Generic Name: sitagliptin and metformin hydrochloride
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
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, Janumet1 should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions (5.1).]
Indications and Usage for Janumet
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).]
Janumet Dosage and Administration
Recommended Dosing
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.
Dosage Forms and Strengths
- 50 mg/500 mg tablets are light pink, capsule-shaped, film-coated tablets with “575” debossed on one side.
- 50 mg/1000 mg tablets are red, capsule-shaped, film-coated tablets with “577” debossed on one side.
Contraindications
Janumet (sitagliptin/metformin HCl) is contraindicated in patients with:
- Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1)].
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
- History of a serious hypersensitivity reaction to Janumet or sitagliptin (one of the components of Janumet), such as anaphylaxis or angioedema. [See Warnings and Precautions (5.14); Adverse Reactions (6.2).]
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)].
Warnings and Precautions
Lactic Acidosis
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)].
Pancreatitis
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.
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.
Assessment 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 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); Use in Specific Populations (8.5).]
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. 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.
Vitamin B12 Levels
In controlled clinical trials of metformin of 29 weeks duration, 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. [See Adverse Reactions (6.1).]
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 two- to three-year intervals may be useful.
Alcohol Intake
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.
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.
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.
Use with Medications Known to Cause Hypoglycemia
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 Medications Affecting 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, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)], should be used with caution.
Radiologic Studies with Intravascular Iodinated Contrast Materials
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-evaluated 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.
Loss of Control of Blood Glucose
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.
Hypersensitivity Reactions
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).]
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Janumet or any other anti-diabetic drug.
Adverse Reactions
Clinical Trials Experience
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.
| Number of Patients (%) | ||||
Placebo | Sitagliptin 100 mg QD | Metformin 500 mg/ Metformin 1000 mg bid† | Sitagliptin 50 mg bid + Metformin 500 mg/ Metformin 1000 mg bid† | |
| N = 176 | N = 179 | N = 364† | N = 372† | |
| ||||
| Diarrhea | 7 (4.0) | 5 (2.8) | 28 (7.7) | 28 (7.5) |
| Upper Respiratory Tract Infection | 9 (5.1) | 8 (4.5) | 19 (5.2) | 23 (6.2) |
| Headache | 5 (2.8) | 2 (1.1) | 14 (3.8) | 22 (5.9) |
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.
| Number of Patients (%) | ||||||
| Study of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise | Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone | |||||
Placebo | Sitagliptin 100 mg QD | Metformin 500 mg/ Metformin 1000 mg bid* | Sitagliptin 50 mg bid + Metformin 500 mg/ Metformin 1000 mg bid* | Placebo and Metformin ≥1500 mg daily | Sitagliptin 100 mg QD and Metformin ≥1500 mg daily | |
| N = 176 | N = 179 | N = 364 | N = 372 | N = 237 | N = 464 | |
| ||||||
| Diarrhea | 7 (4.0) | 5 (2.8) | 28 (7.7) | 28 (7.5) | 6 (2.5) | 11 (2.4) |
| Nausea | 2 (1.1) | 2 (1.1) | 20 (5.5) | 18 (4.8) | 2 (0.8) | 6 (1.3) |
| Vomiting | 1 (0.6) | 0 (0.0) | 2 (0.5) | 8 (2.2) | 2 (0.8) | 5 (1.1) |
| Abdominal Pain† | 4 (2.3) | 6 (3.4) | 14 (3.8) | 11 (3.0) | 9 (3.8) | 10 (2.2) |
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).
| ||
| Add-On to Glimepiride + Metformin (24 weeks) | Sitagliptin 100 mg + Metformin + Glimepiride | Placebo + Metformin + Glimepiride |
| N = 116 | N = 113 | |
| Overall (%) | 19 (16.4) | 1 (0.9) |
| Rate (episodes/patient-year)† | 0.82 | 0.02 |
| Severe (%)‡ | 0 (0.0) | 0 (0.0) |
| Add-On to Insulin + Metformin (24 weeks) | Sitagliptin 100 mg + Metformin + Insulin | Placebo + Metformin + Insulin |
| N = 229 | N = 233 | |
| Overall (%) | 35 (15.3) | 19 (8.2) |
| Rate (episodes/patient-year)† | 0.98 | 0.61 |
| Severe (%)‡ | 1 (0.4) | 1 (0.4) |
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.
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control) [See Warnings and Precautions (5.2).]
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 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. [See Warnings and Precautions (5.5).]
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of Janumet or sitagliptin, one of the components of Janumet. These reactions have been reported when Janumet or sitagliptin have been used alone and/or in combination with other antihyperglycemic agents. 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 including 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 Indications and Usage (1); Warnings and Precautions (5.2)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.4)]; constipation; vomiting; headache.
Drug Interactions
Cationic Drugs
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.
Digoxin
There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 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.
Glyburide
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 Cmax 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.
Furosemide
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 Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax 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.
Nifedipine
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
The Use of Metformin with Other Drugs
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
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 1-800-986-8999.
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
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.
Nursing Mothers
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.
Pediatric Use
Safety and effectiveness of Janumet in pediatric patients under 18 years have not been established.
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