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, Facebook, YouTube 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
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MerckMedia:Pamela Eisele, 267-305-3558orKristen Drake,
908-236-4223orInvestors:Amy Klug, 908-740-1898
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