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As also noted in the FDA statement, the Warnings and Precautions section of the drug labels and the patient Medication Guides for incretin mimetic drugs, including JANUVIA, contain warnings about the risk of acute pancreatitis. The FDA issued a previous safety communication on sitagliptin and pancreatitis in 2009. The safety profile of sitagliptin has been established through an extensive pre-clinical and clinical development program as well as post-marketing surveillance. In more than six years of marketed use, more than 50 million total prescriptions have been dispensed for sitagliptin-containing medicines worldwide. Merck believes that the current product labeling appropriately describes the benefits and risks of sitagliptin-containing medicines to inform prescribing. Healthcare providers should inform their patients of the signs and symptoms of acute pancreatitis and remind them to contact their healthcare provider if these symptoms persist.

Safety information from clinical trials

In 2010, Merck published a thorough analysis of adverse event reports from 19 randomized controlled clinical trials based on data from 10,246 patients who were followed for up to two years; 5,429 of whom took sitagliptin 100 mg daily. In this analysis, the overall rate of pancreatitis in patients taking sitagliptin was low and was the same as the rate for patients who did not take sitagliptin and similar to rates that have been reported in the general diabetic population: 1 per 1000 patient-years in each group.

Since that time, we have continued to actively monitor the safety profile of sitagliptin. Subsequent to the pooled analysis published in 2010, Merck conducted a larger pooled analysis that included data from an additional six randomized controlled clinical studies that enrolled approximately 4,300 patients for a total of more than 14,000 patients. In this updated analysis, there were no differences in the incidence of pancreatitis or pancreatic cancer between patients taking sitagliptin and those who did not take sitagliptin. There were six patients with reports of pancreatic cancer: three patients among those treated with sitagliptin and three patients among those who did not take sitagliptin. Studies in the pooled analysis were not designed or powered to identify or adjudicate events of pancreatitis or pancreatic cancer, and do not allow for inference on the potential for long-term effects.

In addition, the independent Data and Safety Monitoring Board (DSMB) that is overseeing an additional, long-term randomized clinical study of sitagliptin in more than 14,000-patients (which started in 2008) reviewed data from that study in February 2013. The DSMB did not identify any safety concerns to Merck or recommend any changes to the study.

Information from pre-clinical safety studies

The safety of sitagliptin also is supported by an extensive pre-clinical safety program. This includes studies to assess for potential genotoxicity, which tests the ability of a compound to damage DNA, and carcinogenicity, which tests the ability of a compound to cause tumors, in rodents. The latter are conducted over the lifetime of the animals and have been found to be highly predictive of tumor findings in humans. In these studies, sitagliptin was shown not to be genotoxic, and in the carcinogenicity studies conducted at exposures that exceed the clinical exposure of sitagliptin, no adverse effects on the pancreas were observed and sitagliptin was not associated with an increase in the incidence of pancreatic malignancies.

Post-marketing adverse events

Merck actively monitors post-marketing reports we receive about sitagliptin, including those the company has received of pancreatitis and pancreatic cancer, and provides these to regulatory agencies around the world in accordance with each agency’s requirements. The existence of post-marketing reports describing this event does not establish the presence of an association with sitagliptin.

Post-marketing events are reported voluntarily from a population of uncertain size, and it is generally not possible to reliably establish the frequency of such events or to establish a causal relationship from these reports. Spontaneous post-marketing adverse events may be caused by underlying disease, genetic condition, the medication, concomitant medications or background event that may occur in the population. The Prescribing Information is the best source of information on the benefits and risks of sitagliptin including post-marketing adverse event reports.

About JANUVIA^® (sitagliptin) tablets

JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

JANUVIA 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 of developing pancreatitis while taking JANUVIA.

Selected Important Risk Information About JANUVIA^® (sitagliptin)

JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.

Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of JANUVIA is prescribed.

There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.

When JANUVIA was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 12.2 percent (0.59 episodes per patient-year) for JANUVIA 100 mg in combination with glimepiride (with or without metformin), 1.8 percent (0.24 episodes per patient-year) for placebo in combination with glimepiride (with or without metformin), 15.5 percent (1.06 episodes per patient-year) for JANUVIA 100 mg in combination with insulin (with or without metformin), and 7.8 percent (0.51 episodes per patient-year) for placebo in combination with insulin (with or without metformin).