CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see
WARNINGS).
Pregnancy and Lactation: 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 simvastatin to decrease the synthesis of
cholesterol and possibly other products of the cholesterol biosynthesis pathway,
simvastatin is contraindicated during pregnancy and in nursing mothers. Simvastatin
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,
simvastatin should be discontinued immediately and the patient should be apprised of the
potential hazard to the fetus (see PRECAUTIONS, Pregnancy Category X).
WARNINGS
Skeletal Muscle
Simvastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy,
which is manifested as muscle pain or weakness associated with grossly elevated creatine
kinase (CK) (>10´ the upper limit of normal [ULN]). Rhabdomyolysis, with or without
acute renal failure secondary to myoglobinuria, has been reported rarely. In 4S,
there was one case of myopathy among 1399 patients taking simvastatin 20 mg and no
cases among 822 patients taking 40 mg/day for a median duration of 5.4 years. In two
6-month controlled clinical studies, there was one case of myopathy among 436 patients
taking 40 mg and 5 cases among 669 patients taking 80 mg. The risk of myopathy is
increased by concomitant therapy with certain drugs, some of which were excluded by
the designs of these studies (see Myopathy Caused By Drug Interactions).
Myopathy Caused By Drug Interactions
The incidence and severity of myopathy are increased by concomitant administration of
HMG-CoA reductase inhibitors with drugs that can cause myopathy when given alone,
such as gemfibrozil and other fibrates, and lipid-lowering doses (³1 g/day) of niacin
(nicotinic acid).
In addition, the risk of myopathy appears to be increased by high levels of HMG-CoA
reductase inhibitory activity in plasma. Simvastatin is metabolized by the cytochrome
P450 isoform 3A4. Certain drugs which share this metabolic pathway can raise the
plasma levels of simvastatin and may increase the risk of myopathy. These include
cyclosporine, itraconazole, ketoconazole, and other antifungal azoles, the macrolide
antibiotics erythromycin and clarithromycin, HIV protease inhibitors, and the
antidepressant nefazodone.
Reducing the Risk of Myopathy
1. General Measures: Patients starting therapy with simvastatin should be advised
of the risk of myopathy, and told to report promptly unexplained muscle pain,
tenderness or weakness. A CK level above 10´ ULN in a patient with unexplained
muscle symptoms indicates myopathy. Simvastatin therapy should be discontinued if
myopathy is diagnosed or suspected. In most cases, when patients were promptly
discontinued from treatment, muscle symptoms and CK increases resolved.
Of the patients with rhabdomyolysis, many had complicated medical histories. Some had
preexisting renal insufficiency, usually as a consequence of long-standing diabetes. In such
patients, dose escalation requires caution. Also, as there are no known adverse
consequences of brief interruption of therapy, treatment with simvastatin should be
stopped a few days before elective major surgery and when any major acute medical or
surgical condition supervenes.
2. Measures to Reduce the Risk of Myopathy Caused By Drug Interactions: (See
General Measures and DRUG INTERACTIONS). Physicians contemplating
combined therapy with simvastatin and any of the interacting drugs should weigh
the potential benefits and risks, and should carefully monitor patients for any signs
and symptoms of muscle pain, tenderness, or weakness, particularly during the
initial months of therapy and during any periods of upward dosage titration of
either drug. Periodic CK determinations may be considered in such situations, but there
is no assurance that such monitoring will prevent myopathy.
The combined use of simvastatin with fibrates or niacin should be avoided unless the
benefit of further alteration in lipid levels is likely to outweigh the increased risk of this
drug combination. Combinations of fibrates or niacin with low doses of simvastatin have
been used without myopathy in small, short-term clinical studies with careful monitoring.
Addition of these drugs to simvastatin typically provides little additional reduction in
LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. If
one of these drugs must be used with simvastatin, clinical experience suggests that the risk
of myopathy is less with niacin than with the fibrates.
In patients taking concomitant cyclosporine, fibrates or niacin, the dose of
simvastatin should generally not exceed 10 mg (see DOSAGE AND
ADMINISTRATION, General Recommendations and Concomitant Lipid-Lowering
Therapy), as the risk of myopathy increases substantially at higher doses. Interruption of
simvastatin therapy during a course of treatment with a systemic antifungal azole or a
macrolide antibiotic should be considered.
Liver Dysfunction
Persistent increases (to more than 3´ the ULN) in serum transaminases have
occurred in approximately 1% of patients who received simvastatin in clinical
studies. When drug treatment was interrupted or discontinued in these patients, the
transaminase levels usually fell slowly to pretreatment levels. The increases were not
associated with jaundice or other clinical signs or symptoms. There was no evidence of
hypersensitivity.
In 4S (see CLINICAL STUDIES), the number of patients with more than one
transaminase elevation to >3´ ULN, over the course of the study, was not significantly
different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]).
Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the
simvastatin group (n=2221) and 5 in the placebo group (n=2223). Of the 1986
simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, only
8 (0.4%) developed consecutive LFT elevations to >3´ ULN and/or were discontinued
due to transaminase elevations during the 5.4 years (median follow-up) of the study.
Among these 8 patients, 5 initially developed these abnormalities within the first year. All
of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were
titrated to 40 mg.
In 2 controlled clinical studies in 1105 patients, the 12-month incidence of persistent
hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at
the 40- and 80-mg dose, respectively. No patients developed persistent liver function
abnormalities following the initial 6 months of treatment at a given dose.
It is recommended that liver function tests be performed before the initiation of
treatment, and periodically thereafter (e.g., semiannually) for the first year of
treatment or until one year after the last elevation in dose. Patients titrated to the
80-mg dose should receive an additional test at 3 months. 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) return to normal. Should an increase in AST or ALT of 3´ ULN or
greater persist, withdrawal of therapy with simvastatin 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 diseases or unexplained
transaminase elevations are contraindications to the use of simvastatin.
As with other lipid-lowering agents, moderate (less than 3´ ULN) elevations of serum
transaminases have been reported following therapy with simvastatin. These changes
appeared soon after initiation of therapy with simvastatin, were often transient, were not
accompanied by any symptoms and did not require interruption of treatment.
PRECAUTIONS
General
Simvastatin may cause elevation of CK 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 simvastatin.
Information for the Patient
Patients should be advised to report promptly unexplained muscle pain, tenderness, or
weakness (see WARNINGS, Skeletal Muscle).
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 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 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 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 2 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 3 months
at 90 mg/kg/day (19 times) and at 2 years at 50 mg/kg/day (5 times).
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of
25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels
approximately 1, 4, and 8 times higher than the mean human plasma drug level,
respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver
carcinomas were significantly increased in high-dose females and mid- and high-dose
males with a maximum incidence of 90% 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 a tumorigenic effect
was observed at 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no
evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times
higher than humans given 80 mg simvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in
the incidence of thyroid follicular adenomas in female rats exposed to approximately 11
times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by
AUC).
A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day
produced hepatocellular adenomas and carcinomas (in female rats at both doses and in
males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and
females at both doses; thyroid follicular cell carcinomas were increased in females at 100
mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with
findings from other HMG-CoA reductase inhibitors. These treatment levels represented
plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times
(females) the mean human plasma drug exposure after an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test 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 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.
There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25
mg/kg body weight (4 times the maximum human exposure level, based on AUC, in
patients receiving 80 mg/day); however, this effect was not observed during a subsequent
fertility study in which simvastatin was administered at this same dose level to male rats
for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No
microscopic changes were observed in the testes of rats from either study. At 180
mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking
80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis
and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related
testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell
formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC,
at 80 mg/day). The clinical significance of these findings is unclear.
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up
to 10 mg/kg daily. These doses resulted in 3 times (rat) or 3 times (rabbit) the human
exposure based on mg/m2 surface area. However, in studies with another
structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed
in rats and mice.
Rare reports of congenital anomalies have been received following intrauterine exposure
to HMG-CoA reductase inhibitors. In a review1 of approximately 100 prospectively
followed pregnancies in women exposed to simvastatin or another structurally related
HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous
abortions and fetal deaths/stillbirths did not exceed what would be expected in the
general population. The number of cases is adequate only to exclude a 3- to 4-fold
increase in congenital anomalies over the background incidence. In 89% of the
prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and
was discontinued at some point in the first trimester when pregnancy was identified. As
safety in pregnant women has not been established and there is no apparent benefit to
therapy with simvastatin during pregnancy (see CONTRAINDICATIONS), treatment
should be immediately discontinued as soon as pregnancy is recognized. Simvastatin
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.
Nursing Mothers
It is not known whether simvastatin is excreted in human milk. Because a small amount of
another drug in this class is excreted in human milk and because of the potential for
serious adverse reactions in nursing infants, women taking simvastatin should not nurse
their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Because pediatric
patients are not likely to benefit from cholesterol lowering for at least a decade and
because experience with this drug is limited (no studies in subjects below the age of 20
years), treatment of pediatric patients with simvastatin is not recommended at this time.