Further Analyses on the Long-Term Safety and
Efficacy of VYTORIN® from the IMPROVE-IT Study Presented at the
European Society of Cardiology (ESC) Meeting
Merck (NYSE:MRK), known as MSD in the United States and Canada,
today announced results from new analyses from the IMPROVE-IT
study.
“IMPROVE-IT presents us with the opportunity to look at
cardiovascular outcomes data for patients treated with the
combination of simvastatin and ezetimibe (VYTORIN) and allows us to
look at the important aspect of long-term safety and efficacy under
controlled conditions,” said Dr. Michael A. Blazing, Duke
Department of Medicine.
VYTORIN (ezetimibe and simvastatin) and ZETIA (ezetimibe) are
currently indicated for use along with a healthy diet to reduce
elevated LDL cholesterol in patients with hyperlipidemia. The
current U.S. Prescribing Information for both products states that
the effect of ezetimibe on cardiovascular morbidity and mortality,
alone or incremental to statin therapy, has not been determined.
Merck has submitted the data from the IMPROVE-IT study to the U.S.
Food and Drug Administration to support a new indication for
reduction of cardiovascular events for ZETIA and VYTORIN.
Incidence of New Onset Diabetes in the IMPROVE-IT Trial: Does
Adding Ezetimibe to Simvastatin Increase Risk Compared to
Simvastatin Alone?
The results of one of the analyses presented at ESC showed that
patients treated with VYTORIN® – which combines simvastatin with
the non-statin ZETIA® - showed a similar risk of new onset diabetes
mellitus (DM) compared to simvastatin alone over a period of
>5.5 years median follow-up. During the trial, 1,414 patients
(13.3% of those without diabetes at enrollment) developed new onset
DM defined as initiation of a diabetes medication or two
consecutive fasting glucose levels ≥7 mmol/L (126 mg/dL). Of the
new onset DM cases, 50.9% occurred in the VYTORIN (ezetimibe and
simvastatin) arm and 49.1% in the simvastatin arm (hazard ratio
1.04; 95% CI 0.94-1.15).
Safety and Efficacy of Long-term Very Low Achieved LDL-C in
the IMPROVE-IT Trial
This post-hoc analysis compared safety and efficacy data during
the median six years follow-up in patients stratified by achieved
LDL-C at month one of the trial. This analysis assessed patients
achieving LDL-C levels <30 mg/dL, 30 - <50 mg/dL, 50 - <70
mg/dL and ≥70 mg/dL at month one of the trial. The nine selected
safety events of special interest, which included hemorrhagic
stroke and adverse events leading to treatment discontinuation,
showed similar rates in patients with LDL-C <30 mg/dL at month
one (achieved by 6% of patients) compared with patients with higher
achieved LDL-C levels. For a complete list of all the safety
parameters analyzed please visit the ESC website. In addition, this
analysis concluded that cardiovascular events occurred less
frequently in patients who achieved an LDL-C level <70 mg/dL at
month 1 of the trial compared with LDL-C levels ≥70 mg/dL.
Achievement of Dual LDL-C (<70 mg/dL) and hs-CRP (<2
mg/L) Goals More Frequent with Addition of Ezetimibe and Associated
with Better Outcomes in IMPROVE-IT
Additional evidence relating to the efficacy of VYTORIN comes
from another IMPROVE-IT analysis, which assessed outcomes in
subjects achieving specific levels of LDL-C and high sensitivity
C-reactive protein (hs-CRP). CRP levels, a marker of inflammation,
are associated with a higher cardiovascular risk in some settings.
This analysis showed that patients achieving both LDL-C <70
mg/dL and hs-CRP <2 mg/L at one month had a lower rate of the
primary composite endpoint of major CV events over the course of
the trial compared with patients not achieving either level.
Significantly more patients treated with VYTORIN met these
specified dual levels at month one compared to patients treated
with simvastatin alone (50% vs 29%, p<0.001).
About the IMPROVE-IT Trial
IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy
International Trial) was led by the Thrombolysis In Myocardial
Infarction (TIMI) Study Group of Brigham and Women’s Hospital and
the Duke Clinical Research Institute (DCRI) and was sponsored by
Merck. IMPROVE-IT was an international, multi-center, randomized,
double-blind, active comparator trial of 18,144 high-risk patients
presenting with acute coronary syndromes (ACS), including unstable
angina (UA), non-ST-segment elevation acute myocardial infarction
(NSTEMI) and ST-segment elevation acute myocardial infarction
(STEMI). The study assessed the incidence of major CV events, as
measured by a composite of CV death, non-fatal MI, non-fatal
stroke, re-hospitalization for ACS or coronary revascularization
(occurring 30 days or more after the initial event), in patients
treated with ezetimibe/simvastatin (VYTORIN) compared with patients
treated with simvastatin alone.
All patients in the trial were started at doses of ezetimibe and
simvastatin 10/40 mg or simvastatin 40 mg. Prior to a 2011 protocol
amendment, the dose could be titrated to ezetimibe/simvastatin
10/80 mg or simvastatin 80 mg if successive LDL-C values exceeded
79 mg/dL. The study enrolled patients within 10 days of ACS
hospitalization who had sufficient risk as defined in the protocol
and who had an initial LDL-C of ≤125 mg/dL if lipid-lowering drug
naïve or <100 mg/dL if on a prior prescription lipid-lowering
therapy identified as no more potent than simvastatin 40 mg/day.
The LDL-C entry limitations were designed to enroll patients
reasonably anticipated to achieve LDL-C levels of 70 mg/dL or less
in the simvastatin only cohort, which was the optional recommended
target set in the 2004 update to the Adult Treatment Panel (ATP)
III guidelines.
About VYTORIN® (ezetimibe and simvastatin)
VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated
as adjunctive therapy to diet for the reduction of elevated total
cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and
non–HDL cholesterol, and to increase HDL cholesterol in patients
with primary (heterozygous familial and nonfamilial) hyperlipidemia
or mixed hyperlipidemia when diet alone is not enough.
The Prescribing Information for VYTORIN states that no
incremental benefit of VYTORIN on cardiovascular morbidity and
mortality over and above that demonstrated for simvastatin has been
established. VYTORIN is not indicated to reduce cardiovascular
events in patients who have presented with acute coronary
syndromes.
VYTORIN (ezetimibe and simvastatin) should not be taken with
strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,
posaconazole, voriconazole, HIV protease inhibitors, boceprevir,
telaprevir, erythromycin, clarithromycin, telithromycin,
nefazodone, and cobicistat-containing products); or with
gemfibrozil, cyclosporine, or danazol. VYTORIN also should not be
taken by anyone with active liver disease, unexplained persistent
elevations of hepatic transaminase levels, or hypersensitivity to
the product; or by women who are pregnant, nursing or may become
pregnant.
Selected Cautionary Information About VYTORIN (ezetimibe and
simvastatin)
All patients starting therapy with VYTORIN, or whose dose of
VYTORIN is being increased, should be advised of the risk of
myopathy, including rhabdomyolysis, and told to promptly report any
unexplained muscle pain, tenderness, or weakness particularly if
accompanied by malaise or fever or if muscle signs and symptoms
persist after discontinuing VYTORIN. VYTORIN should be discontinued
immediately if markedly elevated creatine kinase (CK) levels occur
or myopathy is diagnosed or suspected. VYTORIN contains
simvastatin, which occasionally causes myopathy manifested as
muscle pain, tenderness, or weakness with CK levels above 10 times
ULN. Myopathy sometimes takes the form of rhabdomyolysis with or
without acute renal failure secondary to myoglobinuria, and rare
fatalities have occurred. Predisposing factors for myopathy include
advanced age (≥65 years), female gender, uncontrolled
hypothyroidism, and renal impairment. The risk of myopathy,
including rhabdomyolysis, is dose related.
The 10/80 mg dose of VYTORIN should not be started in new
patients. The risk of myopathy, including rhabdomyolysis, is
greater in patients taking simvastatin 80 mg compared with other
statin therapies with similar or greater LDL cholesterol lowering
efficacy, and with lower doses of simvastatin. The 10/80 mg dose of
VYTORIN should be used only in patients who have been taking that
dose chronically (e.g., for 12 months or more) without evidence of
muscle toxicity. If a patient who is currently tolerating the 10/80
mg dose needs to be initiated on an interacting drug that is
contraindicated or is associated with a dose cap for simvastatin,
that patient should be switched to an alternative statin or
statin-based regimen with less potential for the drug-drug
interaction. Please read Warnings and Precautions in the
Prescribing Information for additional information.
In addition to drugs that are contraindicated because of an
increased risk of myopathy/rhabdomyolysis, grapefruit juice should
be avoided. Use caution when prescribing VYTORIN with a
fenofibrate, and immediately discontinue both drugs if myopathy is
diagnosed or suspected. Cases of myopathy, including
rhabdomyolysis, have been reported with simvastatin coadministered
with colchicine, and caution should be used when prescribing
VYTORIN (ezetimibe and simvastatin) with colchicine.
The dose of VYTORIN should not exceed 10/10 mg daily in patients
receiving verapamil, diltiazem or dronedarone, and 10/20 mg daily
in patients receiving amiodarone, amlodipine or ranolazine. For
patients with homozygous familial hypercholesterolemia (HoFH)
taking lomitapide, the dose should not exceed 10/20 mg/day (or
10/40 mg/day for patients who have previously taken simvastatin 80
mg/day chronically, e.g., for 12 months or more, without evidence
of muscle toxicity); patients initiating lomitapide should have
their dose of VYTORIN (ezetimibe and simvastatin) reduced by 50%.
The benefits of combined use of VYTORIN with these drugs, other
fenofibrates, or niacin (≥1 g/day) should be carefully weighed
against the potential risk of myopathy/rhabdomyolysis. Caution
should be used when Chinese patients taking niacin (≥1 g/day) are
coadministered doses of VYTORIN exceeding 10/20 mg/day; Chinese
patients should not receive VYTORIN 10/80 mg with niacin.
Persistent elevations in hepatic transaminase can occur. Liver
function tests should be performed at treatment initiation and
thereafter when clinically indicated. If serious liver injury with
clinical symptoms and/or hyperbilirubinemia or jaundice occurs
during treatment, therapy should be interrupted promptly and not
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, the most commonly reported side effects,
regardless of cause, included headache (5.8 percent), increased ALT
(3.7 percent), myalgia (3.6 percent), upper respiratory tract
infection (3.6 percent), and diarrhea (2.8 percent).
VYTORIN tablets contain ezetimibe and simvastatin: 10 mg of
ezetimibe and 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10,
10/20, 10/40, or 10/80 mg, respectively). The usual dosage range is
10/10 mg/day to 10/40 mg/day; patients should not be titrated to
the restricted 10/80-mg dose.
About ZETIA® (ezetimibe)
ZETIA, administered alone or in combination with a statin, is
indicated as adjunctive therapy to diet for the reduction of
elevated total cholesterol, LDL cholesterol, apolipoprotein B, and
non-HDL cholesterol in patients with primary (heterozygous familial
and non-familial) hyperlipidemia when diet alone is not enough.
The Prescribing Information for ZETIA states that the effect of
ZETIA on cardiovascular morbidity and mortality has not been
determined. ZETIA is not indicated for use with a statin to further
reduce cardiovascular events in patients who have presented with
acute coronary syndromes.
ZETIA (ezetimibe) should not be taken by people with
hypersensitivity to any component of the medication. Statin
contraindications also apply when ZETIA is used with these drugs:
statins are contraindicated in patients with active liver disease,
unexplained persistent elevations in hepatic transaminase levels
and in pregnant and nursing women. Refer to individual statin
labels for details about who should not take that statin.
Selected Cautionary Information About ZETIA
(ezetimibe)
When using ZETIA with a statin, also follow the label
recommendations for that specific statin.
When ZETIA was coadministered with a statin, consecutive
elevations in hepatic transaminase levels (greater than or equal to
3 times ULN) were slightly higher (1.3 percent) than those of
statins alone (0.4 percent). Liver function tests should be
performed when ZETIA is added to statin therapy and according to
statin recommendations. Should an increase in ALT or AST greater
than or equal to 3 times ULN persist, consider withdrawal of ZETIA
and/or the statin.
Patients should be advised to promptly report muscle pain,
tenderness, or weakness. Risk for skeletal muscle toxicity
increases with higher statin doses, advanced age (>65),
hypothyroidism, renal impairment, and depending on the statin used,
concomitant use of other drugs. Discontinue drug if myopathy is
diagnosed or suspected.
ZETIA is not recommended in patients with moderate to severe
hepatic impairment.
The coadministration of ZETIA with fibrates other than
fenofibrate is not recommended until use in patients is adequately
studied. Exercise caution when using ZETIA and cyclosporine
concomitantly because exposure to both drugs is increased.
Cyclosporine concentrations should be monitored in these
patients.
ZETIA should be used in pregnant or nursing women only if the
benefit outweighs the risk.
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 vs 3.3
percent), myalgia (3.2 percent vs 2.7 percent), upper respiratory
tract infection (2.9 percent vs 2.8 percent), arthralgia (2.6
percent vs 2.4 percent), and diarrhea (2.5 percent vs 2.2 percent);
for ZETIA administered alone vs placebo: upper respiratory tract
infection (4.3 percent vs 2.5 percent), diarrhea (4.1 percent vs
3.7 percent), arthralgia (3.0 percent vs 2.2 percent), sinusitis
(2.8 percent vs 2.2 percent), pain in extremity (2.7 percent vs 2.5
percent), and fatigue (2.4 percent vs 1.5 percent).
Additional Information About the IMPROVE-IT Trial
IMPROVE-IT was a multi-center, randomized, double-blind active
comparator trial of 18,144 high-risk patients presenting with acute
coronary syndromes (ACS), including unstable angina (UA),
non-ST-segment elevation acute myocardial infarction (NSTEMI) and
ST-segment elevation acute myocardial infarction (STEMI). Patients
were randomized to receive ezetimibe and simvastatin (VYTORIN) or
simvastatin alone, and were followed for up to nine years, with a
median clinical follow-up of approximately six years. The primary
efficacy endpoint was the composite of cardiovascular death,
non-fatal MI, non-fatal stroke, re-hospitalization for ACS or
coronary revascularization (occurring 30 days or more after the
initial event).
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 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 connect
with us on Twitter, Facebook and YouTube.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J, USA
This news release of Merck & Co., Inc., Kenilworth, NJ, 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 healthcare
legislation in the United States and internationally; global trends
toward healthcare 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 2014
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 and simvastatin) at
http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf
and the Patient Information for VYTORIN at
http://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 the Patient Information for ZETIA at
http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_ppi.pdf.
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For MerckMedia:Pamela Eisele, 267-305-3558orMichael Close,
267-305-1211orInvestors:Justin Holko, 908-740-1879
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