CONTRAINDICATIONS
Active liver disease or unexplained persistent elevations of serum transaminases.
Hypersensitivity to any component of this medication.
Pregnancy and Lactation: Atherosclerosis is a chronic process and discontinuation of
lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy
of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are
essential components for fetal development lincluding synthesis of steroids and cell membranes).
Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of
other biologically active substances derived from cholesterol, they may cause fetal harm when
administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated
during pregnancy and in nursing mothers. ATORVASTATIN SHOULD BE ADMINISTERED
TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY
UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL
HAZARDS. If the patient becomes pregnant while taking this drug, therapy should be discontinued
and the patient apprised of the potential hazard to the fetus.
WARNINGS
Liver Dysfunction
HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with
biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of
normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in
0.7% of patients who received atorvastatin in clinical trials. The incidence of these
abnormalities was 0.2%, 0.6%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other
patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction,
drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels
without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a
reduced dose of atorvastatin.
It is recommended that liver function tests be performed prior to and at 12 weeks
following initiation of therapy and any elevation of dose, and periodically (e.g.,
semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of
treatment with atorvastatin. Patients who develop increased transaminase levels should be
monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN
persist, reduction of dose or withdrawal of atorvastatin is recommended.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol
and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase
elevations are contraindications to the use of atorvastatin (see CONTRAINDICATIONS).
Skeletal Muscle
Rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported
with other drugs in this class.
Uncomplicated myalgia has been reported in atorvastatin-treated patients (see ADVERSE
REACTIONS). Myopathy, defined as muscle aches or muscle weakness in conjunction with
increases in creatine phosphokinase (CPK) values >10 times ULN, should be considered in any
patient wlth diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK.
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness,
particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if
markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with other drugs in this class is increased with concurrent
administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole antifungals.
Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin,
immunosuppressive drugs, azole antifungals, or lipid-lowering doses of niacin should carefully weigh
the potential benefits and risks and should carefully monitor patients for any signs or 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 creatine phosphokinase (CPK)
determinations may be considered in such situations, but there is no assurance that such monitoring
will prevent the occurence of severe myopathy.
Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an
acute, serious condition suggestive of a myopathy or having a risk factor predisposing to
the development of renal failure secondary to rhabdomyolysis (e.g., severe acute
infection, hypotension, major surgery, trauma, severe metabolic, endocrine and
electrolyte disorders, and uncontrolled seizures).
PRECAUTIONS
General
Before instituting therapy with atorvastatin, an attempt should be made to control
hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients, and to
treat other underlying medical problems (see INDICATIONS AND USAGE).
Information for the Patient
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness,
particularly if accompanied by malaise or fever.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt
adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not
reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of HMG-CoA
reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The
effects, if any, on the pituitary gonadal axis in premenopausal women are unknown. Caution should
be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may
decrease the levels or activity of endogenous steroid hormones, such as ketoconazole,
spironolactone, and cimetidine.
CNS Toxicity
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain
hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in
moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose
resulted in a systemic exposure approximately 16 times the human plasma area-under-the curve
(AUC, 0-24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion
was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a
2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years
at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6-11 times
(mouse) and 8-16 times (rat) the human AUC (0-24) based on the maximum recommended human
dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell
infiltration of perivascular spaces, have been observed in dogs treated with other members of this
class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian
degeneration of retino geniculate fibers) in clinically normal dogs in a dose-dependent fashion at a
dose that produced plasma drug levels about 30 times higher than the mean drug level in humans
taking the highest recommended dose.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors
were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another,
there was a fibrosarcoma. This dose represents a plasma AUC (0-24) value of approximately 16
times the mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant
increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These
findings occurred at plasma AUC (0-24) values of approximately 6 times the mean human plasma
drug exposure after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without
metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the
HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration
assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus
test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no
changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with
100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis
weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100
mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility,
spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse
effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or
120 mg/kg for 2 years.
Pregnancy, Teratogenic Effects, Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established. Atorvastatin crosses the rat placenta and
reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic
in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses
resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on
surface area (mg/m2).
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21
(weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of
mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of
mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91
at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and
acoustic startle at 225 mg/kg/day; pinnae detachment and eye opening at 225 mg/kg/day). These
doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day.
Rare reports of congenital anomalies have been received following intrauterine exposure to
HMG-CoA reductase inhibitors. There has been one report of severe congenital bony deformity,
tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who
took lovastatin with dextroamphetamine sulfate during the first trimester of pregnancy. Atorvastatin
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. If the woman becomes
pregnant while taking atorvastatin, it should be discontinued and the patient advised again as to the
potential hazards to the fetus.
Nursing Mothers
Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their
mother's milk. Because of the potential for adverse reactions in nursing infants, women taking
atorvastatin should not breast-feed (see CONTRAINDICATIONS).
Pediatric Use
Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80 mg/day for
1 year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in
these patients. None of these patients was below 9 years of age.
Geriatric Use
Treatment experience in adults age ³70 years with doses of atorvastatin up to 80 mg/day has been
evaluated in 221 patients. The safety and efficacy of atorvastatin in this population were similar to
those of patients <70 years of age.