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April 7, 2017 6:30 am ET

Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
issued a Complete Response Letter regarding Merck’s Supplemental New
Drug Applications for JANUVIA^® (sitagliptin), JANUMET^®
(sitagliptin and metformin HCl) and JANUMET XR^® (sitagliptin
and metformin HCl extended-release). With these applications, Merck is
seeking to include data from TECOS (Trial Evaluating Cardiovascular
Outcomes with Sitagliptin) in the prescribing information of
sitagliptin-containing medicines. Merck is reviewing the letter and will
discuss next steps with the FDA.

Important Information about 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.

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.

Postmarketing cases of bullous pemphigoid requiring hospitalization have
been reported with DPP-4 inhibitor use. In reported cases, patients
typically recovered with topical or systemic immunosuppressive treatment
and discontinuation of the DPP-4 inhibitor. Tell patients to report
development of blisters or erosions while receiving JANUVIA. If bullous
pemphigoid is suspected, JANUVIA should be discontinued and referral to
a dermatologist should be considered for diagnosis and appropriate
treatment.

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.

Important Information about JANUMET

^®


(sitagliptin and metformin HCl) 50/500 mg and 50/1000 mg tablets and
JANUMET

^®

XR (sitagliptin and metformin HCl
extended-release) 50/500 mg, 500/1000 mg and 100/1000 mg 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 XR 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 extended-release is appropriate.

JANUMET or JANUMET XR should not be used in patients with type 1
diabetes or for the treatment of diabetic ketoacidosis.

JANUMET or JANUMET XR 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 or JANUMET XR.

Selected Important Risk Information about JANUMET

^®


and JANUMET

^®

XR

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have
resulted in death, hypothermia, hypotension, and resistant
bradyarrhythmias. The onset of metformin-associated lactic acidosis is
often subtle, accompanied only by nonspecific symptoms such as malaise,
myalgias, respiratory distress, somnolence, and abdominal pain.
Metformin-associated lactic acidosis was characterized by elevated blood
lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of
ketonuria or ketonemia), an increased lactate/pyruvate ratio, and
metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal
impairment, concomitant use of certain drugs (e.g., carbonic anhydrase
inhibitors such as topiramate), age 65 years old or greater, having a
radiological study with contrast, surgery and other procedures, hypoxic
states (e.g., acute congestive heart failure), excessive alcohol intake,
and hepatic impairment.

If metformin-associated lactic acidosis is suspected, immediately
discontinue JANUMET or JANUMET XR and institute general supportive
measures in a hospital setting. Prompt hemodialysis is recommended.

JANUMET and JANUMET XR are contraindicated in patients with severe renal
impairment (estimated glomerular filtration rate [eGFR] below 30
mL/min/1.73 m²); hypersensitivity to metformin hydrochloride;
acute or chronic metabolic acidosis, including diabetic ketoacidosis; or
history of a serious hypersensitivity reaction to JANUMET, JANUMET XR,
or sitagliptin, such as anaphylaxis or angioedema.

Postmarketing metformin-associated lactic acidosis cases primarily
occurred in patients with significant renal impairment. The risk of
metformin accumulation and metformin-associated lactic acidosis
increases with the severity of renal impairment because metformin is
substantially excreted by the kidney.

JANUMET: Before initiating JANUMET, obtain an eGFR. JANUMET is
contraindicated in patients with an eGFR below 30 mL/min/1.73 m².
JANUMET is not recommended in patients with an eGFR between 30 and <45
mL/min/1.73 m² because these patients require a lower dosage
of sitagliptin than what is available in the fixed combination product
of JANUMET. Obtain an eGFR at least annually in all patients taking
JANUMET. In patients at increased risk for the development of renal
impairment (e.g., the elderly), renal function should be assessed more
frequently.

JANUMET XR: Before initiating JANUMET XR, obtain an eGFR. JANUMET XR is
contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².
Discontinue JANUMET XR if the patient’s eGFR later falls below 30
mL/min/1.73 m². Initiation of JANUMET XR is not recommended
in patients with an eGFR between 30 and 45 mL/min/1.73 m². In
patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m²,
assess the benefit and risk of continuing therapy. Obtain an eGFR at
least annually in all patients taking JANUMET XR. In patients at
increased risk for the development of renal impairment (e.g., the
elderly), renal function should be assessed more frequently.

The concomitant use of JANUMET or JANUMET XR with specific drugs may
increase the risk of metformin-associated lactic acidosis: those that
impair renal function, result in significant hemodynamic change,
interfere with acid-base balance, or increase metformin accumulation.
Consider more frequent monitoring of patients.

The risk of metformin-associated lactic acidosis increases with the
patient’s age because elderly patients have a greater likelihood of
having hepatic, renal, or cardiac impairment than younger patients.
Assess renal function more frequently in elderly patients.

Administration of intravascular iodinated contrast agents in
metformin-treated patients has led to an acute decrease in renal
function and the occurrence of lactic acidosis. Stop JANUMET or JANUMET
XR at the time of, or prior to, an iodinated contrast imaging procedure
in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in
patients with a history of hepatic impairment, alcoholism, or heart
failure; or in patients who will be administered intra-arterial
iodinated contrast. Re-evaluate eGFR 48 hours after the imaging
procedure; restart JANUMET or JANUMET XR if renal function is stable.

Withholding of food and fluids during surgical or other procedures may
increase the risk for volume depletion, hypotension, and renal
impairment. JANUMET or JANUMET XR should be temporarily discontinued
while patients have restricted food and fluid intake.

Postmarketing cases of metformin-associated lactic acidosis have
occurred in the setting of acute congestive heart failure (particularly
when accompanied by hypoperfusion and hypoxemia). Cardiovascular
collapse (shock), acute myocardial infarction, sepsis, and other
conditions associated with hypoxemia have been associated with lactic
acidosis and may also cause prerenal azotemia. Discontinue JANUMET or
JANUMET XR if this occurs.

Alcohol potentiates the effect of metformin on lactate metabolism and
this may increase the risk of metformin-associated lactic acidosis. Warn
patients against excessive alcohol intake while receiving JANUMET or
JANUMET XR.

Patients with hepatic impairment have developed metformin-associated
lactic acidosis. This may be due to impaired lactate clearance resulting
in higher lactate blood levels. Avoid using JANUMET or JANUMET XR in
patients with clinical or laboratory evidence of hepatic disease.

There have been postmarketing reports of acute pancreatitis, including
fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients
taking sitagliptin with or without metformin. After initiating JANUMET
or JANUMET XR, observe patients carefully for signs and symptoms of
pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET
or JANUMET XR and initiate appropriate management. It is unknown whether
patients with a history of pancreatitis are at increased risk of
developing pancreatitis while taking JANUMET or JANUMET XR.

There have been postmarketing reports of worsening renal function in
patients taking sitagliptin with or without metformin, including acute
renal failure, sometimes requiring dialysis. Before initiating JANUMET
or JANUMET XR and at least annually thereafter, renal function should be
assessed. In patients in whom development of renal dysfunction is
anticipated, particularly in elderly patients, renal function should be
assessed more frequently and JANUMET or JANUMET XR discontinued if
evidence of renal impairment is present.

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. Patients also receiving insulin or an insulin
secretagogue (e.g., 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.

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 and JANUMET XR, such as anaphylaxis, angioedema, and exfoliative
skin conditions including Stevens-Johnson syndrome. Onset of these
reactions occurred within the first 3 months after initiating
sitagliptin, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue JANUMET or JANUMET
XR, assess for other potential causes for the event, and institute
alternative diabetes treatment.

Angioedema has also been reported with other dipeptidyl peptidase-4
(DPP-4) inhibitors. Use caution in a patient with a history of
angioedema to another DPP-4 inhibitor because it is unknown whether such
patients will be predisposed to angioedema with JANUMET or JANUMET XR.

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.

Postmarketing cases of bullous pemphigoid requiring hospitalization have
been reported with DPP-4 inhibitor use. In reported cases, patients
typically recovered with topical or systemic immunosuppressive treatment
and discontinuation of the DPP-4 inhibitor. Tell patients to report
development of blisters or erosions while receiving JANUMET or JANUMET
XR. If bullous pemphigoid is suspected, JANUMET or JANUMET XR should be
discontinued and referral to a dermatologist should be considered for
diagnosis and appropriate treatment.

There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with JANUMET or JANUMET XR or any other
antidiabetic drug.

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 hypoglycemia (13.7% vs 4.9%), diarrhea
(12.5% vs 5.6%), and nausea (6.7% vs 4.2%) for extended-release
metformin vs placebo when added to glyburide. Other adverse events with
an incidence of ≥5% included diarrhea, nausea/vomiting, flatulence,
abdominal discomfort, indigestion, asthenia, and headache for metformin
immediate release.

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%).

About Merck

For over a century, Merck has been a global health care leader working
to help the world be well. Merck is known as MSD outside the United
States and Canada. Through our prescription medicines, vaccines,
biologic therapies, and animal health products, we work with customers
and operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
health care through far-reaching policies, programs and partnerships.
For more information, visit www.merck.com
and connect with us on Twitter,
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and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the
“company”) includes “forward-looking statements” within the meaning of
the safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. These statements are based upon the current beliefs
and expectations of the company’s management and are subject to
significant risks and uncertainties. If underlying assumptions prove
inaccurate or risks or uncertainties materialize, actual results may
differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation in the
United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; the company’s ability to
accurately predict future market conditions; manufacturing difficulties
or delays; financial instability of international economies and
sovereign risk; dependence on the effectiveness of the company’s patents
and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause results
to differ materially from those described in the forward-looking
statements can be found in the company’s 2016 Annual Report on Form 10-K
and the company’s other filings with the Securities and Exchange
Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for JANUVIA

^®


(sitagliptin) at

http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf


and Medication Guide for JANUVIA at

http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_mg.pdf

Please see Prescribing Information for JANUMET

^®


(sitagliptin and metformin HCl), including the Boxed Warning about
lactic acidosis, at

http://www.merck.com/product/usa/pi_circulars/j/janumet/janumet_pi.pdf

and Medication Guide for JANUMET at

http://www.merck.com/product/usa/pi_circulars/j/janumet/janumet_mg.pdf

Please see Prescribing Information for JANUMET XR

^®


(sitagliptin and metformin HCl extended-release), including the Boxed
Warning about lactic acidosis, at


http://www.merck.com/product/usa/pi_circulars/j/janumet_xr/janumet_xr_pi.pdf


and Medication Guide for JANUMET XR at

http://www.merck.com/product/usa/pi_circulars/j/janumet_xr/janumet_xr_mg.pdf

Merck
Media:
Pamela Eisele, 267-305-3558
or
Kristen Drake, 908-236-4223
or
Investors:
Amy Klug, 908-740-1898