Published: November 02, 2011
FDA Advisory Committee Unanimously Recommends Approval of Merck's VYTORIN (ezetimibe/simvastatin) for Use in Patients with Pre-Dialysis Chronic Kidney Disease
WHITEHOUSE STATION, N.J. - (BUSINESS WIRE) - Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that the Endocrinologic and Metabolic Drugs Advisory
Committee of the U.S. Food and Drug Administration (FDA) unanimously
voted to recommend approval of Merck's VYTORIN
(ezetimibe/simvastatin) for use in patients with pre-dialysis chronic
kidney disease. The Committee's vote was mixed (with the majority not in
favor) regarding whether there is sufficient evidence to support
approval specifically for patients with end-stage renal disease who are
receiving dialysis. Merck is seeking indications for VYTORIN and for
ZETIA (ezetimibe) in combination with simvastatin to reduce
the risk of major cardiovascular events in patients with chronic kidney
disease based on the results of the Study of Heart and
Renal Protection (SHARP) trial. Neither product is
currently indicated for this use.
The Committee's recommendation will be considered by the FDA in its
assessment of these investigational uses for VYTORIN and ZETIA. The FDA
is not bound by the Committee's guidance, but takes its advice into
account. Merck plans to discuss the results of today's Advisory
Committee meeting with the FDA in the near future. Currently, the
Company's supplemental new drug applications remain under review, with
agency action expected in the first quarter of 2012.
"We are pleased with the panel's recommendation and will continue
working with the FDA on its evaluation of the proposed new indications
for VYTORIN and ZETIA. If approved for these uses, these medicines have
the potential to help to address a significant, unmet need among people
with chronic kidney disease," said Peter S. Kim, Ph.D., president, Merck
Research Laboratories. "The Advisory Committee vote brings VYTORIN and
ZETIA one step closer to being an option for these patients who are at
increased risk for cardiovascular events and procedures, such as heart
attacks, strokes and certain types of heart surgery."
The Committee reviewed the results of SHARP, which involved more than
9,000 patients, about two-thirds of whom were pre-dialysis and one-third
was undergoing dialysis at study entry. SHARP studied the effect of the
ezetimibe/simvastatin 10/20 mg combination tablet (VYTORIN) compared to
placebo on the occurrence of major cardiovascular events in patients
who, on average, had advanced or end stage chronic kidney disease and
who did not have a history of heart attack or coronary
revascularization, such as heart bypass surgery. The results of SHARP
were published in the June 9 issue of The Lancet.
Important information about VYTORIN (ezetimibe/simvastatin)
VYTORIN contains 2 active ingredients: ezetimibe and simvastatin.
VYTORIN is indicated as adjunctive therapy to diet for the reduction of
total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and
non–HDL cholesterol and to increase HDL-C in patients with primary
(heterozygous familial and nonfamilial) hyperlipidemia or mixed
hyperlipidemia.
VYTORIN is not indicated to reduce major cardiovascular events in
patients with chronic kidney disease. The prescribing information for
VYTORIN currently states that no incremental benefit of VYTORIN on
cardiovascular morbidity and mortality over and above that demonstrated
for simvastatin has been established.
VYTORIN is a prescription medicine and should not be taken with strong
CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole,
erythromycin, clarithromycin, telithromycin, HIV protease inhibitors,
and nefazodone); with gemfibrozil, cyclosporine, or danazol; by anyone
with active liver disease, unexplained persistent elevations of serum
transaminases, or hypersensitivity to the product; or by women who are
of childbearing age (unless highly unlikely to conceive), are nursing or
who are pregnant.
No dosage adjustment is necessary in patients with mild or moderate
renal impairment. Caution should be exercised when VYTORIN is
administered to patients with severe renal insufficiency. VYTORIN should
not be initiated in such patients unless they already have tolerated
treatment with simvastatin.
Selected cautionary information about VYTORIN
Muscle pain, tenderness, or weakness in people taking simvastatin should
be reported to a doctor promptly because these could be signs of a
serious side effect. Simvastatin occasionally causes myopathy manifested
as muscle pain, tenderness, or weakness with creatine phosphokinase (CK)
levels above 10 × ULN. Myopathy sometimes takes the form of
rhabdomyolysis with or without acute renal failure secondary to
myoglobinuria, and rare fatalities have occurred. The risk of myopathy,
including rhabdomyolysis, is dose related. Predisposing factors for
myopathy include advanced age (≥65 years), female gender, uncontrolled
hypothyroidism, and renal impairment. Therapy with VYTORIN should be
discontinued immediately if markedly elevated CK levels occur or
myopathy is diagnosed or suspected. VYTORIN also should be temporarily
withheld in any patient experiencing an acute or serious condition
predisposing to the development of renal failure secondary to
rhabdomyolysis.
The risk of myopathy, including rhabdomyolysis, is greater in patients
taking simvastatin 80 mg compared with other statin therapies with
similar or greater LDL-C-lowering efficacy, and with lower doses of
simvastatin. Patients using VYTORIN 10/80 mg should be advised of this
increased risk. Use of the 10/80 mg dose is restricted.
Because of the increased risk of myopathy/rhabdomyolysis, particularly
at higher doses of simvastatin, concomitant use is contraindicated with
drugs that are strong CYP3A4 inhibitors or with gemfibrozil,
cyclosporine or danazol, and large quantities of grapefruit juice (>1
quart daily) should be avoided. The use of other fibrates with VYTORIN
is not recommended. Use caution when prescribing VYTORIN with
colchicine. The dose of VYTORIN should not exceed 10/10 mg daily in
patients receiving concomitant therapy with verapamil or diltiazem, and
10/20 mg daily in patients receiving amiodarone, amlodipine or
ranolazine. The use of VYTORIN with these drugs, or with lipid-lowering
doses of niacin, should be carefully weighed against the potential risk
of myopathy/rhabdomyolysis with these combinations. Chinese patients
should not receive VYTORIN 10/80 mg daily with niacin (≥1 g/day), and
caution should be used when Chinese patients taking niacin are
co-administered VYTORIN doses exceeding 10/20 mg/day. Adjustment of the
VYTORIN dose may be needed when used with voriconazole. To help avoid
serious side effects, patients should talk to their doctor about
medicine or food they should avoid while taking VYTORIN.
Due to the unknown effects of the increased exposure to ezetimibe in
patients with moderate or severe hepatic impairment, VYTORIN is not
recommended in these patients.
Doctors should perform blood tests to check for liver problems before
treatment and if symptoms of liver problems occur during treatment. In
three placebo-controlled, 12 week trials, the incidence of consecutive
elevations (≥3 × ULN) in serum transaminases was 1.7% overall and
appeared to be dose related, with an incidence of 2.6% for patients
treated with VYTORIN 10/80 mg. In controlled long-term (48-week)
extensions, which included both newly treated and previously treated
patients, the incidence of consecutive elevations (≥3 × ULN) in serum
transaminases was 1.8% overall and 3.6% for patients treated with 10/80
mg. These elevations were generally asymptomatic, not associated with
cholestasis, and reversible whether treatment was maintained or
discontinued.
There have been rare postmarketing reports of fatal and non-fatal
hepatic failure in patients taking statins, including simvastatin. If
serious liver injury with clinical symptoms and/or hyperbilirubinemia or
jaundice occurs during treatment, therapy should be promptly interrupted
and should not be restarted unless an alternate etiology is found.
Increases in HbA1c and fasting serum glucose levels have been reported
with statins, including simvastatin.
In clinical trials of VYTORIN, the most commonly reported side effects,
regardless of cause, included headache (5.8%), increased ALT (3.7%),
myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea
(2.8%).
Selected additional dosage and administration information about
VYTORIN
VYTORIN is available as tablets containing 10 mg of ezetimibe combined
with 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40,
or 10/80 mg, respectively). The recommended usual starting dose is 10/10
mg/day or 10/20 mg/day. Patients who require a larger reduction in LDL-C
(greater than 55%) may be started at 10/40 mg/day. The usual dosage
range is 10/10 mg/day to 10/40 mg/day. Because the 10/80 mg dose of
VYTORIN contains 80 mg of simvastatin, patients should not be titrated
to the 10/80 mg dose. The 10/80 mg dose of VYTORIN should be restricted
to patients who have been taking that dose chronically (eg, for 12
months or more) without evidence of muscle toxicity, and who do not need
to be initiated on an interacting drug that is contraindicated or
associated with a dose cap for simvastatin. See Dosage and
Administration section of Prescribing Information for additional
information.
Important information about ZETIA (ezetimibe)
ZETIA, along with diet, is indicated for use either by itself or
together with statins or fenofibrate in patients with high cholesterol
to reduce total cholesterol, LDL cholesterol, apolipoprotein B, and
non-HDL cholesterol when the response to diet and exercise has been
inadequate.
ZETIA is not indicated for use in reducing major cardiovascular events
in patients with chronic kidney disease. The prescribing information for
ZETIA currently states that its effect on cardiovascular morbidity and
mortality has not been determined.
ZETIA is a prescription medication and should not be taken by people who
are allergic to any of its ingredients. When ZETIA is prescribed with a
statin, it should not be taken by women who are nursing or pregnant or
who may become pregnant, or by anyone with active liver disease. Statins
should not be taken by anyone with these conditions. For people who have
ever had liver problems or are pregnant or nursing, their doctor will
decide if ZETIA is right for them. Refer to statin label for details
about who should not take that statin.
Selected cautionary information about ZETIA
When using ZETIA with a statin, also follow the label recommendations
for that specific statin.
Due to the unknown effects of increased exposure to ZETIA in patients
with moderate or severe hepatic insufficiency, ZETIA is not recommended
in these patients. In clinical trials, there was no increased incidence
of myopathy (muscle pain) or rhabdomyolysis (muscle breakdown)
associated with ZETIA; however myopathy and rhabdomyolysis are known
adverse reactions to statins and other lipid-lowering drugs. There are
no adequate and well-controlled studies of ZETIA in pregnant women.
ZETIA should not be used in pregnant or nursing women unless the benefit
outweighs the potential risks.
Doctors may do blood tests to check the patient's liver before the
patient starts taking ZETIA with a statin, and during treatment
according to the recommendations of the statin. When ZETIA was
co-administered with a statin, consecutive elevations in liver
enzymes,more than three times the upper limit of normal, were slightly
higher than those with the statin alone (1.3 percent vs. 0.4 percent).
These elevations were generally asymptomatic and returned to baseline
after discontinuation of therapy or with continued treatment. When ZETIA
was co-administered with fenofibrate, consecutive elevations in liver
enzymes more than three times the upper limit of normal, were 2.7
percent, and 4.5 percent in patients treated with fenofibrate alone.
Caution should be exercised when initiating ZETIA in patients treated
with cyclosporine, particularly in patients with severe renal
insufficiency, due to increased blood levels of ZETIA.
In clinical trials, regardless of causality assessment, the most
frequent side effects for ZETIA coadministered with a statin versus a
statin alone included nasopharyngitis (3.7 percent versus 3.3 percent),
myalgia (3.2 percent versus 2.7 percent), upper respiratory tract
infection (2.9 percent versus 2.8 percent), arthralgia (2.6 percent
versus 2.4 percent), and diarrhea (2.5 percent versus 2.2 percent); and
for ZETIA administered alone versus placebo: upper respiratory tract
infection (4.3 percent versus 2.5 percent), diarrhea (4.1 percent versus
3.7 percent), arthralgia (3.0 percent versus 2.2 percent), sinusitis
(2.8 percent versus 2.2 percent), pain in extremity (2.7 percent versus
2.5 percent), and fatigue (2.4 percent versus 1.5 percent).
About Merck
Today's Merck is a global healthcare 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
consumer care 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
healthcare through far-reaching policies, programs and partnerships. For
more information, visit www.merck.com and
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Forward-Looking Statement
This news release includes "forward-looking statements" within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. Such statements may include,
but are not limited to, statements about the benefits of the merger
between Merck and Schering-Plough, including future financial and
operating results, the combined company's plans, objectives,
expectations and intentions and other statements that are not historical
facts. Such statements are based upon the current beliefs and
expectations of Merck's management and are subject to significant risks
and uncertainties. Actual results may differ from those set forth in the
forward-looking statements.
The following factors, among others, could cause actual results to
differ from those set forth in the forward-looking statements: the
possibility that the expected synergies from the merger of Merck and
Schering-Plough will not be realized, or will not be realized within the
expected time period; the impact of pharmaceutical industry regulation
and health care legislation; the risk that the businesses will not be
integrated successfully; disruption from the merger making it more
difficult to maintain business and operational relationships; Merck's
ability to accurately predict future market conditions; dependence on
the effectiveness of Merck's patents and other protections for
innovative products; the risk of new and changing regulation and health
policies in the U.S. and internationally and the exposure to litigation
and/or regulatory actions.
Merck 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 Merck's 2010 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 VYTORIN (ezetimibe/simvastatin)
at www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf
and Patient Information for VYTORIN at www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_ppi.pdf.
Please see Prescribing Information for ZETIA (ezetimibe) at http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf
and Patient Information for ZETIA at http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_ppi.pdf.
Merck
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