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FDA Approves Combo of Januvia Plus Metformin in Once A Day Dosage

The FDA approved JANUMET® XR (sitagliptin and metformin hydrochloride (HCl) extended-release) tablets, a treatment for type 2 diabetes that combines sitagliptin, which is the active component of JANUVIA® (sitagliptin), with extended-release metformin….

JANUMET XR provides a convenient once-daily treatment option for patients who need help to control their blood sugar. JANUMET XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both sitagliptin and extended-release metformin is appropriate. JANUMET XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUMET XR 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 XR.

The FDA approved JANUMET XR based upon a clinical bioequivalence study that demonstrated that administration of JANUMET XR was equivalent to co-administration of corresponding doses of the two individual medications, sitagliptin and metformin HCl extended- release. Extended-release metformin was as effective as immediate-release metformin.

The labeling for JANUMET XR contains a boxed warning for lactic acidosis, a rare, but serious complication that can occur due to metformin accumulation.

JANUMET XR is contraindicated in patients with renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; hypersensitivity to metformin HCl; acute or chronic metabolic acidosis, including diabetic ketoacidosis (diabetic ketoacidosis should be treated with insulin); history of a serious hypersensitivity reaction to JANUMET XR or sitagliptin, such as anaphylaxis or angioedema.

When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with JANUMET XR and at least annually thereafter, renal function should be assessed and verified as normal. There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET XR should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET XR.

The combination of sitagliptin and metformin1 provided greater A1C goal attainment compared to sitagliptin or metformin alone

In a randomized, double-blind, placebo-controlled factorial study in 1,091 patients with type 2 diabetes who had inadequate glycemic control on diet and exercise, the co-administration of metformin immediate-release and sitagliptin twice-daily resulted in a reduction of A1C relative to placebo at 24 weeks. Mean placebo adjusted reduction was 2.1 percent with initial therapy combining sitagliptin 100 mg daily and metformin immediate-release 2000 mg dailyi (n=178) from a mean baseline A1C of 8.8 percent (p <0.001). The mean placebo-adjusted A1C reductions in the other arms of the study were 1.6 percent with sitagliptin 100 mg daily and metformin immediate-release 1000 mg dailyii (n=183); 1.3 percent with metformin immediate-release 2000 mg dailyiii (n=177); 1.0 percent with metformin immediate-release 1000 mgiv daily (n=178); and 0.8 percent with sitagliptin (n=175), (p<0.001 for all treatment groups versus placebo). At 24 weeks, 66 percent of patients treated with the initial combination of sitagliptin 100 mg daily and metformin immediate-release 2000 mg daily achieved the American Diabetes Association (ADA) goal A1C level of less than 7.0 percent, compared to 38 percent of patients treated with metformin immediate-release 2000 mg daily alone. In the other arms of the study, 43 percent of patients treated with sitagliptin 100 mg daily and metformin immediate-release 1000 mg daily, 23 percent of patients treated with metformin immediate-release 1000 mg daily, and 20 percent of patients treated with sitagliptin achieved the ADA goal A1C level of less than 7.0 percent.

In this study, the incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone.

As clinicians select agents to add to the treatment regimens of patients with type 2 diabetes, it is important to consider issues such as weight gain and hypoglycemia. In this study, the decrease in body weight in the groups given sitagliptin in combination with metformin immediate-release was similar to that in the groups given metformin immediate-release alone or placebo. The overall incidence of reported adverse reactions of hypoglycemia was similar across treatment groups (0.6 percent in patients given placebo, 0.6 percent in patients given sitagliptin alone, 0.8 percent in patients given metformin immediate-release alone, and 1.6 percent in patients given sitagliptin in combination with metformin immediate-release).

The most common adverse reactions reported with sitagliptin and metformin immediate-release as initial therapy (greater than or equal to 5 percent) compared to metformin immediate-release alone were diarrhea (7.5 percent vs. 7.7 percent), upper respiratory infection (6.2 percent vs. 5.2 percent) and headache (5.9 percent vs. 3.8 percent).

JANUMET XR targets three key defects of diabetes: insulin deficiency from pancreatic beta cells, insulin resistance, and overproduction of glucose by the liver.

The dose of JANUMET XR 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.

In patients not currently treated with metformin, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and 1000 mg metformin HCl extended-release. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose. In patients already treated with metformin, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and the previously prescribed dose of metformin.

For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin/1000 mg metformin HCl extended-release tablets taken together once daily. Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose. JANUMET XR should be administered with food to reduce the gastrointestinal side effects associated with the metformin component and be given once daily with a meal preferably in the evening. Inform patients that JANUMET XR tablets must not be split, broken, crushed, or chewed before swallowing.

The 100 mg sitagliptin/1000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using two JANUMET XR tablets (such as two 50 mg sitagliptin/500 mg metformin HCl extended-release tablets or two 50 mg sitagliptin/1000 mg metformin HCl extended-release tablets) should take the two tablets together once daily.

JANUMET XR is available in tablets of 100 mg sitagliptin/1000 mg metformin HCl extended-release, 50 mg sitagliptin/500 mg metformin HCl extended-release, and 50 mg sitagliptin/1000 mg metformin HCl extended-release.

News Release Feb. 2012