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FDA Approves Supplemental New Drug Applications for Januvia (sitagliptin)

Merck & Co., announced that the U.S. Food and Drug Administration (FDA) has approved expanded labeling for JANUVIA(TM) (sitagliptin), the only DPP-4 inhibitor available in the United States for the treatment of type 2 diabetes.

JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. JANUVIA should not be used in patients with type 1 diabetes. JANUVIA has not been studied in combination with insulin. The new regimens with JANUVIA described in the updated labeling include, as an adjunct to diet and exercise, initial therapy in combination with metformin; add-on therapy to a sulfonylurea (glimepiride) when the single agent alone does not provide adequate glycemic control; and, add-on therapy to the combination of a sulfonylurea (glimepiride) and metformin when dual therapy does not provide adequate glycemic control.

New data contained in three studies support the efficacy and safety of JANUVIA. Initial therapy with the combination of JANUVIA and metformin provided substantial A1C reductions. JANUVIA demonstrated similar efficacy to a sulfonylurea (glipizide) in patients inadequately controlled on metformin. JANUVIA also provided significant placebo-adjusted A1C reductions in patients being treated with a sulfonylurea (glimepiride), with or without metformin

The expanded labeling for JANUVIA was also updated, within Warnings and Precautions, to include post-marketing reports of hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Since its initial approval in October 2006, over two million prescriptions have been written for JANUVIA. In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In these clinical studies, the most common adverse reactions reported with JANUVIA (greater than or equal to 5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection and headache. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, JANUVIA demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.
Initial therapy with the combination of JANUVIA and metformin provides significantly greater A1C reductions with a similar GI tolerability profile compared to metformin alone

JANUVIA as initial therapy in combination with metformin is supported by a randomized, double-blind, placebo-controlled factorial study in 1,091 patients with type 2 diabetes who experienced inadequate glycemic control with diet and exercise alone. In this study, the mean reduction of A1C relative to placebo at 24 weeks was 2.1 percent with initial therapy combining JANUVIA 100 mg daily and metformin 2000 mg daily(1) (n=178) from a mean baseline A1C of 8.8 percent (p less than 0.001). The mean placebo-adjusted A1C reductions in the other arms of the study were 1.6 percent with JANUVIA 100 mg daily and metformin 1000 mg daily(2) (n=183); 1.3 percent with metformin 2000 mg daily(3) (n=177); 1.0 percent with metformin 1000 mg(4) daily (n=178); and 0.8 percent with JANUVIA (n=175), (pless than 0.001 for all treatment groups versus placebo).

At 24 weeks, 66 percent of patients treated with the initial combination of JANUVIA 100 mg daily and metformin 2000 mg daily achieved the American Diabetes Association’s (ADA) goal A1C level of less than 7 percent vs. 38 percent of patients treated with metformin 2000 mg daily alone. In the other arms of the study, 43 percent of patients treated with JANUVIA 100 mg daily and metformin 1000 mg daily, 23 percent of patients treated with metformin 1000 mg daily, and 20 percent of patients treated with JANUVIA achieved the ADA goal A1C level of less than 7 percent.

This study also included an open label cohort of an additional 117 patients with severely elevated baseline A1C (mean: 11.2 percent). These patients experienced a significant mean A1C reduction from baseline of 2.9 percent at 24 weeks with initial therapy combining JANUVIA 100 mg daily and metformin 2000 mg daily.

This study also compared the efficacy of JANUVIA to two common doses of metformin in a subset of patients not on any anti-hyperglycemic agent at study entry. In this patient population, patients treated with JANUVIA experienced a mean A1C reduction from baseline of 1.1 percent compared to 1.1 percent in patients treated with metformin 1000 mg daily and 1.2 percent in patients treated with metformin 2000 mg daily.

“The substantial A1C reductions that are seen when JANUVIA is used in combination with metformin as first-line therapy in patients with type 2 diabetes are meaningful. The data show that this approach helped many patients achieve their A1C goal and the rate of gastrointestinal side effects was similar to that seen with metformin alone,” said Barry J. Goldstein, M.D., Ph.D., professor of medicine, Biochemistry and Molecular Pharmacology; director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College, Philadelphia, PA.

JANUVIA demonstrated similar efficacy compared to a sulfonylurea (glipizide) with significantly less hypoglycemia, and patients treated with JANUVIA experienced mean weight loss from baseline of 1.5 kg

The new regimens for adding JANUVIA to a sulfonylurea (glimepiride) with or without metformin are supported by a 24-week, randomized, double-blind, placebo-controlled study examining the efficacy and safety of JANUVIA in 441 patients with type 2 diabetes and inadequate glycemic control (A1C 7.5 percent to 10.5 percent) on a sulfonylurea (glimepiride) and metformin or on a sulfonylurea (glimepiride) alone. In this study, JANUVIA demonstrated a significant mean difference from placebo in A1C of -0.9 percent when added to patients on glimepiride and metformin and -0.6 percent when added to patients on glimepiride alone (p less than 0.001 for both comparisons versus placebo).

The recommended dose of JANUVIA is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl greater than or equal to 50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in end-stage renal disease (ESRD) patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to less than 50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl less than 30 mL/min) or with ESRD requiring dialysis, the dose of JANUVIA is 25 mg once daily. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.

FACT:
Major Development In Cure For Diabetes: A discovery at Washington University in St. Louis may lead to a care for diabetes.  Researchers report they have successfully transplanted embryonic pig pancreas into diabetic monkeys.  Doctors say within weeks the monkeys showed dramatic improvement in insulin production. Dr. Marc Hammerman says, “They are a lot healthier. We’re very close to being able to cure them.  So if this is carried forward it is a cure for diabetes, potentially juvenile diabetes and adult onset diabetes.  That’s huge.” Dr. Hammerman also says the transplants were done without the need for risky immune suppression drugs that prevent rejection. He says more research on monkeys is needed and that human trials may be about five years away.  See this week’s Item #8