Presentation and Status in Health Basket
56 x 50 mg / 500 mg
Recommended Dosing: The dosage of antihyperglycemic therapy with JANUET 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. JANUET 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 JANUET should be based on the patient’s current regimen. JANUET 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.
Patients inadequately controlled with diet and exercise alone: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled with diet and exercise alone, the recommended starting dose is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients with inadequate glycemic control on this dose can be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.
Patients inadequately controlled on metformin monotherapy: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient inadequately controlled on metformin alone, the recommended starting dose of JANUET 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 JANUET is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.
Patients inadequately controlled on sitagliptin monotherapy: If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a patient inadequately controlled on sitagliptin alone, the recommended starting dose of JANUET is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients with inadequate control on this dose can be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily. Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to JANUET.
Patients switching from co-administration of sitagliptin and metformin: For patients switching from sitagliptin coadministrated with metformin, JANUET may be initiated at the dose of sitagliptin and metformin already being taken.
Patients inadequately controlled on dual combination therapy with any two of the following antihyperglycemic agents: sitagliptin, metformin or a sulfonylurea If therapy with a combination tablet containing
sitagliptin and metformin is considered appropriate in this setting, the usual starting dose of JANUET should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose). In determining the starting dose of the metformin component, the patient’s level of glycemic control and current dose (if any) of metformin should be considered. Gradual dose escalation to reduce the gastrointestinal (GI) side effects associated with metformin should be considered. Patients currently on or initiating a sulfonylurea may require lower sulfonylurea doses to reduce the risk of hypoglycemia. No studies have been performed specifically examining the safety and efficacy of JANUET in patients previously treated with other oral antihyperglycemic agents and switched to JANUET. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.
Indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin.
Important Limitations of Use JANUET 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.
JANUET has not been studied in combination with insulin.
Renal disease or dysfunction (serum creatinine > 1.5 mg/dl males, > 1.4 mg/dl females or abnormal creatinine clearance). Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. History of a serious hypersensitivity reaction to product or sitagliptin, such as anaphylaxis or angioedema. Patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials (temporarily discontinue therapy).
– Do not use JANUET in patients with hepatic disease.
– Before initiating JANUET and at least annually thereafter, assess renal function and verify as normal.
– Measure hematologic parameters annually.
– Warn patients against excessive alcohol intake.
– May need to discontinue JANUET and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.
– Promptly evaluate patients previously controlled on JANUET who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.
– When used with an insulin secretagogue (e.g., sulfonylurea, meglitinide), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.
– There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of JANUET), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUET, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
– There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUET or any other oral anti-diabetic drug.
For full details see prescribing information.
The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache. Adverse reactions reported in ≥5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.Nasopharyngitis was the only adverse reaction reported in ≥5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
For full details see prescribing information.
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 JANUET 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 JANUET 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 JANUET 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 coadministered 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 and Lactation
Pregnancy Category B: JANUET There are no adequate and well-controlled studies in pregnant women with JANUET or its individual components; therefore, the safety of JANUET in pregnant women is not known. JANUET should be used during pregnancy only if clearly needed. No animal studies have been conducted with the combined products in JANUET 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 JANUET. 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 JANUET is administered to a nursing woman.
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. 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 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 overdose is suspected.
For full details see prescribing information.