Following FDA Approval, Agreement will Broaden Access to
Cholesterol-Reducing Medicine
PHILADELPHIA and WHITEHOUSE STATION, N.J., Nov. 26 /PRNewswire/ --
GlaxoSmithKline, Philadelphia, PA, USA (GSK) and Merck & Co., Inc.,
Whitehouse Station, NJ, USA (Merck), announced today that they have entered
into an agreement for over-the-counter (OTC) marketing rights for
MEVACOR(R) (lovastatin). Under the agreement, GSK will have exclusive
rights to market non-prescription MEVACOR in the United States. Terms of
the agreement are confidential but include milestone and royalty payments
from GSK to Merck.
MEVACOR was introduced in the United States in 1987 by Merck as the
first in a class of cholesterol-reducing medicines known as "statins". The
U.S. patent for MEVACOR expired in 2001.
Commenting on the agreement, JP Garnier, chief executive officer,
GlaxoSmithKline said, "This new partnership with Merck will enable GSK to
address the important public health issue of high cholesterol and help
patients better manage their health. OTC Mevacor will be a dynamic new
addition to our fast-growing over-the-counter business and is further
evidence of GSK's ability to partner in new OTC switch opportunities."
"With MEVACOR, Merck pioneered the development of cholesterol-lowering
medicines known as "statins" which are recognized worldwide and remain the
standard of care today," said Richard T. Clark, chief executive officer,
Merck. "We are pleased to be able to partner with GSK as a way to bring
MEVACOR directly to consumers in the United States."
Application for OTC MEVACOR to be reviewed by FDA
The new drug application (NDA) for OTC MEVACOR will be reviewed by the
U.S. Food and Drug Administration (FDA) in a joint meeting of the
Nonprescription Drugs Advisory Committee (NDAC) and the Endocrinologic and
Metabolic Drugs Advisory Committee (EMDAC) on December 13. The NDA, filed
by Merck, is seeking approval of OTC MEVACOR 20 mg taken once daily to help
lower cholesterol. OTC MEVACOR 20 mg is proposed for use in women age 55
and older and men age 45 and older with moderately elevated cholesterol and
one or more heart disease risk factors.
About prescription MEVACOR
MEVACOR is a prescription medicine that is approved in the United
States for the treatment of elevated cholesterol levels that lifestyle
changes alone cannot control and to reduce the risk of first heart attack,
unstable angina and coronary revascularization procedures in healthy men
and women with average or moderately elevated cholesterol levels.
According to the prescribing information, MEVACOR should not be used by
anyone allergic to any of its components, people with liver disease, or by
women who are pregnant, breast-feeding or likely to become pregnant. It is
recommended that liver function tests be performed in all patients prior to
daily use of MEVACOR 40 mg or more.
Muscle pain or weakness in patients taking prescription MEVACOR should
be reported to a doctor because these could be signs of a serious side
effect. Patients should tell their doctors about other medications they are
taking in order to avoid possible drug interactions.
The most common adverse events reported with MEVACOR 20 mg taken once a
day were diarrhea, flatulence, headache and myalgia.
About GSK
GlaxoSmithKline is one of the world's leading research-based
pharmaceutical and healthcare companies and is committed to improving the
quality of human life by enabling people to do more, feel better and live
longer. For more information, visit GlaxoSmithKline at http://www.gsk.com.
Nicorette, NicoDerm CQ and alli trademarks are either owned by and/or
licensed to GSK or associated companies. Xenical is a registered trademark
of the Roche Group.
About GSK Consumer Healthcare
OTC MEVACOR would be marketed in the United States by GSK Consumer
Healthcare, a GSK division with a well-established record of bringing
informed access to OTC medicines.
In 1996, GSK Consumer Healthcare launched the first OTC nicotine
replacement therapies, Nicorette and NicoDerm CQ, together with an
innovative Committed Quitters behavioral support program. Through increased
access to GSK's smoking cessation brands and support, more than five
million adults in the United States have quit smoking.
In 2004, GSK Consumer Healthcare acquired the OTC marketing rights to
orlistat in the United States from the Roche Group (orlistat 120 mg is
marketed as the prescription product Xenical(R) by Roche). In June 2007,
GSK Consumer Healthcare launched alli in the United States, the first
FDA-approved OTC weight control medicine. alli (orlistat 60mg) provides
overweight adults a proven weight loss medicine and a comprehensive,
tailored, behavioral support program.
GSK's education programs provide consumers with information and the
tools to support them through the behavioral modifications that are
essential for their success with OTC medicines and that require long-term
lifestyle changes.
GSK forward-looking statement
Under the safe harbor provisions of the U.S. Private Securities
Litigation Reform Act of 1995, GSK cautions investors that any
forward-looking statements or projections made by GSK, including those made
in this announcement, are subject to risks and uncertainties that may cause
actual results to differ materially from those projected. Factors that may
affect GSK's operations are described under 'Risk Factors' in the Operating
and Financial Review and Prospects in the company's Annual Report on Form
20-F for 2006.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company
dedicated to putting patients first. Established in 1891, Merck currently
discovers, develops, manufactures and markets vaccines and medicines to
address unmet medical needs. The Company devotes extensive efforts to
increase access to medicines through far-reaching programs that not only
donate Merck medicines but help deliver them to the people who need them.
Merck also publishes unbiased health information as a not-for-profit
service. For more information, visit http://www.merck.com.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995. These
statements are based on management's current expectations and involve risks
and uncertainties, which may cause results to differ materially from those
set forth in the statements. The forward-looking statements may include
statements regarding product development, product potential or financial
performance. No forward-looking statement can be guaranteed and actual
results may differ materially from those projected. Merck undertakes no
obligation to publicly update any forward-looking statement, whether as a
result of new information, future events, or otherwise. Forward-looking
statements in this press release should be evaluated together with the many
uncertainties that affect Merck's business, particularly those mentioned in
the risk factors and cautionary statements in Item 1A of Merck's Form 10-K
for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q
and Form 8-K, which the Company incorporates by reference.
Full prescribing information for MEVACOR follows.
TABLETS
MEVACOR(R)
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a
strain of Aspergillus terreus. After oral ingestion, lovastatin, which is
an inactive lactone, is hydrolyzed to the corresponding beta-hydroxyacid
form. This is a principal metabolite and an inhibitor of
3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase. This enzyme
catalyzes the conversion of HMG- CoA to mevalonate, which is an early and
rate limiting step in the biosynthesis of cholesterol.
Lovastatin is [1S-[1alpha(R*),3alpha,7beta,8beta (2S*,4S*), 8abeta]]-
1,2,3,7, 8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-
pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula
of lovastatin is C24H36O5 and its molecular weight is 404.55.
Lovastatin is a white, nonhygroscopic crystalline powder that is
insoluble in water and sparingly soluble in ethanol, methanol, and
acetonitrile.
Tablets MEVACOR are supplied as 20 mg and 40 mg tablets for oral
administration. In addition to the active ingredient lovastatin, each
tablet contains the following inactive ingredients: cellulose, lactose,
magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as
a preservative. Tablets MEVACOR 20 mg also contain FD&C Blue 2 aluminum
lake. Tablets MEVACOR 40 mg also contain D&C Yellow 10 aluminum lake and
FD&C Blue 2 aluminum lake.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in
atherogenesis has been well-documented in clinical and pathological
studies, as well as in many animal experiments. Epidemiological and
clinical studies have established that high LDL-C and low high-density
lipoprotein cholesterol (HDL-C) are both associated with coronary heart
disease. However, the risk of developing coronary heart disease is
continuous and graded over the range of cholesterol levels and many
coronary events do occur in patients with total cholesterol (total-C) and
LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C
concentrations. LDL is formed from very low-density lipoprotein (VLDL) and
is catabolized predominantly by the high affinity LDL receptor. The
mechanism of the LDL-lowering effect of MEVACOR may involve both reduction
of VLDL-C concentration, and induction of the LDL receptor, leading to
reduced production and/or increased catabolism of LDL-C. Apolipoprotein B
also falls substantially during treatment with MEVACOR. Since each LDL
particle contains one molecule of apolipoprotein B, and since little
apolipoprotein B is found in other lipoproteins, this strongly suggests
that MEVACOR does not merely cause cholesterol to be lost from LDL, but
also reduces the concentration of circulating LDL particles. In addition,
MEVACOR can produce increases of variable magnitude in HDL-C, and modestly
reduces VLDL-C and plasma triglycerides (TG) (see Tables I-III under
Clinical Studies). The effects of MEVACOR on Lp(a), fibrinogen, and certain
other independent biochemical risk markers for coronary heart disease are
unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which
catalyzes the conversion of HMG-CoA to mevalonate. The conversion of
HMG-CoA to mevalonate is an early step in the biosynthetic pathway for
cholesterol.
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the
corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase.
Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the beta-hydroxyacid metabolites (active
inhibitors) and, following base hydrolysis, active plus latent inhibitors
(total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the
dose was excreted in urine and 83% in feces. The latter represents absorbed
drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma
concentrations of total radioactivity (lovastatin plus 14C-metabolites)
peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours
postdose. Absorption of lovastatin, estimated relative to an intravenous
reference dose, in each of four animal species tested, averaged about 30%
of an oral dose. In animal studies, after oral dosing, lovastatin had high
selectivity for the liver, where it achieved substantially higher
concentrations than in non- target tissues. Lovastatin undergoes extensive
first-pass extraction in the liver, its primary site of action, with
subsequent excretion of drug equivalents in the bile. As a consequence of
extensive hepatic extraction of lovastatin, the availability of drug to the
general circulation is low and variable. In a single dose study in four
hypercholesterolemic patients, it was estimated that less than 5% of an
oral dose of lovastatin reaches the general circulation as active
inhibitors. Following administration of lovastatin tablets the coefficient
of variation, based on between-subject variability, was approximately 40%
for the area under the curve (AUC) of total inhibitory activity in the
general circulation.
Both lovastatin and its beta-hydroxyacid metabolite are highly bound
(>95%) to human plasma proteins. Animal studies demonstrated that
lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the beta-
hydroxyacid of lovastatin, its 6'-hydroxy derivative, and two additional
metabolites. Peak plasma concentrations of both active and total inhibitors
were attained within 2 to 4 hours of dose administration. While the
recommended therapeutic dose range is 10 to 80 mg/day, linearity of
inhibitory activity in the general circulation was established by a single
dose study employing lovastatin tablet dosages from 60 to as high as 120
mg. With a once- a-day dosing regimen, plasma concentrations of total
inhibitors over a dosing interval achieved a steady state between the
second and third days of therapy and were about 1.5 times those following a
single dose. When lovastatin was given under fasting conditions, plasma
concentrations of total inhibitors were on average about two-thirds those
found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine
clearance 10-30 mL/min), the plasma concentrations of total inhibitors
after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who
received MEVACOR 80 mg/day, the mean plasma level of HMG-CoA reductase
inhibitory activity was increased approximately 45% compared with 18
patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Although the mechanism is not fully understood, cyclosporine has been
shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in
AUC for lovastatin and lovastatin acid is presumably due, in part, to
inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase
inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the
plasma levels of HMG-CoA reductase inhibitory activity and increase the
risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS,
Drug Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see
PRECAUTIONS, Drug Interactions). Grapefruit juice contains one or more
components that inhibit CYP3A4 and can increase the plasma concentrations
of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200 mL
of double-strength grapefruit juice (one can of frozen concentrate diluted
with one rather than 3 cans of water) three times daily for 2 days and an
additional 200 mL double-strength grapefruit juice together with and 30 and
90 minutes following a single dose of 80 mg lovastatin on the third day.
This regimen of grapefruit juice resulted in a mean increase in the serum
concentration of lovastatin and its beta-hydroxyacid metabolite (as
measured by the area under the concentration-time curve) of 15-fold and
5-fold, respectively [as measured using a chemical assay -- high
performance liquid chromatography.] In a second study, 15 subjects consumed
one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive
days and a single dose of 40 mg lovastatin in the evening of the third day.
This regimen of grapefruit juice resulted in a mean increase in the plasma
concentration (as measured by the area under the concentration-time curve)
of active and total HMG-CoA reductase inhibitory activity [using an enzyme
inhibition assay both before (for active inhibitors) and after (for total
inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and
of lovastatin and its beta- hydroxyacid metabolite [measured using a
chemical assay -- liquid chromatography/tandem mass spectrometry --
different from that used in the first** study] of 1.94-fold and 1.57-fold,
respectively. The effect of amounts of grapefruit juice between those used
in these two studies on lovastatin pharmacokinetics has not been studied.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and
LDL- C in heterozygous familial and non-familial forms of primary
hypercholesterolemia and in mixed hyperlipidemia. A marked response was
seen within 2 weeks, and the maximum therapeutic response occurred within
4-6 weeks. The response was maintained during continuation of therapy.
Single daily doses given in the evening were more effective than the same
dose given in the morning, perhaps because cholesterol is synthesized
mainly at night.
In multicenter, double-blind studies in patients with familial or non-
familial hypercholesterolemia, MEVACOR, administered in doses ranging from
10 mg q.p.m. to 40 mg b.i.d., was compared to placebo. MEVACOR consistently
and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and
LDL- C/HDL-C ratio. In addition, MEVACOR produced increases of variable
magnitude in HDL-C, and modestly decreased VLDL-C and plasma TG (see Tables
I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are
presented in Table I.
TABLE I
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
LDL-C/ TOTAL-C/
DOSAGE N TOTAL-C LDL-C HDL-C HDL-C HDL-C TG.
Placebo 33 -2 -1 -1 0 +1 +9
MEVACOR
10 mg q.p.m. 33 -16 -21 +5 -24 -19 -10
20 mg q.p.m. 33 -19 -27 +6 -30 -23 +9
10 mg b.i.d. 32 -19 -28 +8 -33 -25 -7
40 mg q.p.m. 33 -22 -31 +5 -33 -25 -8
20 mg b.i.d. 36 -24 -32 +2 -32 -24 -6
MEVACOR was compared to cholestyramine in a randomized open parallel
study. The study was performed with patients with hypercholesterolemia who
were at high risk of myocardial infarction. Summary results are presented in
Table II.
TABLE II
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
LDL-C/ TOTAL-C/
TREATMENT N TOTAL-C LDL-C HDL-C HDL-C HDL-C VLDL-C TG.
(mean) (mean) (mean) (mean) (mean) (median) (mean)
MEVACOR
20 mg b.i.d. 85 -27 -32 +9 -36 -31 -34 -21
40 mg b.i.d. 88 -34 -42 +8 -44 -37 -31 -27
Cholestyramine
12 g b.i.d. 88 -17 -23 +8 -27 -21 +2 +11
MEVACOR was studied in controlled trials in hypercholesterolemic
patients with well-controlled non-insulin dependent diabetes mellitus with
normal renal function. The effect of MEVACOR on lipids and lipoproteins and
the safety profile of MEVACOR were similar to that demonstrated in studies
in nondiabetics. MEVACOR had no clinically important effect on glycemic
control or on the dose requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with
hypercholesterolemia (total-C 240-300 mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C
>160 mg/dL [4.1 mmol/L]) in the randomized, double-blind, parallel, 48-week
EXCEL study. All changes in the lipid measurements (Table III) in MEVACOR
treated patients were dose-related and significantly different from placebo (p
Less Than or Equal To 0.001). These results were sustained throughout the
study.
TABLE III
MEVACOR vs. Placebo
(Percent Change from Baseline --
Average Values Between Weeks 12 and 48)
LDL-C/ TOTAL-C/
DOSAGE N** TOTAL-C LDL-C HDL-C HDL-C HDL-C TG.
(mean) (mean) (mean) (mean) (mean) (median)
Placebo 1663 +0.7 +0.4 +2.0 +0.2 +0.6 +4
MEVACOR
20 mg q.p.m. 1642 -17 -24 +6.6 -27 -21 -10
40 mg q.p.m. 1645 -22 -30 +7.2 -34 -26 -14
20 mg b.i.d. 1646 -24 -34 +8.6 -38 -29 -16
40 mg b.i.d. 1649 -29 -40 +9.5 -44 -34 -19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary
prevention study, demonstrated that treatment with MEVACOR decreased the
rate of acute major coronary events (composite endpoint of myocardial
infarction, unstable angina, and sudden cardiac death) compared with
placebo during a median of 5.1 years of follow-up. Participants were
middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated
total-C and LDL-C, below average HDL-C, and who were at high risk based on
elevated total-C/HDL-C. In addition to age, 63% of the participants had at
least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family
history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based
on the following lipid entry criteria: total-C range of 180-264 mg/dL,
LDL-C range of 130-190 mg/dL, HDL-C of Less Than or Equal To 45 mg/dL for
men and Less Than or Equal To 47 mg/dL for women, and TG of Less Than or
Equal To 400 mg/dL. Participants were treated with standard care, including
diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301).
Approximately 50% of the participants treated with MEVACOR were titrated to
40 mg daily when their LDL-C remained >110 mg/dL at the 20-mg starting
dose.
MEVACOR reduced the risk of a first acute major coronary event, the
primary efficacy endpoint, by 37% (MEVACOR 3.5%, placebo 5.5%; p<0.001;
Figure 1). A first acute major coronary event was defined as myocardial
infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina
(54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the
secondary endpoints, MEVACOR reduced the risk of unstable angina by 32%
(1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g.,
coronary artery bypass grafting or percutaneous transluminal coronary
angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk reduction
associated with treatment with MEVACOR were consistent across men and
women, smokers and non-smokers, hypertensives and non-hypertensives, and
older and younger participants. Participants with Greater Than or Equal To
2 risk factors had risk reductions (RR) in both acute major coronary events
(RR 43%) and coronary revascularization procedures (RR 37%). Because there
were too few events among those participants with age as their only risk
factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
Figure 1
(Photo: http://www.newscom.com/cgi-bin/prnh/20071126/NEM105 )
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT),
the effect of therapy with lovastatin on coronary atherosclerosis was
assessed by coronary angiography in hyperlipidemic patients. In the
randomized, double- blind, controlled clinical trial, patients were treated
with conventional measures (usually diet and 325 mg of aspirin every other
day) and either lovastatin 20-80 mg daily or placebo. Angiograms were
evaluated at baseline and at two years by computerized quantitative
coronary angiography (QCA). Lovastatin significantly slowed the progression
of lesions as measured by the mean change per-patient in minimum lumen
diameter (the primary endpoint) and percent diameter stenosis, and
decreased the proportions of patients categorized with disease progression
(33% vs. 50%) and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression
Study (MARS), patients were treated with diet and either lovastatin 80 mg
daily or placebo. No statistically significant difference between
lovastatin and placebo was seen for the primary endpoint (mean change per
patient in percent diameter stenosis of all lesions), or for most secondary
QCA endpoints. Visual assessment by angiographers who formed a consensus
opinion of overall angiographic change (Global Change Score) was also a
secondary endpoint. By this endpoint, significant slowing of disease was
seen, with regression in 23% of patients treated with lovastatin compared
to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either
lovastatin or niacin in combination with a bile acid sequestrant for 2.5
years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary
atherosclerotic lesions by QCA compared to diet and, in some cases,
low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the
coronary arteries has been corroborated by similar findings in another
vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS),
the effect of therapy with lovastatin on carotid atherosclerosis was
assessed by B-mode ultrasonography in hyperlipidemic patients with early
carotid lesions and without known coronary heart disease at baseline. In
this double-blind, controlled clinical trial, 919 patients were randomized
in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or
warfarin. Ultrasonograms of the carotid walls were used to determine the
change per patient from baseline to three years in mean maximum
intimal-medial thickness (IMT) of 12 measured segments. There was a
significant regression of carotid lesions in patients receiving lovastatin
alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the
lovastatin group there was a significant reduction in the number of
patients with major cardiovascular events relative to the placebo group (5
vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the
patient population included in the early clinical trials with lovastatin.
During these trials the appearance of new opacities was noted in both the
lovastatin and placebo groups. There was no clinically significant change
in visual acuity in the patients who had new opacities reported nor was any
patient, including those with opacities noted at baseline, discontinued
from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in
hypercholesterolemic patients to assess the effect of lovastatin on the
human lens demonstrated that there were no clinically or statistically
significant differences between the lovastatin and placebo groups in the
incidence, type or progression of lenticular opacities. There are no
controlled clinical data assessing the lens available for treatment beyond
three years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial
Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of
age (mean age 12.7 yrs) with heterozygous familial hypercholesterolemia
(heFH) were randomized to lovastatin (n=67) or placebo (n=65) for 48 weeks.
Inclusion in the study required a baseline LDL-C level between 189 and 500
mg/dL and at least one parent with an LDL-C level >189 mg/dL. The mean
baseline LDL-C value was 253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR
group compared to 248.2 mg/dL (range: 158.5-413.5 mg/dL) in the placebo
group. The dosage of lovastatin (once daily in the evening) was 10 mg for
the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and
apolipoprotein B (see Table IV).
TABLE IV
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous
Familial Hypercholesterolemia
(Mean Percent Change from Baseline at week 48 in Intention-to-Treat
Population)
DOSAGE N TOTAL-C LDL-C HDL-C TG.* Apolipoprotein B
Placebo 61 -1.1 -1.4 -2.2 -1.4 -4.4
MEVACOR 64 -19.3 -24.2 +1.1 -1.9 -21
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in
the MEVACOR group compared to 244.8 mg/dL (range: 135-404 mg/dL) in the
placebo group.
Efficacy of Lovastatin in Post-menarchal Girls with Heterozygous
Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of
age who were at least 1 year post-menarche with heFH were randomized to
lovastatin (n=35) or placebo (n=19) for 24 weeks. Inclusion in the study
required a baseline LDL-C level of 160-400 mg/dL and a parental history of
familial hypercholesterolemia. The mean baseline LDL-C value was 218.3
mg/dL (range: 136.3-363.7 mg/dL) in the MEVACOR group compared to 198.8
mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The dosage of
lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and
40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and
apolipoprotein B (see Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Post-menarchal Girls with
Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat
Population)
DOSAGE N TOTAL-C LDL-C HDL-C TG.* Apolipoprotein B
Placebo 18 +3.6 +2.5 +4.8 -3.0 +6.4
MEVACOR 35 -22.4 -29.2 +2.4 -22.7 -24.4
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in
the MEVACOR group compared to 203.5 mg/dL (range: 135-304 mg/dL) in the
placebo group.
The safety and efficacy of doses above 40 mg daily have not been
studied in children. The long-term efficacy of lovastatin therapy in
childhood to reduce morbidity and mortality in adulthood has not been
established.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor
intervention in those individuals with dyslipidemia at risk for
atherosclerotic vascular disease. MEVACOR should be used in addition to a
diet restricted in saturated fat and cholesterol as part of a treatment
strategy to lower total-C and LDL-C to target levels when the response to
diet and other nonpharmacological measures alone has been inadequate to
reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to
moderately elevated total-C and LDL-C, and below average HDL-C, MEVACOR is
indicated to reduce the risk of:
-- Myocardial infarction
-- Unstable angina
-- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary
atherosclerosis in patients with coronary heart disease as part of a
treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple
risk factor intervention in those individuals at significantly increased
risk for atherosclerotic vascular disease due to hypercholesterolemia.
MEVACOR is indicated as an adjunct to diet for the reduction of elevated
total-C and LDL- C levels in patients with primary hypercholesterolemia
(Types IIa and IIb***), when the response to diet restricted in saturated
fat and cholesterol and to other nonpharmacological measures alone has been
inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and
apolipoprotein B levels in adolescent boys and girls who are at least one
year post-menarche, 10-17 years of age, with heFH if after an adequate
trial of diet therapy the following findings are present:
1. LDL-C remains >189 mg/dL or
2. LDL-C remains >160 mg/dL and:
-- there is a positive family history of premature cardiovascular
disease or
-- two or more other CVD risk factors are present in the adolescent
patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for
hypercholesterolemia (e.g., poorly controlled diabetes mellitus,
hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid
profile performed to measure total-C, HDL-C, and TG. For patients with TG
less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the
following equation:
LDL-C = total-C - [0.2 x (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate
and LDL-C concentrations should be determined by ultracentrifugation. In
hypertriglyceridemic patients, LDL-C may be low or normal despite elevated
total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines
are summarized below:
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
LDL Level at Which
LDL Goal to Initiate LDL Level at Which
Risk Category (mg/dL) Therapeutic to Consider Drug
Lifestyle Changes Therapy
(mg/dL) (mg/dL)
CHD+ or CHD risk <100 Greater Than or Equal Greater Than or Equal
equivalents To 100 To 130
(10-year risk >20%) (100-129: drug optional)
++
2+ Risk factors <130 Greater Than or Equal 10-year risk 10-20%:
(10 year risk Less To 130 Greater Than or Equal
Than or Equal To 20%) To 130
10-year risk <10%:
Greater Than or Equal
To 160
0-1 Risk factor+++ <160 Greater Than or Equal Greater Than or Equal
To 160 To 190
(160-189: LDL-lowering
drug optional)
+ CHD, coronary heart disease
++ Some authorities recommend use of LDL-lowering drugs in this
category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify
triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment
also may call for deferring drug therapy in this subcategory.
+++ Almost all people with 0-1 risk factor have a 10-year risk <10%;
thus, 10-year risk assessment in people with 0-1 risk factor is not
necessary.
After the LDL-C goal has been achieved, if the TG is still Greater Than
or Equal To 200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary
target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event,
consideration can be given to initiating drug therapy at discharge if the
LDL-C is Greater Than or Equal To 130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that
LDL-C levels be used to initiate and assess treatment response. Only if
LDL-C levels are not available, should the total-C be used to monitor
therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in
patients with combined hypercholesterolemia and hypertriglyceridemia where
hypercholesterolemia is the major abnormality (Type IIb
hyperlipoproteinemia), it has not been studied in conditions where the
major abnormality is elevation of chylomicrons, VLDL or IDL (i.e.,
hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a
familial history of hypercholesterolemia or premature cardiovascular disease
is summarized below:
Category Total-C (mg/dL) LDL-C (mg/dL)
Acceptable <170 <110
Borderline 170-199 110-129
High Greater Than or Equal To 200 Greater Than or Equal To 130
Children treated with lovastatin in adolescence should be re-evaluated
in adulthood and appropriate changes made to their cholesterol-lowering
regimen to achieve adult goals for LDL-C.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum
transaminases (see WARNINGS).
Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing
Mothers). Atherosclerosis is a chronic process and the discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the
outcome of long-term therapy of primary hypercholesterolemia. Moreover,
cholesterol and other products of the cholesterol biosynthesis pathway are
essential components for fetal development, including synthesis of steroids
and cell membranes. Because of the ability of inhibitors of HMG-CoA
reductase such as MEVACOR to decrease the synthesis of cholesterol and
possibly other products of the cholesterol biosynthesis pathway, MEVACOR is
contraindicated during pregnancy and in nursing mothers. MEVACOR should be
administered to women of childbearing age only when such patients are
highly unlikely to conceive. If the patient becomes pregnant while taking
this drug, MEVACOR should be discontinued immediately and the patient
should be apprised of the potential hazard to the fetus (see PRECAUTIONS,
Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally
causes myopathy manifested as muscle pain, tenderness or weakness with
creatine kinase (CK) above ten times the upper limit of normal (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 is increased by high levels of HMG-CoA
reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of
myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in
which patients were carefully monitored and some interacting drugs were
excluded, there was one case of myopathy among 4933 patients randomized to
lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients
randomized to 80 mg daily.
All patients starting therapy with lovastatin, or whose dose of
lovastatin is being increased, should be advised of the risk of myopathy
and told to report promptly any unexplained muscle pain, tenderness or
weakness. Lovastatin therapy should be discontinued immediately if myopathy
is diagnosed or suspected. In most cases, muscle symptoms and CK increases
resolved when treatment was promptly discontinued. Periodic CK
determinations may be considered in patients starting therapy with
lovastatin or whose dose is being increased, but there is no assurance that
such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with
lovastatin have had complicated medical histories, including renal
insufficiency usually as a consequence of long-standing diabetes mellitus.
Such patients merit closer monitoring. Therapy with lovastatin should be
temporarily stopped a few days prior to elective major surgery and when any
major medical or surgical condition supervenes.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of
lovastatin with the following:
Potent inhibitors of CYP3A4: Lovastatin, like several other inhibitors
of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). When
lovastatin is used with a potent inhibitor of CYP3A4, elevated plasma
levels of HMG-CoA reductase inhibitory activity can increase the risk of
myopathy and rhabdomyolysis, particularly with higher doses of lovastatin.
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors
itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin,
HIV protease inhibitors, nefazodone, or large quantities of grapefruit
juice (>1 quart daily) should be avoided. Concomitant use of other
medicines labeled as having a potent inhibitory effect on CYP3A4 should be
avoided unless the benefits of combined therapy outweigh the increased
risk. If treatment with itraconazole, ketoconazole, erythromycin,
clarithromycin or telithromycin is unavoidable, therapy with lovastatin
should be suspended during the course of treatment.
Gemfibrozil, particularly with higher doses of lovastatin: The dose of
lovastatin should not exceed 20 mg daily in patients receiving concomitant
medication with gemfibrozil. The combined use of lovastatin with
gemfibrozil should be avoided, unless the benefits are likely to outweigh
the increased risks of this drug combination.
Other lipid-lowering drugs (other fibrates or Greater Than or Equal To
1 g/day of niacin): The dose of lovastatin should not exceed 20 mg daily in
patients receiving concomitant medication with other fibrates or Greater
Than or Equal To 1 g/day of niacin. Caution should be used when prescribing
other fibrates or lipid-lowering doses (Greater Than or Equal To 1 g/day)
of niacin with lovastatin, as these agents can cause myopathy when given
alone. The benefit of further alterations in lipid levels by the combined
use of lovastatin with other fibrates or niacin should be carefully weighed
against the potential risks of these combinations.
Cyclosporine or danazol, with higher doses of lovastatin: The dose of
lovastatin should not exceed 20 mg daily in patients receiving concomitant
medication with cyclosporine or danazol. The benefits of the use of
lovastatin in patients receiving cyclosporine or danazol should be
carefully weighed against the risks of these combinations.
Amiodarone or verapamil: The dose of lovastatin should not exceed 40 mg
daily in patients receiving concomitant medication with amiodarone or
verapamil. The combined use of lovastatin at doses higher than 40 mg daily
with amiodarone or verapamil should be avoided unless the clinical benefit
is likely to outweigh the increased risk of myopathy. The risk of
myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is
used concomitantly with higher doses of a closely related member of the
HMG- CoA reductase inhibitor class.
Prescribing recommendations for interacting agents are summarized in
Table VI (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS,
Drug Interactions; DOSAGE AND ADMINISTRATION).
Table VI
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents Prescribing Recommendations
Itraconazole Avoid lovastatin
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Gemfibrozil Do not exceed 20 mg lovastatin daily
Other fibrates
Lipid-lowering doses
(Greater Than or Equal To 1 g/day)
of niacin
Cyclosporine
Danazol
Amiodarone Do not exceed 40 mg lovastatin daily
Verapamil
Grapefruit juice Avoid large quantities of grapefruit
juice (>1 quart daily)
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal)
in serum transaminases occurred in 1.9% of adult patients who received
lovastatin for at least one year in early clinical trials (see ADVERSE
REACTIONS). When the drug was interrupted or discontinued in these
patients, the transaminase levels usually fell slowly to pretreatment
levels. The increases usually appeared 3 to 12 months after the start of
therapy with lovastatin, and were not associated with jaundice or other
clinical signs or symptoms. There was no evidence of hypersensitivity. In
the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), the
incidence of persistent increases in serum transaminases over 48 weeks was
0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80
mg/day in patients on lovastatin. However, in post- marketing experience
with MEVACOR, symptomatic liver disease has been reported rarely at all
dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive
elevations of either alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) (> 3 times the upper limit of normal), over a median
of 5.1 years of follow- up, was not significantly different between the
MEVACOR and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of
MEVACOR was 20 mg/day; 50% of the MEVACOR treated participants were
titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred
in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in
participants titrated to 40 mg/day. Elevated transaminases resulted in
discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group
(n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to
initiation of therapy in patients with a history of liver disease, or when
otherwise clinically indicated. It is recommended that liver function tests
be performed in all patients prior to use of 40 mg or more daily and
thereafter when clinically indicated. Patients who develop increased
transaminase levels should be monitored with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent
liver function tests until the abnormality(ies) returns to normal. Should
an increase in AST or ALT of three times the upper limit of normal or
greater persist, withdrawal of therapy with MEVACOR is recommended.
The drug should be used with caution in patients who consume
substantial quantities of alcohol and/or have a past history of liver
disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times
the upper limit of normal) elevations of serum transaminases have been
reported following therapy with MEVACOR (see ADVERSE REACTIONS). These
changes appeared soon after initiation of therapy with MEVACOR, were often
transient, were not accompanied by any symptoms and interruption of
treatment was not required.
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels
(see WARNINGS and ADVERSE REACTIONS). This should be considered in the
differential diagnosis of chest pain in a patient on therapy with
lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial
hypercholesterolemia, possibly because these patients have no functional
LDL receptors. MEVACOR appears to be more likely to raise serum
transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised about substances they should not take
concomitantly with lovastatin and be advised to report promptly unexplained
muscle pain, tenderness, or weakness (see list below and WARNINGS,
Myopathy/Rhabdomyolysis). Patients should also be advised to inform other
physicians prescribing a new medication that they are taking MEVACOR.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory
activity; therefore it is not expected to affect the plasma concentrations
of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below)
increase the risk of myopathy by reducing the elimination of lovastatin.
See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY,
Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (>1 quart daily)
Interactions with lipid-lowering drugs that can cause myopathy when
given alone
The risk of myopathy is also increased by the following lipid-lowering
drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy
when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (Greater Than or Equal To 1 g/day)
Other drug interactions
Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is
increased by concomitant administration of cyclosporine or danazol
particularly with higher doses of lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is
increased when either amiodarone or verapamil is used concomitantly with a
closely related member of the HMG-CoA reductase inhibitor class (see
WARNINGS, Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin
was administered to warfarin treated patients, no effect on prothrombin
time was detected. However, another HMG-CoA reductase inhibitor has been
found to produce a less than two-second increase in prothrombin time in
healthy volunteers receiving low doses of warfarin. Also, bleeding and/or
increased prothrombin time have been reported in a few patients taking
coumarin anticoagulants concomitantly with lovastatin. It is recommended
that in patients taking anticoagulants, prothrombin time be determined
before starting lovastatin and frequently enough during early therapy to
insure that no significant alteration of prothrombin time occurs. Once a
stable prothrombin time has been documented, prothrombin times can be
monitored at the intervals usually recommended for patients on coumarin
anticoagulants. If the dose of lovastatin is changed, the same procedure
should be repeated. Lovastatin therapy has not been associated with
bleeding or with changes in prothrombin time in patients not taking
anticoagulants.
Propranolol: In normal volunteers, there was no clinically significant
pharmacokinetic or pharmacodynamic interaction with concomitant
administration of single doses of lovastatin and propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant
administration of lovastatin and digoxin resulted in no effect on digoxin
plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in
hypercholesterolemic non-insulin dependent diabetic patients, there was no
drug interaction with glipizide or with chlorpropamide (see CLINICAL
PHARMACOLOGY, Clinical Studies).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and
as such might theoretically blunt adrenal and/or gonadal steroid
production. Results of clinical trials with drugs in this class have been
inconsistent with regard to drug effects on basal and reserve steroid
levels. However, clinical studies have shown that lovastatin does not
reduce basal plasma cortisol concentration or impair adrenal reserve, and
does not reduce basal plasma testosterone concentration. Another HMG-CoA
reductase inhibitor has been shown to reduce the plasma testosterone
response to HCG. In the same study, the mean testosterone response to HCG
was slightly but not significantly reduced after treatment with lovastatin
40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase
inhibitors on male fertility have not been studied in adequate numbers of
male patients. The effects, if any, on the pituitary-gonadal axis in
pre-menopausal women are unknown. Patients treated with lovastatin who
develop clinical evidence of endocrine dysfunction should be evaluated
appropriately. Caution should also be exercised if an HMG- CoA reductase
inhibitor or other agent used to lower cholesterol levels is administered
to patients also receiving other drugs (e.g., ketoconazole, spironolactone,
cimetidine) that may decrease the levels or activity of endogenous steroid
hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of
retinogeniculate fibers) in clinically normal dogs in a dose-dependent
fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug
levels about 30 times higher than the mean drug level in humans taking the
highest recommended dose (as measured by total enzyme inhibitory activity).
Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell
chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day,
a dose which resulted in a mean plasma drug level (Cmax) similar to that
seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and
edema, mononuclear cell infiltration of perivascular spaces, perivascular
fibrin deposits and necrosis of small vessels, were seen in dogs treated
with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma
drug levels (Cmax) which were about 30 times higher than the mean values in
humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with
other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180
mg/kg/day and 1 year at 60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically
significant increase in the incidence of hepatocellular carcinomas and
adenomas in both males and females at 500 mg/kg/day. This dose produced a
total plasma drug exposure 3 to 4 times that of humans given the highest
recommended dose of lovastatin (drug exposure was measured as total HMG-CoA
reductase inhibitory activity in extracted plasma). Tumor increases were
not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3
to 2 times that of humans at the 80 mg/day dose. A statistically
significant increase in pulmonary adenomas was seen in female mice at
approximately 4 times the human drug exposure. (Although mice were given
300 times the human dose [HD] on a mg/kg body weight basis, plasma levels
of total inhibitory activity were only 4 times higher in mice than in
humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular
mucosa of the stomach of mice beginning at exposures of 1 to 2 times that
of humans. The glandular mucosa was not affected. The human stomach
contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose
response relationship for hepatocellular carcinogenicity in males at drug
exposures between 2-7 times that of human exposure at 80 mg/day (doses in
rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a
response that has been seen with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72
weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum
drug levels approximately 3, 15, and 33 times higher than the mean human
serum drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high dose females
and mid- and high dose males, with a maximum incidence of 90 percent in
males. The incidence of adenomas of the liver was significantly increased
in mid- and high dose females. Drug treatment also significantly increased
the incidence of lung adenomas in mid- and high dose males and females.
Adenomas of the Harderian gland (a gland of the eye of rodents) were
significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test
using mutant strains of Salmonella typhimurium with or without rat or mouse
liver metabolic activation. In addition, no evidence of damage to genetic
material was noted in an in vitro alkaline elution assay using rat or mouse
hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro
chromosome aberration study in CHO cells, or an in vivo chromosomal
aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis,
spermatocytic degeneration and giant cell formation were seen in dogs
starting at 20 mg/kg/day. Similar findings were seen with another drug in
this class. No drug-related effects on fertility were found in studies with
lovastatin in rats. However, in studies with a similar drug in this class,
there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg
body weight, although this effect was not observed in a subsequent
fertility study when this same dose was administered for 11 weeks (the
entire cycle of spermatogenesis, including epididymal maturation). In rats
treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous
tubule degeneration (necrosis and loss of spermatogenic epithelium) was
observed. No microscopic changes were observed in the testes from rats of
either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established. Lovastatin has been shown to produce skeletal malformations in
offspring of pregnant mice and rats dosed during gestation at 80 mg/kg/day
(affected mouse fetuses/total: 8/307 compared to 4/289 in the control
group; affected rat fetuses/total: 6/324 compared to 2/308 in the control
group). Female rats dosed before mating through gestation at 80 mg/kg/day
also had fetuses with skeletal malformations (affected fetuses/total: 1/152
compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7
times the human dose based on body surface area and in rats results in 5
times the human exposure based on AUC. In pregnant rats given doses of 2,
20, or 200 mg/kg/day and treated through lactation, the following effects
were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively,
compared to 0.6% in the control group), decreased pup body weights
throughout lactation (up to 5%, 8%, and 38%, respectively, below control),
supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and
11/79, respectively, compared to 0/5 in the control group), delays in
ossification in dead pups (affected fetuses/total: 0/7, 0/17, and 1/79,
respectively, compared to 0/5 in the control group) and delays in pup
development (delays in the appearance of an auditory startle response at
200 mg/kg/day and free-fall righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10
mg/kg/day of the open hydroxyacid form of lovastatin resulted in delayed
passive avoidance learning in female rats (mean of 8.3 trials to criterion,
compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no
effects on retention 1 week later) at exposures 4 times the human systemic
exposure at 80 mg/day based on AUC. No effect was seen in male rats. No
evidence of malformations was observed when pregnant rabbits were given 5
mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body
surface area) or a maternally toxic dose of 15 mg/kg/day (3 times the human
dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine
exposure to HMG-CoA reductase inhibitors have been received. However, in an
analysis+ of greater than 200 prospectively followed pregnancies exposed
during the first trimester to MEVACOR or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable
to that seen in the general population. This number of pregnancies was
sufficient to exclude a 3-fold or greater increase in congenital anomalies
over the background incidence.
Maternal treatment with MEVACOR may reduce the fetal levels of
mevalonate, which is a precursor of cholesterol biosynthesis.
Atherosclerosis is a chronic process, and ordinarily discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the
long-term risk associated with primary hypercholesterolemia. For these
reasons, MEVACOR should not be used in women who are pregnant, or can
become pregnant (see CONTRAINDICATIONS). MEVACOR should be administered to
women of child-bearing potential only when such patients are highly
unlikely to conceive and have been informed of the potential hazards.
Treatment should be immediately discontinued as soon as pregnancy is
recognized.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a
small amount of another drug in this class is excreted in human breast milk
and because of the potential for serious adverse reactions in nursing
infants, women taking MEVACOR should not nurse their infants (see
CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have
been evaluated in controlled clinical trials of 48 weeks duration in
adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with
lovastatin had an adverse experience profile generally similar to that of
patients treated with placebo. Doses greater than 40 mg have not been
studied in this population. In these limited controlled studies, there was
no detectable effect on growth or sexual maturation in the adolescent boys
or on menstrual cycle length in girls. See CLINICAL PHARMACOLOGY, Clinical
Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent Patients; and
DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be
counseled on appropriate contraceptive methods while on lovastatin therapy
(see CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Lovastatin has not been
studied in pre-pubertal patients or patients younger than 10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of
HMG-CoA reductase inhibitory activity to be approximately 45% higher in
elderly patients between 70-78 years of age compared with patients between
18- 30 years of age; however, clinical study experience in the elderly
indicates that dosage adjustment based on this age-related pharmacokinetic
difference is not needed. In the two large clinical studies conducted with
lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were
Greater Than or Equal To 65 years of age. Lipid-lowering efficacy with
lovastatin was at least as great in elderly patients compared with younger
patients, and there were no overall differences in safety over the 20 to 80
mg/day dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have
been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated
with MEVACOR, the adverse experience profile was similar to that shown
below for the 8,245-patient EXCEL study (see Expanded Clinical Evaluation
of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see
WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK
levels of at least twice the normal value on one or more occasions. The
corresponding values for the control agent cholestyramine was 9 percent.
This was attributable to the noncardiac fraction of CK. Large increases in
CK have sometimes been reported (see WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with
hypercholesterolemia (total-C 240-300 mg/dL [6.2-7.8 mmol/L]) in the
randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse
experiences reported as possibly, probably or definitely drug-related in
Greater Than or Equal To 1% in any treatment group are shown in the table
below. For no event was the incidence on drug and placebo statistically
different.
Placebo MEVACOR MEVACOR MEVACOR MEVACOR
20 mg q.p.m. 40 mg q.p.m. 20 mg b.i.d. 40 mg b.i.d.
(N=1663) (N=1642) (N=1645) (N=1646) (N=1649)
% % % % %
Body As a Whole
Asthenia 1.4 1.7 1.4 1.5 1.2
Gastrointestinal
Abdominal pain 1.6 2.0 2.0 2.2 2.5
Constipation 1.9 2.0 3.2 3.2 3.5
Diarrhea 2.3 2.6 2.4 2.2 2.6
Dyspepsia 1.9 1.3 1.3 1.0 1.6
Flatulence 4.2 3.7 4.3 3.9 4.5
Nausea 2.5 1.9 2.5 2.2 2.2
Musculoskeletal
Muscle cramps 0.5 0.6 0.8 1.1 1.0
Myalgia 1.7 2.6 1.8 2.2 3.0
Nervous System/
Psychiatric
Dizziness 0.7 0.7 1.2 0.5 0.5
Headache 2.7 2.6 2.8 2.1 3.2
Skin
Rash 0.7 0.8 1.0 1.2 1.3
Special Senses
Blurred vision 0.8 1.1 0.9 0.9 1.2
Other clinical adverse experiences reported as possibly, probably or
definitely drug-related in 0.5 to 1.0 percent of patients in any
drug-treated group are listed below. In all these cases the incidence on
drug and placebo was not statistically different. Body as a Whole: chest
pain; Gastrointestinal: acid regurgitation, dry mouth, vomiting;
Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous
System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus;
Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6%
of the patients treated up to 48 weeks were discontinued due to clinical or
laboratory adverse experiences which were rated by the investigator as
possibly, probably or definitely related to therapy with MEVACOR. The value
for the placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies)
involving 6,605 participants treated with 20-40 mg/day of MEVACOR (n=3,304)
or placebo (n=3,301), the safety and tolerability profile of the group
treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences
reported in AFCAPS/TexCAPS were similar to those reported in EXCEL (see
ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL)
Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered
concomitantly with cholestyramine, no adverse reactions peculiar to this
concomitant treatment were observed. The adverse reactions that occurred
were limited to those reported previously with lovastatin or
cholestyramine. Other lipid-lowering agents were not administered
concomitantly with lovastatin during controlled clinical studies.
Preliminary data suggests that the addition of gemfibrozil to therapy with
lovastatin is not associated with greater reduction in LDL-C than that
achieved with lovastatin alone. In uncontrolled clinical studies, most of
the patients who have developed myopathy were receiving concomitant therapy
with cyclosporine, gemfibrozil or niacin (nicotinic acid). The combined use
of lovastatin at doses exceeding 20 mg/day with cyclosporine, gemfibrozil,
other fibrates or lipid-lowering doses (Greater Than or Equal To 1 g/day)
of niacin should be avoided (see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not
all the effects listed below have necessarily been associated with
lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis,
arthralgias.
Neurological: dysfunction of certain cranial nerves (including
alteration of taste, impairment of extra-ocular movement, facial paresis),
tremor, dizziness, vertigo, memory loss, paresthesia, peripheral
neuropathy, peripheral nerve palsy, psychic disturbances, anxiety,
insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has
been reported rarely which has included one or more of the following
features: anaphylaxis, angioedema, lupus erythematous-like syndrome,
polymyalgia rheumatica, dermatomyositis, vasculitis, purpura,
thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase,
eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity,
fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis,
erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active
hepatitis, cholestatic jaundice, fatty change in liver; and rarely,
cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules,
discoloration, dryness of skin/mucous membranes, changes to hair/nails)
have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase,
gamma-glutamyl transpeptidase, and bilirubin; thyroid function
abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and
a 24-week controlled study in girls who were at least 1 year post-menarche
with heFH (n=54), the safety and tolerability profile of the groups treated
with MEVACOR (10 to 40 mg daily) was generally similar to that of the
groups treated with placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in
Adolescent Patients and PRECAUTIONS, Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose
observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin
as a single dose without clinically significant adverse experiences. A few
cases of accidental overdosage have been reported; no patients had any
specific symptoms, and all patients recovered without sequelae. The maximum
dose taken was 5-6 g.
Until further experience is obtained, no specific treatment of
overdosage with MEVACOR can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known
at present.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet
before receiving MEVACOR and should continue on this diet during treatment
with MEVACOR (see NCEP Treatment Guidelines for details on dietary
therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the
evening meal. The recommended dosing range of lovastatin is 10-80 mg/day in
single or two divided doses; the maximum recommended dose is 80 mg/day.
Doses should be individualized according to the recommended goal of therapy
(see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring
reductions in LDL-C of 20% or more to achieve their goal (see INDICATIONS
AND USAGE) should be started on 20 mg/day of MEVACOR. A starting dose of 10
mg of lovastatin may be considered for patients requiring smaller
reductions. Adjustments should be made at intervals of 4 weeks or more. The
10 mg dosage is provided for information purposes only. Although lovastatin
tablets 10 mg are available in the marketplace, MEVACOR is no longer
marketed in the 10 mg strength.
Cholesterol levels should be monitored periodically and consideration
should be given to reducing the dosage of MEVACOR if cholesterol levels
fall significantly below the targeted range.
Dosage in Patients taking Cyclosporine or Danazol
In patients taking cyclosporine or danazol concomitantly with
lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis), therapy should begin
with 10 mg of lovastatin and should not exceed 20 mg/day.
Dosage in Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with MEVACOR,
the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis
and PRECAUTIONS, Drug Interactions, Other drug interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial
Hypercholesterolemia
The recommended dosing range of lovastatin is 10-40 mg/day; the maximum
recommended dose is 40 mg/day. Doses should be individualized according to
the recommended goal of therapy (see NCEP Pediatric Panel Guidelines++,
CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring
reductions in LDL-C of 20% or more to achieve their goal should be started
on 20 mg/day of MEVACOR. A starting dose of 10 mg of lovastatin may be
considered for patients requiring smaller reductions. Adjustments should be
made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid
sequestrants. If MEVACOR is used in combination with gemfibrozil, other
fibrates or lipid-lowering doses (Greater Than or Equal To 1g/day) of
niacin, the dose of MEVACOR should not exceed 20 mg/day (see WARNINGS,
Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30
mL/min), dosage increases above 20 mg/day should be carefully considered
and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY
and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 3561 -- Tablets MEVACOR 20 mg are light blue, octagonal tablets,
coded MSD 731 on one side and MEVACOR on the other. They are supplied as
follows:
NDC 0006-0731-61 unit of use bottles of 60
NDC 0006-0731-94 unit of use bottles of 90
NDC 0006-0731-82 bottles of 1,000.
No. 3562 -- Tablets MEVACOR 40 mg are green, octagonal tablets, coded
MSD 732 on one side and MEVACOR on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60
NDC 0006-0732-94 unit of use bottles of 90
NDC 0006-0732-82 bottles of 1,000.
Storage
Store between 5-30 degrees Celsius (41-86 degrees Fahrenheit). Tablets
MEVACOR must be protected from light and stored in a well-closed, light-
resistant container.
Issued May 2007
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT (C) 1987-2007 MERCK & CO., Inc.
All rights reserved
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins Elevations
Type elevated major minor
I chylomicrons TG ^>C
IIa LDL C -
IIb LDL, VLDL C TG
III (rare) IDL C/TG -
IV VLDL TG ^>C
V (rare) chylomicrons, VLDL TG ^>C
IDL = intermediate-density lipoprotein.
+ Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P.,
Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
++ National Cholesterol Education Program (NCEP): Highlights of the
Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501. 1992.
SOURCE GlaxoSmithKline
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