Pharmaceutical Approval Update
Sitagliptin/Metformin drug HCl Tablets (Janumet)
Manufacturer: Merck, Inc., Whitehouse Station, NJ Indication: Sitagliptin/metformin HCl tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type-2 diabetes mellitus when glucose levels are not adequately controlled with generic metformin (Glucophage generic, Bristol-Myers Squibb) or sitagliptin (Januvia, Merck) alone or in patients who are already using a sitagliptin/metformin combination.
Limitation of Use: These tablets should not be used in patients with type-1 diabetes or diabetic ketoacidosis.
Drug Class: The tablets contain two oral antihyperglycemic drugs:
1. Sitagliptin is an orally active inhibitor of the dipeptidyl pep tidase-4 (DPP-4) enzyme. It is present in the form of sitagliptin phosphate monohydrate, which is described chemically as 7-[(3$-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.
2. Metformin HCl (NN-dimethylimidodicarbonimidic di-amide HCl) is a member of the biguanide class. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.
Uniqueness of Drug: The two antihyperglycemic agents have complementary mechanisms of action.
Sitagliptin is believed to slow the inactivation of incretin hormones; it increases the concentration of the active intact hormones, thereby increasing and prolonging their action. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4.
The incretins are part of an endogenous system involved in the physiological regulation of glucose homeostasis. When blood glucose levels are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic adeno-sine monophosphate (cAMP). GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
Metformin improves glucose tolerance by lowering both basal and postprandial plasma glucose levels. Its pharmacological mechanisms of action differ from those of other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike the sulfonylureas, metformin does not produce hypo-glycemia in patients with type-2 diabetes or in normal subjects (except in special circumstances) and does not cause hyper-insulinemia. Insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Black-Box Warning: Lactic acidosis is a rare but serious complication that can result from the accumulation of metformin. The risk increases with sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and abdominal distress. Laboratory abnormalities include low pH, an increased anion gap, and elevated blood lactate levels. If acidosis is suspected, sitagliptin/metformin HCl tablets should be discontinued and the patient should be hospitalized immediately.
Warnings and Precautions:
Lactic acidosis. Lactic acidosis can occur from metformin tablet accumulation during treatment with sitagliptin/metformin HCl tablets, and it is fatal in approximately 50% of cases. It may also occur in association with some pathophysiological conditions (diabetes mellitus) and whenever there is 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 lac-tate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels above 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low (0.03 cases per 1,000 patient-years, or 0.015 fatal cases per 1,000 patient-years).
In more than 20,000 patient-years of exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical-surgical problems and multiple concomitant medications.
Patients with congestive heart failure requiring pharmacological management, especially those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at an increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk, therefore, may be decreased by regular monitoring of renal function in patients taking metformin, especially older patients, and by using the minimum effective dose of metformin.
Metformin therapy should not be initiated in patients who are 80 years of age and older unless the creatinine clearance (CrCl) demonstrates that renal function is not reduced, because these patients are more susceptible to developing lactic acidosis.
Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
Because impaired hepatic function may limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake; alcohol potentiates the effects of metformin on lactate metabolism.
Metformin should be temporarily discontinued before any intravascular radioiodine contrast studies and before surgical procedures.
The onset of lactic acidosis may be subtle, accompanied only by nonspecific symptoms (malaise, myalgias, respiratory distress, somnolence, abdominal distress). There may be associated hypothermia, hypotension, and resistant brady-arrhythmias with more marked acidosis.
Patients and their physicians must be aware of the possible importance of such symptoms. Patients should be instructed to notify their physicians immediately if symptoms occur. Met-formin should be withdrawn until the problem has been identified.
Determination of serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and even blood metformin levels may be useful. After the patient is stabilized on any dose level of metformin, gastrointestinal (GI) symptoms, which are common during initiation of therapy, are unlikely to be drug-related. GI symptoms that occur later can result from lactic acidosis or another serious disease. canadian antibiotics
Levels of fasting venous plasma lactate above the upper limit of normal (ULN) but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis; they may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in handling samples.
Lactic acidosis should be suspected in diabetic patients with metabolic acidosis who lack evidence of ketoacidosis (i.e., ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital. If the patient has been taking metformin, the drug should be discontinued immediately and general supportive measures should be instituted promptly. Because metformin is dialyzable (with a clearance of up to 170 mL/minute under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and to remove the accumulated metformin. Such management often results in a prompt reversal of symptoms and in recovery.