Merck Statement About JANUVIA (sitagliptin) and JANUMET (sitagliptin/metformin)

Merck Statement About JANUVIA (sitagliptin) and JANUMET (sitagliptin/metformin)

WHITEHOUSE STATION, N.J., Sept. 25, 2009 - Merck & Co., Inc., issued the following statement today in response to the U.S. Food and Drug Administration's (FDA's) update on JANUVIA (sitagliptin) and JANUMET (sitagliptin/metformin).
 
"Merck has thoroughly reviewed the safety data for sitagliptin, and sitagliptin was not associated with an increase in the incidence of pancreatitis in preclinical studies or in clinical trials of up to two years in duration with more than 6,000 patients.  Merck has also carefully reviewed post marketing adverse experience reports, and Merck believes these data do not demonstrate that a causal relationship exists between sitagliptin and pancreatitis.  Merck appreciates the important role that the FDA plays in assessing the safety of medicines and, as we do with all of our medicines, we will continue to monitor the safety of JANUVIA and will share the data with regulatory agencies and the medical community," said John Amatruda, M.D., senior vice president and franchise head, Diabetes and Obesity, Merck Research Laboratories.  "Patients with type 2 diabetes are more likely to develop pancreatitis than other people, and as FDA noted in a publication earlier this year, 'diagnosis [of drug-induced pancreatitis] poses a challenge since it can be difficult to rule out other causes.'  Merck would encourage any patient with concerns to speak with their physician."

There have been reports of pancreatitis following use of many other prescription medications and non-prescription medications, including other type 2 diabetes prescription medications.

JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes.  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 and JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.  JANUMET and JANUVIA have not been studied in combination with insulin.
 
Merck carefully monitors post marketing reports for all of our medicines, including JANUVIA and JANUMET, and updates the label as appropriate.  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 establish a causal relationship between a medicine and a specific adverse event.

Merck has carefully reviewed the reports of pancreatitis in the post-marketing database, including the reports of more serious cases.  In our review, the reports showed that the more serious cases also had other serious medical conditions.  As is often the case with post-marketing reports, any causal association between sitagliptin and pancreatitis is difficult to assess due to such factors as the incompleteness of the reports and other serious concurrent conditions in some of the patients.  Based on a qualitative assessment of the reports, Merck voluntarily added pancreatitis to the post-marketing adverse events section of the labeling for JANUVIA and JANUMET earlier this year as a reported adverse event to make physicians aware of these reports.

The safety profile of JANUVIA and JANUMET has been established through an extensive clinical development program.  In addition, in the nearly three years of marketed use, more than 18 million total prescriptions have been dispensed for sitagliptin worldwide.

Merck has published a peer-reviewed analysis of safety data pooled from twelve Phase IIb/III trials in 6,139 patients studied for up to two years in our clinical development program, in which the incidence rates of pancreatitis (0.1% sitagliptin vs. 0% non-exposed), acute pancreatitis (0 percent vs. 0.1percent), and chronic pancreatitis (0.1percent vs. 0percent) reported in patients treated with sitagliptin were not meaningfully different from that in patients not exposed to sitagliptin.

Merck will continue communicating with patients and healthcare providers about JANUVIA and JANUMET in ways that will help inform their decisions about appropriate treatment choices.  Patients should talk with their healthcare providers if they have any questions, and before starting or stopping treatment with any prescription medicine.

Selected cautionary information for JANUVIA
JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis and angioedema.  As is typical with other anti-hyperglycemic agents used in combination with a sulfonylurea, when JANUVIA is used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo.  Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.  Because JANUVIA is renally eliminated, and to achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, a dosage adjustment is recommended in patients with moderate renal insufficiency and in patients with severe renal insufficiency or with ESRD requiring hemodialysis or peritoneal dialysis.  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.  Safety and effectiveness of JANUVIA in pediatric patients have not been established.  There are no adequate and well-controlled studies in pregnant women.  JANUVIA should be used during pregnancy only if clearly needed.  It is not known whether sitagliptin is excreted in human milk.  Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman.
 
There have been 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.  Onset of these reactions occurred within the first three months after initiation of treatment with JANUVIA, with some reports occurring after the first dose.  If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event and institute alternative treatment for diabetes.

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

Selected Adverse Reactions for JANUVIA
In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidences 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 (≥ 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.

In a pre-specified pooled analysis of two monotherapy studies, an add-on to metformin study, and an add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia in patients treated with JANUVIA 100 mg was similar to placebo (1.2 percent vs. 0.9 percent).  Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required.  In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the incidence of hypoglycemia was 0.6 percent in patients given placebo, 0.6 percent in patients given sitagliptin alone, 0.8 percent in patients given metformin alone and 1.6 percent in patients given sitagliptin in combination with metformin.

Selected cautionary information for JANUMET
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 is contraindicated in patients with renal disease, renal dysfunction, or abnormal creatinine clearance; and acute or chronic metabolic acidosis, including diabetic ketoacidosis.  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.

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.

There have been post-marketing 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 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 or a sulfonylurea alone, 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.

Selected Adverse Reactions for JANUMET
The most common adverse reactions reported in >/= 5percent of patients started simultaneously on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.  Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs.  The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them.  Merck also publishes unbiased health information as a not-for-profit service.  For more information, visit www.merck.com.

Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995.  These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements.  The forward-looking statements may include statements regarding product development, product potential or financial performance.  No forward-looking statement can be guaranteed and actual results may differ materially from those projected.  Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.  Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

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