Janumet

Common name: sitagliptin/metformin extended-release tablets

Trade name: Janumet XR

Full names: sitagliptin/metformin extended-release tablets, Janumet XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product that can be used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes when appropriately treated with sitagliptin and metformin extended-release.

Important limitations of use:

Not used to treat type 1 diabetes or diabetic ketoacidosis.

Patients with a history of pancreatitis have not been studied.

Dosage:

Personalize the starting dose of JANUMET XR based on the patient's current treatment regimen.

Adjust dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin extended-release.

Once a day, preferably with a meal in the evening. Escalate the dose gradually to reduce gastrointestinal effects caused by metformin.

Before starting, assess renal function and estimated glomerular filtration rate (eGFR)

Do not use in patients with eGFR less than 30mL/min/1.73m2.

If eGFR is lower than 30mL/min/1.73m2, stop using it.

Triggering is not recommended for patients whose eGFR is between 30-45mL/min/1.73m2.

If eGFR is less than 45mL/min/1.73m2, evaluate the risk/benefit of continuing.

If eGFR drops below 45mL/min/1.73m2, limit the dose of sitagliptin to 50mg once daily.

JANUMET XR may need to be discontinued during or before iodination contrast imaging procedures.

Strength:

(50/1000) mg/tablet

Adverse Reactions:

The most common adverse reactions reported in ≥5% of patients initiated concurrently with sitagliptin and metformin and occurred more commonly in patients taking sitagliptin and metformin than in patients taking placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported by ≥5% of patients treated with sitagliptin in combination with a sulfonylurea and metformin were hypoglycemia and headache more commonly than in patients treated with a sulfonylurea and metformin combined with placebo.

Hypoglycemia was the only adverse reaction reported in ≥5% of patients treated with sitagliptin in combination with insulin and metformin, and more commonly in patients treated with placebo in combination with insulin and metformin.

Contraindications:

Severe renal impairment: eGFR lower than 30mL/min/1.73m2.

Metabolic acidosis, including diabetic ketoacidosis.

History of serious allergic reaction (e.g., anaphylaxis or angioedema) to JANUMET XR or one of its components.

Notes:

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis in patients treated with sitagliptin. If pancreatitis is suspected, JANUMET XR should be discontinued immediately.

Heart failure was observed with two other members of the DPP-4 inhibitor class. Consider the risks and benefits of JANUMET XR in patients with known risk factors for heart failure. Monitor patients for signs and symptoms.

There have been postmarketing reports of acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin. Before starting JANUMET XR, assess kidney function at least annually.

Vitamin B12 deficiency: Metformin may reduce vitamin B12 levels. Hematological parameters were measured annually.

When used with an insulin secretagogue (e.g., a sulfonylurea) or with insulin, lower doses of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia.

There have been postmarketing reports of serious allergic reactions and anaphylaxis, such as anaphylaxis, angioedema, and exfoliative dermatoses including Stevens-Johnson syndrome, in patients treated with sitagliptin. In such cases, JANUMET XR should be discontinued immediately, other potential causes evaluated, appropriate monitoring and treatment instituted, and alternative diabetes treatment initiated.

Severe and disabling joint pain has been reported in patients taking DPP-4 inhibitors. Consider this as a possible cause of severe joint pain and discontinue medication as appropriate.

There have been reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report the development of blisters or erosions. If bullous pemphigoid is suspected, discontinue JANUMET XR.

No clinical studies have established conclusive evidence that JANUMET XR reduces macrovascular risk.

Storage:

Store at 20-25°C (68-77°F), deviation from temperature 15-30°C (59-86°F) allowed.

Mechanism of Action:

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

Sitagliptin

Sitagliptin is a DPP-4 inhibitor that works in patients with type 2 diabetes by slowing down the inactivation of the incretin hormone. Sitagliptin increases the concentration of active intact hormones, thereby increasing and prolonging the effects of these hormones. Incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestines throughout the day, and levels increase in response to meals. These hormones are rapidly inactivated by the DPP-4 enzyme. Incretins are part of the endogenous system involved in the physiological 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 through intracellular signaling pathways involving cyclic AMP. GLP-1 also reduces 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 circulating glucagon levels in a glucose-dependent manner. Sitagliptin exhibits selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approaching those from therapeutic doses.

Metformin Hydrochloride

Metformin is a biguanide drug that can improve blood sugar control and reduce basal and postprandial blood sugar in patients with type 2 diabetes. Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose absorption and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or healthy subjects except under certain circumstances [see Warnings and Precautions], and does not cause hyperinsulinemia. During treatment with metformin, insulin secretion remains unchanged, whereas fasting insulin levels and whole-day plasma insulin responses may actually decrease.

Safety and Efficacy:

FDA approval of Janumet XR is based on the results of a clinical bioequivalence study, which showed that the use of Janumet XR was equivalent to the corresponding doses of these two drugs - sitagliptin and extended-release metformin. Extended-release metformin is equivalent to immediate-release metformin.

According to Merck, the combination of sitagliptin and metformin reduced hemoglobin A1c (HbA1c) levels to a greater extent than either sitagliptin or metformin alone. In a randomized, double-blind, placebo-controlled factorial study of 1,091 patients with type 2 diabetes whose blood sugar was not adequately controlled by diet and exercise, HbA1c levels were reduced at 24 weeks in the twice-daily combination of immediate-release metformin and sitagliptin compared with placebo. The mean HbA1c level at baseline in the sitagliptin 100 mg once-daily plus immediate-release metformin 2000 mg once-daily treatment group (n=178) was 8.8%, with a placebo-adjusted mean decrease of 2.1% (P<0.001). The other groups in the study had placebo-adjusted mean HbA1c reductions of 1.6% (sitagliptin 100 mg once daily + immediate-release metformin 1000 mg once daily, n = 183), 1.3% (immediate-release metformin 2000 mg once daily, n = 177), and 1.0% (immediate-release metformin 1000 mg once daily). mg, once daily treatment group, n=178) and 0.8% (sitagliptin treatment group, n=175) (all treatment groups vs. placebo group: P<0.001). At 24 weeks, 66% of patients who started with sitagliptin 100 mg once daily plus immediate-release metformin 2000 mg once daily achieved the American Diabetes Association (ADA) target hemoglobin A1c level of <7%, compared with 38% of patients who received immediate-release metformin 2000 mg once daily alone. In other arms of the study, 43% of patients in the once-daily combination treatment group with sitagliptin 100 mg once daily + immediate-release metformin 1000 mg once daily, 23% in the immediate-release metformin 1000 mg once-daily treatment group, and 20% in the sitagliptin-treated group achieved the ADA target hemoglobin A1c level of <7%.