WARNINGS AND PRECAUTIONS
5.1).
Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic
transaminases can occur. Monitor liver enzymes before and during treatment (5.2).
A higher incidence of hemorrhagic stroke was seen in patients without CHD but
with stroke or TIA within the previous 6 months in the LIPITOR 80 mg group vs.
placebo (5.5).
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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 (7)
). 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 (7)
,
Clinical Pharmacology
].
Table 1. Drug Interactions Associated with Increased Risk of
Myopathy/Rhabdomyolysis
Interacting Agents |
Prescribing Recommendations |
Cyclosporine
|
Do not exceed 10 mg atorvastatin daily |
Clarithromycin, itraconazole, HIV protease inhibitors
(ritonavir plus saquinavir or lopinavir plus ritonavir) |
Caution when exceeding doses > 20mg atorvastatin daily. The
lowest dose necessary should be used. |
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
Enter section text here
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 (4)
].
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 (4)
and
Pharmacokinetics
].
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