A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Mevacor Side Effects, and Drug Interactions - Lovastatin
Mevacor Side Effects, and Drug Interactions - Lovastatin
SIDE EFFECTS
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 240-300mg/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 =1% in any treatment group are shown in the
table below. For
no event was
the incidence on drug and placebo statistically different.
| TABLE 7 |
| |
|
Lovastatin |
| |
Placebo |
20 mg
qpm |
40 mg
qpm |
20 mg
bid |
40 mg
bid |
| |
(N=1663) |
(N=1642) |
(N=1645) |
(N=1646) |
(N=1649) |
| |
% |
% |
% |
% |
% |
| Body as a Whole |
|
|
1.4
|
1.7
|
1.4
|
1.5
|
1.2
|
| Gastrointestinal |
|
|
1.6
|
2.0
|
2.0
|
2.2
|
2.5
|
|
|
1.9
|
2.0
|
3.2
|
3.2
|
3.5
|
|
|
2.3
|
2.6
|
2.4
|
2.2
|
2.6
|
|
|
1.9
|
1.3
|
1.3
|
1.0
|
1.6
|
|
|
4.2
|
3.7
|
4.3
|
3.9
|
4.5
|
|
|
2.5
|
1.9
|
2.5
|
2.2
|
2.2
|
| Musculoskeletal |
|
|
0.5
|
0.6
|
0.8
|
1.1
|
1.0
|
|
|
1.7
|
2.6
|
1.8
|
2.2
|
3.0
|
| Nervous System/Psychiatric |
|
|
0.7
|
0.7
|
1.2
|
0.5
|
0.5
|
|
|
2.7
|
2.6
|
2.8
|
2.1
|
3.2
|
| Skin |
|
|
0.7
|
0.8
|
1.0
|
1.2
|
1.3
|
| Special Senses |
|
|
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 MEVACOR (Lovastatin)
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 cholesterol
than that achieved with lovastatin alone. In
uncontrolled clinical
studies, most of the patients who have developed myopathy were receiving
concomitant therapy
with immunosuppressive drugs, gemfibrozil
or niacin (nicotinic
acid) (see WARNINGS, Skeletal
Muscle).
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, 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, g-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 ).
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
Cyclosporine
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) (=1 g/day)
Other drug
interactions
Danazol: The risk of
myopathy/rhabdomyolysis is increased by concomitant administration of
danazol particularly with higher doses of lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis).
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 noninsulin
dependent diabetic patients, there was no drug interaction with glipizide
or with chlorpropamide (see CLINICAL PHARMACOLOGY, Clinical Studies).
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