Tredaptive and Janumet recommended for approval in European Union

Food and Drug Administration (FDA) is currently reviewing the combination of extended release (ER) niacin and laropiprant under the trademark Cordaptive (ER niacin/laropiprant). The CHMP recommendation does not apply to regulatory decisions by the FDA and no inferences should be made about pending FDA regulatory actions based on the recommendation of the CHMP.

In a second opinion, the CHMP recommended marketing approval for Janumet (sitagliptin/metformin HCl) for the treatment of type 2 diabetes. Janumet was approved by the FDA in March 2007. The U.S. labeling states that Janumet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate. Janumet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Janumet has not been studied in combination with insulin. The labeling also includes data supporting use of Janumet as initial therapy in adults inadequately controlled with diet and exercise alone and for add-on therapy with a sulfonylurea when the combination of a sulfonylurea and metformin does not provide adequate control.

The CHMP issued its positive opinions following a review of comprehensive data supporting the efficacy, safety and tolerability profiles of Tredaptiveand Janumet. EU marketing authorization by the European Commission is expected within 67 days from the date of the CHMP recommendations. If authorized, the decisions will be applicable to the 27 countries that are members of the EU, plus Norway and Iceland.

Tredaptive

Tredaptivecombines nicotinic acid (niacin) and laropiprant, a novel flushing pathway inhibitor. The proposed indication for Tredaptiveis for the treatment of dyslipidemia, in particular in patients with combined mixed dyslipidemia which is characterized by elevated levels of LDL-cholesterol and triglycerides and low levels of HDL-cholesterol, or primary hypercholesterolemia (heterozygous familial and non-familial). Tredaptiveshould be used in combination with a statin when the cholesterol lowering effect of statins is inadequate, or as monotherapy when statins are considered inappropriate or not tolerated. Diet and other non-pharmacological treatments, such as exercise and weight loss, should continue during therapy with Tredaptive.

Janumet

Janumet helps many patients lower blood sugar levels through the powerful efficacy of sitagliptin, a DPP-4 inhibitor, and metformin, a mainstay of diabetes therapy. For patients uncontrolled on metformin alone, Janumet provides weight loss comparable to metformin alone, with no increased risk of hypoglycemia, edema, or gastrointestinal (GI) disturbances beyond metformin alone.

The CHMP has recommended Janumet to be indicated to improve glycemic control in patients with type 2 diabetes inadequately controlled on diet and exercise plus their maximally tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin. The CHMP also recommended Janumet to be indicated in combination with a sulfonylurea as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulfonylurea.

The mechanism of action for Janumet is distinct in that it targets three core defects ¨C insulin deficiency from beta cells, insulin resistance and overproduction of glucose by the liver. The sitagliptin component in Janumet targets two of the three key defects. By inhibiting DPP-4, sitagliptin enhances the levels of the body's own active incretins; incretins are natural hormones that increase insulin synthesis and release from pancreatic beta cells and lowers glucagon secretion from pancreatic alpha cells leading to reduced production of glucose by the liver. Metformin targets insulin resistance by increasing the uptake and utilization of glucose. Metformin also decreases production of glucose by the liver in a manner that is complementary to sitagliptin.

In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in ¡Ý5 percent of patients and more commonly than in patients treated with placebo were as follows: diarrhea, upper respiratory tract infection and headache (for sitagliptin and metformin combination therapy); nasopharyngitis (for sitagliptin monotherapy); and diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia and headache (due to initiation of metformin therapy).

Dosing of Janumet (U.S.)

Janumet should be given twice daily with meals, with gradual dose escalation as needed to reduce the GI side effects due to metformin. In this formulation, the dose of sitagliptin remains constant (100 mg daily) and is combined with the two most widely prescribed doses of metformin (1000 mg daily or 2000 mg daily). The recommended starting dose of Janumet for patients not on prior metformin therapy and for those not adequately controlled on sitagliptin is 50 mg sitagliptin and 500 mg metformin twice daily with meals. For patients already receiving metformin therapy, the starting dose should be based on the patient¡¯s current metformin regimen. The total daily dose should not exceed 100 mg sitagliptin and 2000 mg metformin. For patients taking metformin 850 mg twice daily, the recommended starting dose of Janumet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Janumet. In the elderly, Janumet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. Any dose adjustment should be based on a careful assessment of renal function. Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal.

Cautionary information for Janumet (U.S.)

Consistent with the labeling for metformin alone, Janumet is contraindicated in patients with renal disease, renal dysfunction or abnormal creatinine clearance; and acute or chronic metabolic acidosis, including diabetic ketoacidosis. Janumet should not be used in patients with type 1 diabetes.

Consistent with the labeling for metformin alone, the labeling for Janumet contains a boxed warning for lactic acidosis, a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Janumet.

Janumet should be avoided in patients with evidence of hepatic disease. Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal. Patients should be warned against excessive alcohol intake while receiving Janumet. Patients may require discontinuation of Janumet and temporary use of insulin during periods of stress and decreased intake of fluids and food such as may occur with fever, trauma, infection or surgery. Patients previously controlled on Janumet who develop laboratory abnormalities or clinical illness should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50 percent of cases.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Janumet. 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. Onset of these reactions occurred within the first three months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Janumet, assess for other potential causes for the event and institute alternative treatment for diabetes.

As is typical with other anti-hyperglycemic agents used in combination with a sulfonylurea, when sitagliptin was used in combination with metformin and a sulfonylurea, a medication known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo in combination with metformin and a sulfonylurea. Therefore, patients on sitagliptin also receiving an insulin secretagogue (e.g., sulfonylurea, meglitinide) may require a lower dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Clinicians should be mindful that hypoglycemia could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Janumet or any other oral anti-diabetic drug.

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