In more than 20,000 patient-years of exposure to metformin in clinical trials, there were no reports of lactic acidosis. Cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often those with multiple concomitant medical or surgical problems and those who were taking multiple concomitant medications. Patients with CHF requiring pharmacological management, in particular those with unstable or acute CHF who are at risk of hypoperfusion and hypoxemia, are at increased risk for lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age; thus, the risk may be significantly decreased by regular monitoring of renal function in patients taking repaglinide/metformin and by the use of a minimum effective dose of the agent. Treatment of the elderly should be accompanied by careful monitoring of renal function. Repaglinide/metformin should not be initiated in patients 80 years of age or older unless creatinine clearance levels show that renal function is not reduced, because these patients are more susceptible to developing lactic acidosis. PrandiMet should be promptly withheld if the patient has any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, this drug should generally be avoided in patients with evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake when taking repaglinide/metformin, because alcohol potentiates the effects of metformin on lactate metabolism. The combination should be temporarily discontinued before intravascular radiocontrast studies and before any surgical procedures. The onset of lactic acidosis often is subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. Patients and their physicians must be aware of the possible importance of such symptoms, and patients should be instructed to notify the physician immediately if symptoms occur. Repaglinide/metformin should be withdrawn until the situation is clarified. Determining serum levels of electrolytes, ketones, blood glucose, and (if indicated) blood pH, lactate, and even metformin may be useful. After the patient is stabilized on any dose Vol. 33 No. 9 • September 2008 • P&T® 551

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - September 2008

Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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