Janumet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: In post-marketing experience there have been reports of acute pancreatitis including fatal and nonfatal hemorrhagic or necrotizing pancreatitis (see Side Effects) in patients taking sitagliptin. Because these reports are made voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patients should be informed of the characteristic symptom of acute pancreatitis: Persistent, severe abdominal pain.
Resolution of pancreatitis has been observed after discontinuation of sitagliptin. If pancreatitis is suspected, Janumet and other potentially suspected medicinal products should be discontinued.
Monitoring of Renal Function: Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Janumet. In patients with advanced age, Janumet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. In elderly patients, particularly those ≥80 years, renal function should be monitored regularly.
Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Janumet be discontinued if evidence of renal impairment is present.
Sitagliptin Phosphate: Hypoglycemia in Combination with a Sulfonylurea or with Insulin: In clinical trials of sitagliptin as monotherapy and as part of combination therapy with agents not known to cause hypoglycemia [ie, metformin or a PPARγ agonist (eg, thiazolidinedione)], rates of hypoglycemia reported with sitagliptin were similar to rates in patients taking placebo. As typical with other antihyperglycemic agents, when sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of sulfonylurea- or insulin-induced hypoglycemia was increased over that of placebo (see Side Effects). Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered (see Dosage & Administration).
Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Janumet. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin with some reports occurring after the 1st dose. If a hypersensitivity reaction is suspected, discontinue Janumet; assess for other potential causes for the event and institute alternative treatment for diabetes (see Contraindications and Side Effects).
Metformin hydrochloride: Lactic Acidosis: Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during treatment with Janumet (sitagliptin phosphate/metformin hydrochloride); when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a 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.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In >20,000 patient-years 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 pharmacologic management, in particular those 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 the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly 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, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis is often subtle and accompanied only by nonspecific symptoms eg, malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms, and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal, but <5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis, and may be explainable by other mechanisms eg, poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see Contraindications).
Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (eg, sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs.
Use of Concomitant Medications that may Affect Renal Function or Metformin Disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change, or may interfere with the disposition of metformin eg, cationic drugs that are eliminated by renal tubular secretion (see Interactions), should be used with caution.
Radiologic Studies Involving the Use of Intravascular Iodinated Contrast Materials [eg, IV Urogram, IV Cholangiography, Angiography and Computed Tomography (CT) Scans with Intravascular Contrast Materials]: Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see Contraindications). Therefore, in patients in whom any such study is planned, Janumet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hrs subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
Hypoxic States: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Janumet therapy, the drug should be promptly discontinued.
Surgical Procedures: Use of Janumet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Therefore, patients should be warned against excessive acute or chronic alcohol intake while receiving Janumet.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Janumet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Levels: In a 29-week duration of controlled clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels without clinical manifestations was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Janumet, and any apparent abnormalities should be appropriately investigated and managed.
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes: A patient with type 2 diabetes previously well controlled on Janumet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Janumet must be stopped immediately and other appropriate corrective measures initiated.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Janumet and temporarily administer insulin. Janumet may be reinstituted after the acute episode is resolved.
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women with Janumet or its individual components; therefore, the safety of Janumet in pregnant women is not known. Janumet, like other oral antihyperglycemic agents, is not recommended for use in pregnancy.
No animal studies have been conducted with the combined products in Janumet to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.
Sitagliptin Phosphate: Sitagliptin was not teratogenic in rats at oral doses up to 250 mg/kg or in rabbits given up to 125 mg/kg during organogenesis (up to 32 and 22 times, respectively, the human exposure based on the recommended daily adult human dose of 100 mg/day). In rats, a slight increase in the incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) was observed at oral doses of 1000 mg/kg/day (approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Slight decreases in mean preweaning body weights of both sexes and postweaning body weight gains of males were observed in the offspring of rats given oral dose of 1000 mg/kg/day. However, animal reproduction studies are not always predictive of the human response.
Metformin hydrochloride: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 times and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Use in lactation: No studies in lactating animals have been conducted with the combined components of Janumet. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin is excreted in human milk. Therefore, Janumet should not be used by a woman who is nursing.
Use in children: Safety and effectiveness of Janumet in pediatric patients under 18 years have not been established.
Use in the elderly: Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, Janumet should be used with caution as age increases. Care should be taken in dose selection, and should be based on careful and regular monitoring of renal function (see previously mentioned Monitoring of Renal Function).
Sitagliptin Phosphate: In clinical studies, the safety and effectiveness of sitagliptin in the elderly (≥65 years) were comparable to those seen in younger patients (<65 years).
Metformin hydrochloride: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin should only be used in patients with normal renal function (see Contraindications).