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Content
Heart Disease
Heart Attack
Congestive Heart Failure
Generic Drugs
Alternative Heart Disease Treatment |
Heart Disease
Generic Drugs Zocor Side
Effects
From Merck
SIDE EFFECTS In the pre-marketing controlled clinical studies and
their open extensions (2,423 patients with mean duration of follow-up of
approximately 18 months), 1.4% of patients were discontinued due to adverse
experiences attributable to ZOCOR. Adverse reactions have usually been mild and
transient. ZOCOR has been evaluated for serious adverse reactions in more than
21,000 patients and is generally well tolerated.
Clinical Adverse Experiences In Adults
Adverse experiences occurring in adults at an incidence of 1% or greater in
patients treated with ZOCOR, regardless of causality, in controlled clinical
studies are shown in Table 1.
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TABLE 1 Adverse Experiences in Clinical Studies Incidence
1 Percent or Greater, Regardless of Causality |
| |
ZOCOR |
Placebo |
Cholestyramine |
| |
(N = 1,583) |
(N = 157) |
(N = 179) |
| |
% |
% |
% |
|
Body as a Whole |
|
Abdominal pain |
3.2 |
3.2 |
8.9 |
|
Asthenia |
1.6 |
2.5 |
1.1 |
|
Gastrointestinal |
|
Constipation |
2.3 |
1.3 |
29.1 |
|
Diarrhea |
1.9 |
2.5 |
7.8 |
|
Dyspepsia |
1.1 |
— |
4.5 |
|
Flatulence |
1.9 |
1.3 |
14.5 |
|
Nausea |
1.3 |
1.9 |
10.1 |
|
Nervous System/ Psychiatric |
|
Headache |
3.5 |
5.1 |
4.5 |
|
Respiratory |
|
Upper respiratory infection |
2.1 |
1.9 |
3.4 |
Scandinavian Simvastatin Survival Study Clinical Adverse Experiences
In 4S involving 4,444 patients treated with 20-40 mg/day of ZOCOR (n=2,221) or
placebo (n=2,223), the safety and tolerability profiles were comparable between
groups over the median 5.4 years of the study. The clinical adverse experiences
reported as possibly, probably, or definitely drug-related in ³ 0.5% in either
treatment group are shown in Table 2.
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TABLE 2 Drug-Related Clinical Adverse Experiences in 4S
Incidence 0.5 Percent or Greater |
| |
ZOCOR |
Placebo |
| |
(N = 2,221) |
(N = 2,223) |
| |
% |
% |
|
Body as a Whole |
|
Abdominal pain |
0.9 |
0.9 |
|
Gastrointestinal |
|
Diarrhea |
0.5 |
0.3 |
|
Dyspepsia |
0.6 |
0.5 |
|
Flatulence |
0.9 |
0.7 |
|
Nausea |
0.4 |
0.6 |
|
Musculoskeletal |
|
Myalgia |
1.2 |
1.3 |
|
Skin |
|
Eczema |
0.8 |
0.8 |
|
Pruritus |
0.5 |
0.4 |
|
Rash |
0.6 |
0.6 |
|
Special Senses |
|
Cataract |
0.5 |
0.8 |
Heart Protection Study Clinical Adverse Experiences
In HPS (see CLINICAL PHARMACOLOGY, Clinical Studies), involving 20,536 patients
treated with ZOCOR 40 mg/day (n=10,269) or placebo (n=10,267), the safety
profiles were comparable between patients treated with ZOCOR and patients
treated with placebo over the mean 5 years of the study. In this large trial,
only serious adverse events and discontinuations due to any adverse events were
recorded. Discontinuation rates due to adverse experiences were comparable (4.8%
in patients treated with ZOCOR compared with 5.1% in patients treated with
placebo). The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated
with ZOCOR.
The following effects have been reported with drugs in this class. Not all the
effects listed below have necessarily been associated with simvastatin 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,
-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Laboratory Tests
Marked persistent increases of serum transaminases have been noted (see
WARNINGS, Liver Dysfunction). About 5% of patients had elevations of CK levels
of 3 or more times the normal value on one or more occasions. This was
attributable to the noncardiac fraction of CK. Muscle pain or dysfunction
usually was not reported.
Concomitant Lipid-Lowering Therapy
In controlled clinical studies in which simvastatin 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 simvastatin or cholestyramine. The
combined use of simvastatin at doses exceeding 10 mg/day with gemfibrozil should
be avoided.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys and girls who were at least 1
year post-menarche, 10-17 years of age with heterozygous familial
hypercholesterolemia (n=175), the safety and tolerability profile of the group
treated with ZOCOR (10-40 mg daily) was generally similar to that of the group
treated with placebo, with the most common adverse experiences observed in both
groups being upper respiratory infection, headache, abdominal pain, and nausea.
DRUG INTERACTIONS CYP3A4 Interactions
Simvastatin 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 simvastatin.
Pharmacokinetics.
Itraconazole Ketoconazole Erythromycin Clarithromycin 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 increased by gemfibrozil (see DOSAGE AND ADMINISTRATION)
and to a lesser extent by other fibrates and niacin (nicotinic acid) (³1 g/day).
Other drug interactions
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased
by concomitant administration of amiodarone or verapamil (see WARNINGS, Myopathy/Rhabdomyolysis).
Propranolol: In healthy male volunteers there was a significant decrease
in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors
with concomitant administration of single doses of ZOCOR and propranolol. The
clinical relevance of this finding is unclear. The pharmacokinetics of the
enantiomers of propranolol were not affected.
Digoxin: Concomitant administration of a single dose of digoxin in
healthy male volunteers receiving simvastatin resulted in a slight elevation
(less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a
radioimmunoassay) compared to concomitant administration of placebo and digoxin.
Patients taking digoxin should be monitored appropriately when simvastatin is
initiated.
Warfarin: In two clinical studies, one in normal volunteers and the other
in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated
the effect of coumarin anticoagulants: the prothrombin time, reported as
International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8
and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With
other reductase inhibitors, clinically evident bleeding and/or increased
prothrombin time has been reported in a few patients taking coumarin
anticoagulants concomitantly. In such patients, prothrombin time should be
determined before starting simvastatin 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 simvastatin is changed or discontinued, the same
procedure should be repeated. Simvastatin therapy has not been associated with
bleeding or with changes in prothrombin time in patients not taking
anticoagulants.
CNS Toxicity
Optic nerve degeneration was seen in clinically normal dogs treated with
simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug
levels about 12 times higher than the mean plasma drug level in humans taking 80
mg/day.
A chemically similar drug in this class also 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 plasma drug level in
humans taking the highest recommended dose (as measured by total enzyme
inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis in dogs treated for 14
weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level 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
simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug
levels that were about 14 times higher than the mean plasma drug levels in
humans taking 80 mg/day. Similar CNS vascular lesions have been observed with
several other drugs of this class.
There were cataracts in female rats after two years of treatment with 50 and 100
mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs
after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day
(5 times).
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