Metformin and sitagliptin: uses, appearance and warnings

ZITUVIMET 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. ( 1 ) Limitations of Use: ZITUVIMET is not recommended in patients with type 1 diabetes mellitus. ( 1 ) ZITUVIMET has not been studied in patients with a history of pancreatitis. ( 1 ) ZITUVIMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ZITUVIMET is not recommended in patients with type 1 diabetes mellitus. ZITUVIMET 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 ZITUVIMET. [see Warnings and Precautions ( 5.2 )].

ZITUVIMET Tablets: • sitagliptin 50 mg and metformin HCl 500 mg tablets • sitagliptin 50 mg and metformin HCl 1,000 mg tablets ( 3 ) Tablets: sitagliptin 50 mg and metformin HCl 500 mg tablets are white to off-white, oval shaped, biconvex, film coated tablets debossed with "1786" on one side and plain on the other side. sitagliptin 50 mg and metformin HCl 1,000 mg tablets are reddish brown, oval shaped, biconvex, film coated tablets debossed with "1787" on one side and plain on the other side.

Tablets supplied as follows: Contents Description How Supplied NDC 50 mg sitagliptin and 500 mg metformin HCl White to off-white, oval shaped, biconvex, film coated tablets debossed with "1786" on one side and plain on the other side. Bottles of 60 tablets with child-resistant closure. NDC 70771-1859-6 Bottles of 180 tablets with child-resistant closure. NDC 70771-1859-8 50 mg sitagliptin and 1,000 mg metformin HCl Reddish brown, oval shaped, biconvex, film coated tablets debossed with "1787" on one side and plain on the other side Bottles of 60 tablets with child-resistant closure. NDC 70771-1860-6 Bottles of 180 tablets with child-resistant closure. NDC 70771-1860-8 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F), [see USP Controlled Room Temperature]. Protect from moisture.

Severe renal impairment: (eGFR below 30 mL/min/1.73 m 2 ) ( 4) Metabolic acidosis, including diabetic ketoacidosis. ( 4 ) History of a serious hypersensitivity reaction to ZITUVIMET, sitagliptin, or metformin, such as anaphylaxis or angioedema. (4) ZITUVIMET is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions ( 5.1 )]. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of a serious hypersensitivity reaction to sitagliptin, metformin, or any of the excipients in ZITUVIMET. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported. [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.2 )].

Lactic Acidosis: See boxed warning . ( 5.1 ) Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue ZITUVIMET. ( 5.2 ) Heart Failure : Has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of ZITUVIMET in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.3 ) Acute Renal Failure: Has been reported postmarketing, sometimes requiring dialysis. Before initiating ZITUVIMET and at least annually thereafter, assess renal function. ( 5.4 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.5 ) Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required. ( 5.6 ) Hypersensitivity Reactions: There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Promptly stop ZITUVIMET, assess for other potential causes, institute appropriate monitoring and treatment. ( 5.7 ) Severe and Disabling Arthralgia: Has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.8 ) Bullous Pemphigoid: There have been postmarketing reports requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue ZITUVIMET. ( 5.9 ) 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of ZITUVIMET. In ZITUVIMET treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue ZITUVIMET and report these symptoms to their health care provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]: Before initiating ZITUVIMET, obtain an estimated glomerular filtration rate (eGFR). ZITUVIMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications ( 4 )]. ZITUVIMET is not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m 2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination ZITUVIMET product. Obtain an eGFR at least annually in all patients taking ZITUVIMET. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions The concomitant use of ZITUVIMET with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ( 7 )]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations ( 8.5 )]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop ZITUVIMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. …

The following adverse reactions are also discussed elsewhere in the prescribing information: Lactic Acidosis [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Heart Failure [see Warnings and Precautions ( 5.3 )] Acute Renal Failure [see Warnings and Precautions ( 5.4 )] Vitamin B12 Deficiency [see Warnings and Precautions ( 5.5 )] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Severe and Disabling Arthralgia [see Warnings and Precautions ( 5.8 )] Bullous Pemphigoid [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥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 h …

Table 4 presents clinically significant drug interactions with ZITUVIMET: Table 4: Clinically Significant Drug Interactions with ZITUVIMET 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 ZITUVIMET may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. …