Presents Pivotal Data for Omarigliptin, Merck’s Investigational Once-Weekly DPP-4 Inhibitor, and Additional Data from the TECOS CV Safety Trial, at European Association for the Study of Diabetes Annual Meeting known as MSD outside the United States and Canada, provided an update today on its diabetes portfolio and re-affirmed the company’s comprehensive, long-term commitment to patients with diabetes. Merck has a proud history in helping patients with type 2 diabetes. Since launching JANUVIA® (sitagliptin) in 2006 as the first DPP-4 inhibitor in the United States, Merck has continued to collaborate with academic and industry partners on advances in the care of patients with diabetes, and to research and develop innovative treatment options. At the 51st European Association for the Study of Diabetes (EASD) Annual Meeting in Stockholm, Sweden, new Phase 3 data on Merck’s investigational once-weekly oral DPP-4 inhibitor, omarigliptin, and additional findings from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) of Merck’s once-daily DPP-4 inhibitor, JANUVIA, are being presented.
“At Merck, our priorities are driven by unmet medical need and our belief in Merck’s ability to advance patient care, which is why diabetes remains a top priority. Our teams are focused on bringing forward both scientific insights and new treatment options that can help patients and physicians better manage the challenges of diabetes,” said Sam Engel, M.D., associate vice president, Merck clinical research, diabetes and endocrinology. “We have a strong portfolio of established medicines, and continue to strengthen our role in the future of diabetes treatment through our own research and development, strategic collaborations and acquisitions.”
Our flagship medicine, JANUVIA, was approved in 2006 in the United States and is now available in more than 127 countries worldwide. More than 83 million prescriptions of JANUVIA and JANUMET® (sitagliptin and metformin HCl) have been dispensed worldwide. The recent presentation of the results of TECOS—the CV safety trial of more than 14,000 patients with type 2 diabetes—has provided important new information on JANUVIA, and additional analyses of safety data from TECOS will be presented on Sept. 18, 2015 at the EASD Annual Meeting. The results of the TECOS CV safety trial will be submitted to the U.S. Food and Drug Administration (FDA) and other regulatory agencies this year.
Indications and Limitations of Use for JANUVIA® (sitagliptin) 25 mg, 50 mg and 100 mg tablets
JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. 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
JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
Other filing updates include:
In August 2015, omarigliptin, an investigational once-weekly DPP-4 inhibitor in development for the treatment of adults with type 2 diabetes, was endorsed by the Special Committee of the Japan Pharmaceuticals and Medical Devices Agency (PDMA) and a final decision on approval of omarigliptin in Japan is expected soon. The clinical development program for omarigliptin, O-QWEST (Omarigliptin Q Weekly Efficacy and Safety in Type 2 Diabetes), includes 10 Phase 3 clinical trials involving approximately 8,000 patients with type 2 diabetes. The company plans to submit a New Drug Application (NDA) to the U.S. FDA for omarigliptin by the end of 2015. Other worldwide regulatory submissions will follow.
Merck plans to submit MK-1293, Merck’s insulin glargine candidate for the treatment of patients with type 1 and type 2 diabetes, for regulatory approval within the next six months. MK-1293 is being developed as part of Merck’s biosimilar collaboration with Samsung Bioepis Co., Ltd.
Merck is collaborating with Pfizer on the development of the investigational SGLT2 inhibitor ertugliflozin, along with fixed-dose combinations of ertugliflozin and sitagliptin, and ertugliflozin and metformin. The alliance initiated Phase 3 clinical trials in late 2013 and expects to submit applications for regulatory approval in the U.S. for ertugliflozin and the two fixed-dose combination tablets by the end of 2016.
Merck has initiated a Phase 2a trial for MK-8521, an investigational GLP-1/ glucagon receptor co-agonist.
Selected Important Risk Information about JANUVIA® (continued)
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% (0.59 episodes/patient-year) for JANUVIA 100 mg in combination with glimepiride (with or without metformin), 1.8% (0.24 episodes/patient-year) for placebo in combination with glimepiride (with or without metformin), 15.5% (1.06 episodes/patient-year) for JANUVIA 100 mg in combination with insulin (with or without metformin), and 7.8% (0.51 episodes/patient-year) for placebo in combination with insulin (with or without metformin).
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 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.
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA.
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years.
Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or with any other antidiabetic drug.
In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in =5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.
Indications and Limitations of Use for JANUMET® (sitagliptin and metformin HCl) tablets
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 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 JANUMET.
Selected Important Risk Information about JANUMET
Lactic acidosis is a rare but serious complication that can occur because of metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately [see Warnings and Precautions].
JANUMET is contraindicated in patients with renal impairment (serum creatinine levels greater than or equal to 1.5 mg/dL for men and greater than or equal to 1.4 mg/dL for women or abnormal creatinine clearance); hypersensitivity to metformin hydrochloride; acute or chronic metabolic acidosis, including diabetic ketoacidosis; or history of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of JANUMET), such as anaphylaxis or angioedema.
Temporarily discontinue JANUMET in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. Avoid use in patients with hepatic disease. Temporarily discontinue for intercurrent serious conditions, infection, or surgery.
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis.
Before initiation of JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.
When lactic acidosis occurs, it is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient- years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.
Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients =80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiating JANUMET, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET.
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, when receiving JANUMET.
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JANUMET should be temporarily discontinued at the time of or before the procedure, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been re-evaluated and found to be normal.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other antidiabetic drug.
Use With Medications Known to Cause Hypoglycemia
Sitagliptin
When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Therefore, patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.
The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.
Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
Metformin hydrochloride
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but 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 postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 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. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET.
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from 1 day to years.
Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue drug if appropriate.
In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in =5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of =5% included nasopharyngitis for sitagliptin monotherapy and diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache for metformin therapy.
