These highlights do not include all the information needed to use JANUMET safely and effectively. See full prescribing information for JANUMET. JANUMET® (sitagliptin/metformin HCl) tabletsInitial U.S. Approval: 2007

Lactic acidosis is a 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.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.

If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions (5.1).]

JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate. [See Clinical Studies (14).]

Important Limitations of Use

JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

JANUMET has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET. [See Warnings and Precautions (5.2).]

The dosage of JANUMET should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

JANUMET should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.

The starting dose of JANUMET should be based on the patient’s current regimen. JANUMET should be given twice daily with meals. The following doses are available:

50 mg sitagliptin/500 mg metformin hydrochloride

50 mg sitagliptin/1000 mg metformin hydrochloride.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of JANUMET is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

Patients treated with an insulin secretagogue or insulin

Co-administration of JANUMET with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.9)].

No studies have been performed specifically examining the safety and efficacy of JANUMET in patients previously treated with other oral antihyperglycemic agents and switched to JANUMET. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

JANUMET (sitagliptin/metformin HCl) is contraindicated in patients with:

JANUMET should be temporarily discontinued 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 [see Warnings and Precautions (5.11)].

Metformin hydrochloride

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET; 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 μg/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 more than 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 of age 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 [see Warnings and Precautions (5.4, 5.6, 5.7, 5.11)].

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as 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 [see Warnings and Precautions (5.12)]. 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 less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling [see Warnings and Precautions (5.8, 5.13)].

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 (4); Warnings and Precautions (5.6, 5.7, 5.10, 5.11, 5.12)].

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiation of JANUMET, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET.

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.

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 the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5).]

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, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B absorption from the B-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B 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. [See Adverse Reactions (6.1).]

Certain individuals (those with inadequate Vitamin Bor calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B levels. In these patients, routine serum Vitamin B measurements at two- to three-year intervals may be useful.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET.

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 eva luated as normal.

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 eva luated promptly for evidence of ketoacidosis or lactic acidosis. eva luation 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.

Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Dosage and Administration (2.1)].

Metformin hydrochloride

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 (such as 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.

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)], should be used with caution.

Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. 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 hours subsequent to the procedure and reinstituted only after renal function has been re-eva luated and found to be normal.

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.

When a patient stabilized on any diabetic regimen is exposed to stress such as 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.

There have been postmarketing 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 first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other anti-diabetic drug.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Sitagliptin and Metformin Co-administration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin were co-administered to patients with type 2 diabetes inadequately controlled on diet and exercise.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin, 1.9%; placebo and metformin, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin alone. See Table 2.

Sitagliptin in Combination with Metformin and Glimepiride

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).

Sitagliptin in Combination with Metformin and Rosiglitazone

In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Sitagliptin in Combination with Metformin and Insulin

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin was co-administered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin co-administered with a sulfonylurea or with insulin (Table 3).

The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.

In the study of sitagliptin and add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1.0% in patients given add-on placebo.

With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.

The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.

The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

Laboratory Tests

Sitagliptin

The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin hydrochloride

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B absorption from the B-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B supplementation. [See Warnings and Precautions (5.5).]

The following additional adverse reactions have been identified during postapproval use of JANUMET or sitagliptin, one of the components of JANUMET. 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.

Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.14)]; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Limitations of Use (1); Warnings and Precautions (5.2)].

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JANUMET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (C, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. These increases are not considered likely to be clinically meaningful. Digoxin, as a cationic drug, has the potential to compete with metformin for common renal tubular transport systems, thus affecting the serum concentrations of either digoxin, metformin or both. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUMET is recommended.

In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain.

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JANUMET the patient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Pregnancy Category B:

JANUMET

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 should be used during pregnancy only if clearly needed.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUMET while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUMET by calling the Pregnancy Registry at (800) 986-8999.

No animal studies have been conducted with the combined products in JANUMET to eva luate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

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 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

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. Because many drugs are excreted in human milk, caution should be exercised when JANUMET is administered to a nursing woman.

Safety and effectiveness of JANUMET in pediatric patients under 18 years have not been established.

JANUMET

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 Warnings and Precautions (5.1, 5.4); Clinical Pharmacology (12.3).]

Sitagliptin

Of the total number of subjects (N=3884) in Phase II and III clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

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 young patients. Metformin should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function. [See Contraindications (4); Warnings and Precautions (5.4); and Clinical Pharmacology (12.3).]

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not considered clinically important [see Clinical Pharmacology (12.2)]. There is no experience with doses above 800 mg in humans. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 400 mg per day for periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

JANUMET (sitagliptin/metformin HCl) tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: sitagliptin and metformin hydrochloride.

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin is present in JANUMET tablets in the form of sitagliptin phosphate monohydrate. Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate with an empirical formula of CHFNO•HPO•HO and a molecular weight of 523.32. The structural formula is:

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of CHN•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

JANUMET

JANUMET is available for oral administration as tablets containing 64.25 mg sitagliptin phosphate monohydrate and metformin hydrochloride equivalent to: 50 mg sitagliptin as free base and 500 mg metformin hydrochloride (JANUMET 50 mg/500 mg) or 1000 mg metformin hydrochloride (JANUMET 50 mg/1000 mg). Each film-coated tablet of JANUMET contains the following inactive ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and black iron oxide.

JANUMET

JANUMET combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. 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 physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. 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 conc

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011