FDA Approves Merck’s LIPTRUZET™ (ezetimibe and atorvastatin), a New Product That Can Help Powerfully Lower LDL Cholesterol
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved LIPTRUZET™ (ezetimibe and atorvastatin) tablets for the
treatment of elevated low-density lipoprotein (LDL) cholesterol in
patients with primary or mixed hyperlipidemia as adjunctive therapy to
diet when diet alone is not enough. LIPTRUZET (pronounced LIP-true-zett)
contains ezetimibe, an efficacious LDL cholesterol lowering therapy, and
atorvastatin, currently one of the most widely prescribed statins in the
U.S.1 Once-daily LIPTRUZET treats two sources of cholesterol
by inhibiting both the absorption of cholesterol in the digestive tract
– through ezetimibe – and the production of cholesterol in the liver –
through atorvastatin.
Liptruzet packaging (Photo: Business Wire)
No incremental benefit of LIPTRUZET on cardiovascular morbidity and
mortality over and above that demonstrated for atorvastatin has been
established.
“A significant percentage of patients are unable to lower their
LDL cholesterol to recommended levels despite treatment,” said Peter H.
Jones, M.D., associate professor of medicine, Baylor College of
Medicine. “Along with a healthy diet, LIPTRUZET (ezetimibe and
atorvastatin) is an effective new lipid-lowering treatment option that
may help address this unmet need as the complementary actions of its
components can provide significant additional LDL lowering beyond
atorvastatin therapy alone.”
Indications, contraindications, and selected dosage and
administration information
LIPTRUZET is indicated as adjunctive therapy to diet for the reduction
of elevated total cholesterol, LDL cholesterol, apolipoprotein B,
triglycerides and non-high-density lipoprotein cholesterol and to
increase high-density lipoprotein (HDL) cholesterol in patients with
primary (heterozygous familial and non-familial) hyperlipidemia or mixed
hyperlipidemia. LIPTRUZET (ezetimibe and atorvastatin) is also indicated
for the reduction of elevated total cholesterol and LDL cholesterol in
patients with homozygous familial hypercholesterolemia (HoFH), as an
adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if
such treatments are unavailable. No incremental benefit of LIPTRUZET on
cardiovascular morbidity and mortality over and above that demonstrated
for atorvastatin has been established.
LIPTRUZET is a prescription medicine and should not be taken by anyone
who has active liver disease or unexplained persistent elevations in
hepatic transaminases or who is hypersensitive to any component of
LIPTRUZET. Women who are pregnant, nursing or who may become pregnant
should not take LIPTRUZET.
LIPTRUZET is available as a once-daily tablet containing 10 mg of
ezetimibe combined with 10, 20, 40, or 80 mg of atorvastatin (LIPTRUZET
10/10, 10/20, 10/40, 10/80 mg, respectively). The dosage range is 10/10
mg/day through 10/80 mg/day.
LIPTRUZET 10/10 and 10/80 mg tablets have been shown to be bioequivalent
to coadministration of corresponding doses of ezetimibe and atorvastatin
tablets.
LIPTRUZET 10/20 and 10/40 mg tablets have been shown to be clinically
equivalent in LDL-C response to the corresponding coadministered doses
of ezetimibe and atorvastatin tablets.
The recommended starting dose of LIPTRUZET is 10/10 mg or 10/20 mg taken
once-daily, or 10/40 mg once-daily for patients who require a larger
reduction in LDL cholesterol (greater than 55 percent). LIPTRUZET can be
taken at any time of day, with or without food.
In a clinical study, LIPTRUZET powerfully lowered LDL cholesterol
across all doses on average by more than 50 percent (53 to 61 percent,
depending on dose)
In a multicenter, double-blind, placebo-controlled clinical study in
which 628 patients with hyperlipidemia were treated for up to 12 weeks,
LIPTRUZET (co-administered as ezetimibe and atorvastatin) provided LDL
cholesterol reductions of 53 percent at the lowest dose (10/10 mg; mean
baseline LDL-C 177 mg/dL), 54 percent at the 10/20 mg dose (mean
baseline LDL-C 184 mg/dL), 56 percent at the 10/40 mg dose (mean
baseline LDL-C 184 mg/dL) and 61 percent at the maximum dose (10/80 mg;
mean baseline LDL-C 183 mg/dL). Individualization of drug dosage should
be based on therapeutic response.
Pooled across doses, LIPTRUZET reduced LDL cholesterol by a mean 56
percent (mean baseline LDL-C 182 mg/dL) compared with 44 percent for all
atorvastatin doses pooled (mean baseline LDL-C 181 mg/dL); p< 0.01. The
LDL cholesterol reductions seen by atorvastatin dose were 37 percent at
10 mg (mean baseline LDL-C 185 mg/dL), 42 percent at 20 mg (mean
baseline LDL-C 177 mg/dL), 45 percent at 40 mg (mean baseline LDL-C 180
mg/dL) and 54 percent at 80 mg (mean baseline LDL-C 184 mg/dL). The
clinical impact of comparative differences in lipid changes between
LIPTRUZET (ezetimibe and atorvastatin) and atorvastatin is not known.
In two separate clinical studies, LIPTRUZET 10/40 mg and 10/20 mg
provided significantly greater LDL cholesterol reductions and helped
more patients get to target LDL cholesterol levels (< 70 mg/dL or < 100
mg/dL) compared to doubling the dose of atorvastatin to 80 mg or 40 mg,
respectively
In a six-week study, 556 high risk patients taking atorvastatin 40 mg
but not at LDL cholesterol < 70 mg/dL were randomized to either
LIPTRUZET 10/40 mg coadministered as ezetimibe and atorvastatin (n =
277; mean baseline LDL-C 89 mg/dL) or atorvastatin 80 mg (n= 279; mean
baseline LDL-C 90 mg/dL). Results showed that LIPTRUZET 10/40 mg further
lowered LDL cholesterol by an average of 27 percent compared to 11
percent when titrating to atorvastatin 80 mg (p<0.05).This greater
additional LDL cholesterol reduction resulted in 74 percent of patients
achieving LDL cholesterol <70 mg/dL as compared to 32 percent of
patients taking atorvastatin 80 mg.
In a separate six-week study, 184 moderately-high risk patients taking
atorvastatin 20 mg but not at LDL cholesterol < 100 mg/dL were
randomized to either LIPTRUZET 10/20 mg coadministered as ezetimibe and
atorvastatin (n = 92; mean baseline LDL-C 120 mg/dL) or atorvastatin 40
mg (n = 92; mean baseline LDL-C 118 mg/dL). Results showed that
LIPTRUZET 10/20 mg further lowered LDL cholesterol by an average of 31
percent compared to 11 percent when titrating to atorvastatin 40 mg
(p<0.05). This greater additional LDL cholesterol reduction resulted in
84 percent of patients treated with LIPTRUZET 10/20 mg achieving LDL
cholesterol <100 mg/dL as compared to 49 percent of patients taking
atorvastatin 40 mg.
Selected cautionary information for LIPTRUZET
LIPTRUZET contains atorvastatin, which occasionally causes myopathy
defined as muscle aches or muscle weakness with increases in creatine
phosphokinase (CPK) values above 10 times the upper limit of normal.
Rare cases of rhabdomyolysis with acute renal failure secondary to
myoglobinuria have been reported with atorvastatin and other statins. A
history of renal impairment may be a risk factor for the development of
rhabdomyolysis. Such patients merit closer monitoring. Other
predisposing factors for myopathy include advanced age (≥65 years) and
hypothyroidism.
All patients starting therapy with LIPTRUZET should be advised of the
risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness, or weakness, particularly if accompanied by malaise or
fever or if muscle signs or symptoms persist after discontinuing
LIPTRUZET (ezetimibe and atorvastatin).Therapy should be discontinued
immediately if markedly elevated CPK levels occur or if myopathy is
diagnosed or suspected.
The concomitant use of higher doses of atorvastatin with certain drugs
such as cyclosporine and strong CYP3A4 inhibitors increases the risk of
myopathy/rhabdomyolysis. This includes an increased risk of myopathy
when used with fibric acid derivatives, erythromycin, clarithromycin,
hepatitis C protease inhibitors, combinations of HIV protease
inhibitors, niacin, or azole antifungals. Physicians should carefully
weigh the potential benefits and risks of combined therapy with any of
these drugs, consider lower doses of LIPTRUZET, and carefully monitor
patients for signs and symptoms of myopathy early during therapy and
when titrating the dose of either drug.
Avoid LIPTRUZET with cyclosporine, tipranavir plus ritonavir,
telaprevir, or gemfibrozil. Use caution when prescribing LIPTRUZET with
a fenofibrate, and immediately discontinue both drugs if myopathy if
diagnosed or suspected. Cases of myopathy, including rhabdomyolysis,
have been reported with atorvastatin coadministered with colchicine, and
caution should be used when prescribing LIPTRUZET with colchicine.
The dose of LIPTRUZET should not exceed 10/20 mg daily in patients
receiving clarithromycin, itraconazole, saquinavir plus ritonavir,
darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus
ritonavir, and 10/40 mg daily in patients receiving nelfinavir or
boceprevir. Physicians should use caution and the lowest dose necessary
with lopinavir plus ritonavir or saquinavir plus ritonavir.
Persistent elevations in hepatic transaminase can occur. Liver enzyme
tests should be performed prior to treatment initiation and thereafter
when clinically indicated. If serious liver injury with clinical
symptoms and/or hyperbilirubinemia or jaundice occurs during treatment,
promptly interrupt therapy and do not restart unless an alternate
etiology is found.
Increases in HbA1c and fasting serum glucose levels have been reported
with statins, including atorvastatin.
In a post-hoc analysis of a study in patients without coronary heart
disease who had a stroke or transient ischemic attack within the
preceding six months, a higher incidence of hemorrhagic stroke was seen
in the atorvastatin 80 mg group compared to placebo. Some baseline
characteristics, including hemorrhagic and lacunar stroke on study
entry, were associated with a higher incidence of hemorrhagic stroke in
the atorvastatin group.
In a clinical trial of LIPTRUZET, the most commonly reported side
effects, regardless of cause, included increased alanine transaminase
(ALT) (5 percent), increased aspartate transaminase (AST) (4 percent),
and musculoskeletal pain (4 percent).
Availability
LIPTRUZET (ezetimibe and atorvastatin) will be available for wholesalers
to order the week of May 6.
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.
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consumer care and animal health products, we work with customers 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. These statements are based
upon the current beliefs and expectations of Merck’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
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including obtaining regulatory approval; Merck ability to accurately
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Merck undertakes no obligation to publicly update any forward-looking
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materially from those described in the forward-looking statements can be
found in Merck’s 2012 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 accompanying prescribing information for
LIPTRUZET™(ezetimibe and atorvastatin) Tablets at http://www.merck.com/product/usa/pi_circulars/l/liptruzet/liptruzet_pi.pdf
and patient information for LIPTRUZET™(ezetimibe and atorvastatin)
Tablets at http://www.merck.com/product/usa/pi_circulars/l/liptruzet/liptruzet_ppi.pdf.
1 This information is an estimate derived from a custom study
of the retail market performed for Merck using IMS Health LifeLink ™
data for the period February 2013. IMS expressly reserves all rights,
including rights of copying, distribution and republication.
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