JANUMET XR (Page 4 of 8)

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

8.4 Pediatric Use

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

8.5 Geriatric Use

JANUMET XR

Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients. [See Warnings and Precautions (5.1, 5.4); Clinical Pharmacology (12.3).]

Sitagliptin

Of the total number of subjects (N=3884) in premarketing 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 HCl

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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients. [See Contraindications (4); Warnings and Precautions (5.4); Clinical Pharmacology (12.3).]

8.6 Renal Impairment

JANUMET XR

The dose of the sitagliptin component should be limited to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m2. JANUMET XR is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2. [See Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]

Sitagliptin

Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m2 (moderate and severe renal impairment, as well as in ESRD patients requiring dialysis).

Metformin HCl

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JANUMET XR is not recommended in patients with hepatic impairment. [See Warnings and Precautions (5.1).]

10 OVERDOSAGE

In the event of overdose with JANUMET XR, contact the Poison Control Center.

In the event of an overdose, it is reasonable to employ 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.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl 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.

11 DESCRIPTION

JANUMET XR tablets contain two oral antidiabetic medications: sitagliptin and metformin HCl extended-release.

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin phosphate monohydrate drug substance is used to manufacture JANUMET XR. 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-α]pyrazine phosphate (1:1) monohydrate with an empirical formula of C16 H15 F6 N5 O•H3 PO4 •H2 O and a molecular weight of 523.32. The structural formula is:

image of sitagliptin chemical structure
(click image for full-size original)

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 HCl

Metformin HCl (N ,N -dimethylimidodicarbonimidic diamide HCl) is a white to off-white crystalline compound with a molecular formula of C4 H11 N5 •HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown:

image of metaformin chemical structureimage of metaformin chemical structure

JANUMET XR

JANUMET XR is available as film-coated tablets containing:

  • 64.25 mg sitagliptin monohydrate equivalent to 50 mg sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin HCl (JANUMET XR 50/500).
  • 64.25 mg sitagliptin monohydrate equivalent to 50 mg sitagliptin and 779.86 mg of metformin equivalent to 1000 mg metformin HCl (JANUMET XR 50/1000).
  • 128.5 mg sitagliptin monohydrate equivalent to 100 mg sitagliptin and 779.86 mg of metformin equivalent to 1000 mg metformin HCl (JANUMET XR 100/1000).

All doses of JANUMET XR contain the following inactive ingredients: povidone, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate, propyl gallate, polyethylene glycol, and kaolin. The JANUMET XR 50 mg/500 mg tablet contains the additional inactive ingredient microcrystalline cellulose. In addition, the film coating for all doses contains the following inactive ingredients: hypromellose, hydroxypropyl cellulose, titanium dioxide, FD&C #2/Indigo Carmine Aluminum Lake and carnauba wax. The JANUMET XR 50 mg/1000 mg tablet film coating also contains the inactive ingredient yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

JANUMET XR

JANUMET XR tablets combine two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin HCl extended-release, a member of the biguanide class.

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which exerts 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 concentrations approximating those from therapeutic doses.

Metformin HCl

Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

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