Metformin and Sitagliptin

JANUMET ® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use JANUMET should not be used in patients with type 1 diabetes mellitus. 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. JANUMET is a combination of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: JANUMET should not be used in patients with type 1 diabetes.

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

Take JANUMET orally twice daily with meals. Individualize the dosage of JANUMET on the basis of the patient’s current regimen, effectiveness, and tolerability. The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin HCl. The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin and 500 mg metformin HCl 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 HCl 850 mg twice daily, the recommended starting dose of JANUMET is 50 mg sitagliptin and 1000 mg metformin HCl twice daily.

JANUMET is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of a serious hypersensitivity reaction to JANUMET, sitagliptin, or metformin, such as anaphylaxis or angioedema. Severe renal impairment: (eGFR below 30 mL/min/1.73 m 2 ). Metabolic acidosis, including diabetic ketoacidosis.

Boxed warning (lactic acidosis): Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Lactic Acidosis: See boxed warning. Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET. Heart Failure: Has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of JANUMET in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms.

The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis Pancreatitis Heart Failure Acute Renal Failure Vitamin B 12 Deficiency Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Hypersensitivity Reactions Severe and Disabling Arthralgia Bullous Pemphigoid 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.

Table 4 presents clinically significant drug interactions with JANUMET: Table 4: Clinically Significant Drug Interactions with JANUMET Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with JANUMET may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.

Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F).