Merck Receives Complete Response Letter from the U.S. FDA for ZETIA® (ezetimibe) and VYTORIN® (ezetimibe and simvastatin)
February 15, 2016 5:30 pm ET
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that the U.S. Food and Drug Administration (FDA) has
issued a Complete Response Letter regarding Merck’s Supplemental New
Drug Applications for ZETIA® and VYTORIN® for the reduction of the risk
of cardiovascular events (cardiovascular death, nonfatal myocardial
infarction, nonfatal stroke, hospitalization for unstable angina, or
need for revascularization) in patients with coronary heart disease. The
applications were based on the results of IMPROVE-IT (IMProved Reduction
of Outcomes: Vytorin Efficacy International Trial). Merck is reviewing
the letter and will determine next steps.
ZETIA and VYTORIN are indicated for use along with a healthy diet to
reduce elevated LDL cholesterol in patients with hyperlipidemia. The
effect of ZETIA on cardiovascular morbidity and mortality has not been
determined. VYTORIN contains 2 active ingredients: ezetimibe and
simvastatin. No incremental benefit of VYTORIN on cardiovascular
morbidity and mortality over and above that demonstrated for simvastatin
has been established.
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.
ZETIA 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
Selected cautionary information about ZETIA
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.
Because renal impairment is a risk factor for statin-associated
myopathy, doses of simvastatin exceeding 20 mg should be used with
caution and close monitoring when administered concomitantly with ZETIA
in patients with moderate to severe renal impairment (eGFR <60 mL/min/1.73 m2).
ZETIA is not recommended in patients with moderate to severe hepatic
The coadministration of ZETIA (ezetimibe) 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
About VYTORIN® (ezetimibe and simvastatin)
VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated 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
VYTORIN should not be taken with strong CYP3A4 inhibitors; 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
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. Please read Warnings and Precautions in the Prescribing
Information for additional information.
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
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 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 percent. 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
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.
See Dosage and Administration in the Prescribing Information for
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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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