Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been
reported with LIPITOR and with other drugs in this class. A history of renal impairment
may be a risk factor for the development of rhabdomyolysis. Such patients merit closer
monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or
muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10
times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as
cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV
protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
Myopathy should be considered in any patient with 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. LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or
myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent
administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin,
combination of ritonavir plus saquinavir or lopinavir plus ritonavir, niacin, or azole
antifungals. Physicians considering combined therapy with LIPITOR and fibric acid derivatives,
erythromycin, clarithromycin, a combination of ritonavir plus saquinavir or lopinavir plus
ritonavir, immunosuppressive drugs, azole antifungals, or lipid-modifying 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. Lower starting and maintenance doses of atorvastatin should be considered when
taken concomitantly with the aforementioned drugs (see Drug Interactions). Periodic
creatine phosphokinase (CPK) determinations may be considered in such situations, but
there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in
Table 1 [see also Dosage and Administration, Drug Interactions, Clinical Pharmacology].
Table 1. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
LIPITOR 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).
Liver Dysfunction
Statins, 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 LIPITOR in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%,
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 LIPITOR.
It is recommended that liver function tests be performed prior to and at 12 weeks following
both the 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 LIPITOR. 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 LIPITOR is
recommended.
LIPITOR 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 LIPITOR
[see Contraindications].
Endocrine Function
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or
gonadal steroid production. Clinical studies have shown that LIPITOR does not reduce basal
plasma cortisol concentration or impair adrenal reserve. The effects of statins 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 a statin 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 to 11 times (mouse) and 8 to 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 retinogeniculate 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.
Use in Patients with Recent Stroke or TIA
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol
Levels (SPARCL) study where LIPITOR 80 mg vs. placebo was administered in 4,731 subjects
without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence
of hemorrhagic stroke was seen in the LIPITOR 80 mg group compared to placebo (55, 2.3%
atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence
of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the
atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic
stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the
placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar
stroke on study entry, were associated with a higher incidence of hemorrhagic stroke
in the atorvastatin group [see Adverse Reactions].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category X
LIPITOR is contraindicated in women who are or may become pregnant. Serum cholesterol and
triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit
during pregnancy because cholesterol and cholesterol derivatives are needed for normal
fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia
therapy.
There are no adequate and well-controlled studies of atorvastatin use during pregnancy.
There have been rare reports of congenital anomalies following intrauterine exposure to
statins. In a review of about 100 prospectively followed pregnancies in women exposed to
other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal
deaths/stillbirths did not exceed the rate expected in the general population. However,
this study was only able to exclude a three-to-four-fold increased risk of congenital
anomalies over background incidence. In 89% of these cases, drug treatment started before
pregnancy and stopped during the first trimester when pregnancy was identified.
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)
[see Contraindications, Pregnancy].
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.
Statins may cause fetal harm when administered to a pregnant woman. LIPITOR should be
administered to women of childbearing 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 LIPITOR, it should be discontinued immediately and the
patient advised again as to the potential hazards to the fetus and the lack of known
clinical benefit with continued use during pregnancy.
Nursing Mothers
It is not known whether atorvastatin is excreted in human milk, but a small amount of another
drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug
levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug
levels may not accurately reflect human breast milk levels. Because another drug in this class
passes into human milk and because statins have a potential to cause serious adverse
reactions in nursing infants, women requiring LIPITOR treatment should be advised not to
nurse their infants [see Contraindications].
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heterozygous familial
hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’
duration in adolescent boys and postmenarchal girls. Patients treated with LIPITOR had an
adverse experience profile generally similar to that of patients treated with placebo.
The most common adverse experiences observed in both groups, regardless of causality
assessment, were infections. Doses greater than 20 mg have not been studied in this patient
population. In this limited controlled study, there was no significant effect on growth or
sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies;
Adverse Reactions, Pediatric Patients (ages 10-17 years); and Dosage and
Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years
of age)]. Adolescent females should be counseled on appropriate contraceptive methods
while on LIPITOR therapy [see Contraindications, Pregnancy and Use in Specific
Populations, Pregnancy]. LIPITOR has not been studied in controlled clinical trials
involving pre-pubertal patients or patients younger than 10 years of age.
Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled
study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies,
Homozygous Familial Hypercholesterolemia].
Geriatric Use
Of the 39,828 patients who received LIPITOR in clinical studies, 15,813 (40%) were ≥65 years
old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical experience
has not identified differences in responses between the elderly and younger patients, but
greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years)
is a predisposing factor for myopathy, LIPITOR should be prescribed with caution in the elderly.
Hepatic Impairment
Lipitor is contraindicated in patients with active liver disease which may include unexplained
persistent elevations in hepatic transaminase levels [see Contraindications and
Pharmacokinetics].
PATIENT COUNSELING INFORMATION
Patients taking LIPITOR should be advised that cholesterol is a chronic condition and they should adhere to their medication along with
their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing
of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with atorvastatin [see Warnings and Precautions].
Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking LIPITOR.
Muscle Pain
All patients starting therapy with LIPITOR should be advised of the risk of myopathy and told to report promptly any unexplained
muscle pain, tenderness, or weakness. The risk of this occurring is increased when taking certain types of medication or consuming
larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with
their healthcare professional.
Liver Enzymes
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy, and any
elevation of dose, and periodically (e.g., semiannually) thereafter.
Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using LIPITOR.
Discuss future pregnancy plans with your patients, and discuss when to stop LIPITOR if they are trying to conceive. Patients should be
advised that if they become pregnant, they should stop taking LIPITOR and call their healthcare professional.
Breastfeeding
Women who are breastfeeding should be advised to not use LIPITOR. Patients who have a lipid disorder and are breastfeeding, should
be advised to discuss the options with their healthcare professional.