ATORVASTATIN
DESCRIPTION:
ATORLIP (atorvastatin calcium) is a synthetic lipid-lowering agent.
Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an
early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium is (R- (R*,R*))-2-(4-fluorophenyl)-(beta), (delta)-
dihydroxy-5-(1-methylethyl)-3-phenyl- 4-((phenylamino)carbonyl)-1H-pyrrole-1-
heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of
atorvastatin calcium is (C33H34FN2O5)2Ca*3H2O and its molecular weight is
1209.42.
Atorvastatin calcium is a white to off-white crystalline powder that is
insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very
slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile,
slightly soluble in ethanol, and freely soluble in methanol.
ATORLIP tablets for oral administration contain 10, 20, or 40 mg atorvastatin
and the following inactive ingredients: calcium carbonate, USP; candelilla wax,
FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose
monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry
White YS-1-7040 (hydroxypropylmethylcellulose, polyethylene glycol, talc,
titanium dioxide); polysorbate 80, NF; simethicone emulsion.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the
rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl- coenzyme A to
mevalonate, a precursor of sterols, including cholesterol. Cholesterol and
triglycerides circulate in the bloodstream as part of lipoprotein complexes.
With ultracentrifugation, these complexes separate into HDL (high-density
lipoprotein), IDL (intermediate-density lipoprotein), LDL (low- density
lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides
(TG) and cholesterol in the liver are incorporated into VLDL and released into
the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is
catabolized primarily through the high- affinity LDL receptor. Clinical and
pathologic studies show that elevated plasma levels of total cholesterol (total-
C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human
atherosclerosis and are risk factors for developing cardiovascular disease,
while increased levels of HDL-C are associated with a decreased cardiovascular
risk.
In animal models, ATORLIP lowers plasma cholesterol and lipoprotein levels by
inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by
increasing the number of hepatic LDL receptors on the cell-surface to enhance
uptake and catabolism of LDL; ATORLIP also reduces LDL production and the number
of LDL particles. ATORLIP reduces LDL-C in some patients with homozygous
familial hypercholesterolemia (FH), a population that rarely responds to other
lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C,
LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis.
Similarly, decreased levels of HDL-C (and its transport complex, apo A) are
associated with the development of atherosclerosis. Epidemiologic investigations
have established that cardiovascular morbidity and mortality vary directly with
the level of total-C and LDL-C, and inversely with the level of HDL-C.
ATORLIP reduces total-C, LDL-C, and apo B in patients with homozygous and
heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed
dyslipidemia. ATORLIP also reduces VLDL-C and TG and produces variable increases
in HDL-C and apolipoprotein A-1. The effect of ATORLIP on cardiovascular
morbidity and mortality has not been determined.
PHARMACODYNAMICS
Atorvastatin as well as some of its metabolites are pharmacologically active in
humans. The liver is the primary site of action and the principal site of
cholesterol synthesis and LDL clearance. Drug dosage rather than systemic drug
concentration correlates better with LDL-C reduction. Individualization of drug
dosage should be based on therapeutic response (see DOSAGE AND ADMINISTRATION).
PHARMACOKINETICS AND DRUG METABOLISM
ABSORPTION: Atorvastatin is rapidly absorbed after oral administration; maximum
plasma concentrations occur within 1 to 2 hours. Extent of absorption increases
in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin
(parent drug) is approximately 12% and the systemic availability of HMG-CoA
reductase inhibitory activity is approximately 30%. The low systemic
availability is attributed to presystemic clearance in gastrointestinal mucosa
and/or hepatic first-pass metabolism. Although food decreases the rate and
extent of drug absorption by approximately 25% and 9%, respectively, as assessed
by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with
or without food. Plasma atorvastatin concentrations are lower (approximately 30%
for Cmax and AUC) following evening drug administration compared with morning.
However, LDL-C reduction is the same regardless of the time of day of drug
administration (see DOSAGE AND ADMINISTRATION).
DISTRIBUTION: Mean volume of distribution of atorvastatin is approximately 565
liters. Atorvastatin is (>/=)98% bound to plasma proteins. A blood/plasma ratio
of approximately 0.25 indicates poor drug penetration into red blood cells.
Based on observations in rats, atorvastatin is likely to be secreted in human
milk (see CONTRAINDICATIONS, Pregnancy and Lactation), and PRECAUTIONS, Nursing
Mothers).
METABOLISM: Atorvastatin is extensively metabolized to ortho- and
parahydroxylated derivatives and various beta-oxidation products. IN VITRO
inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is
equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory
activity for HMG- CoA reductase is attributed to active metabolites. IN VITRO
studies suggest the importance of atorvastatin metabolism by cytochrome P450
3A4, consistent with increased plasma concentrations of atorvastatin in humans
following coadministration with erythromycin, a known inhibitor of this
isoenzyme (see PRECAUTIONS, Drug Interactions). In animals, the ortho-hydroxy
metabolite undergoes further glucuronidation.
EXCRETION: Atorvastatin and its metabolites are eliminated primarily in bile
following hepatic and/or extrahepatic metabolism; however, the drug does not
appear to undergo enterohepatic recirculation. Mean plasma elimination half-life
of atorvastatin in humans is approximately 14 hours, but the half-life of
inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the
contribution of active metabolites. Less than 2% of a dose of atorvastatin is
recovered in urine following oral administration.
SPECIAL POPULATIONS
GERIATRIC: Plasma concentrations of atorvastatin are higher (approximately 40%
for Cmax and 30% for AUC) in healthy elderly subjects (age (>/=)65 years) than
in young adults. LDL-C reduction is comparable to that seen in younger patient
populations given equal doses of ATORLIP.
PEDIATRIC: Pharmacokinetic data in the pediatric population are not available.
GENDER: Plasma concentrations of atorvastatin in women differ from those in men
(approximately 20% higher for Cmax and 10% lower for AUC); however, there is no
clinically significant difference in LDL-C reduction with ATORLIP between men
and women.
RENAL INSUFFICIENCY: Renal disease has no influence on the plasma
concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in
patients with renal dysfunction is not necessary (see DOSAGE AND
ADMINISTRATION).
HEMODIALYSIS: While studies have not been conducted in patients with end-stage
renal disease, hemodialysis is not expected to significantly enhance clearance
of atorvastatin since the drug is extensively bound to plasma proteins.
HEPATIC INSUFFICIENCY: In patients with chronic alcoholic liver disease, plasma
concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-
fold greater in patients with Childs- Pugh A disease. Cmax and AUC are
approximately 16-fold and 11-fold increased, respectively, in patients with
Childs-Pugh B disease (see CONTRAINDICATIONS).
CLINICAL STUDIES:
HYPERCHOLESTEROLEMIA (HETEROZYGOUS FAMILIAL AND NONFAMILIAL) AND MIXED
DYSLIPIDEMIA (FREDRICKSON TYPES IIA AND IIB)
ATORLIP reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in
patients with hypercholesterolemia and mixed dyslipidemia. Therapeutic response
is seen within 2 weeks, and maximum response is usually achieved within 4 weeks
and maintained during chronic therapy.
ATORLIP is effective in a wide variety of patient populations with
hypercholesterolemia, with and without hypertriglyceridemia, in men and women,
and in the elderly. Experience in pediatric patients has been limited to
patients with homozygous FH.
In two multicenter, placebo-controlled, dose- response studies in patients with
hypercholesterolemia, ATORLIP given as a single dose over 6 weeks significantly
reduced total-C, LDL-C, apo B, and TG (Pooled results are provided in Table 1).
TABLE 1. DOSE-RESPONSE IN PATIENTS WITH PRIMARY HYPERCHOLESTEROLEMIA
(ADJUSTED MEAN % CHANGE FROM BASELINE)(A)
Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/HDL-C
-----------------------------------------------------------------------------------------------------------------------------------------------------------------
Placebo 21 4 4 3 10 -3 7
10 22 -29 -39 -32 -19 6 -34
20 20 -33 -43 -35 -26 9 -41
40 21 -37 -50 -42 -29 6 -45
80 23 -45 -60 -50 -37 5 -53
(A) Results are pooled from 2 dose-response studies.
In three multicenter, double-blind studies in patients with
hypercholesterolemia, ATORLIP was compared to other HMG-CoA reductase
inhibitors. After randomization, patients were treated for 16 weeks with either
ATORLIP 10 mg per day or a fixed dose of the comparative agent (Table 2).
TABLE 2. MEAN PERCENT CHANGE FROM BASELINE AT END POINT
(DOUBLE-BLIND, RANDOMIZED, ACTIVE-CONTROLLED TRIALS)
Treatment Non-HDL-C/
(Daily Dose) N Total-C LDL-C Apo B TG HDL-C HDL-C
STUDY 1
Atorvastatin
10 mg 707 -27(a) -36(a) -28(a) -17(a) +7 -37(a)
Lovastatin
20 mg 191 -19 -27 -20 -6 +7 -28
95% CI for
Diff(1) -9.2, -10.7, -10.0, -15.2, -1.7, -11.1,
-6.5 -7.1 -6.5 -7.1 2.0 -7.1
STUDY 2
Atorvastatin
10 mg 222 -25(b) -35(b) -27(b) -17 (b) +6 -36(b)
Pravastatin
20 mg 77 -17 -23 -17 -9 +8 -28
95% CI for
Diff(1) -10.8, -14.5, -13.4 , -14.1, -4.9, -11.5,
-6.1 -8.2 -7.4 -0.7 1.6 -4.1
STUDY 3
Atorvastatin
10 mg 132 -29(c) -37(c) -34(c) -23(c) +7 -39(c)
Simvastatin
10 mg 45 -24 -30 -30 -15 +7 -33
95% CI for
Diff(1) -8.7, -10.1, -8.0, -15.1, -4.3, -9.6,
-2.7 -2.6 -1.1 -0.7 3.9 -1.9
(1) A negative value for the 95% CI for the difference between treatments
favors atorvastatin for all except HDL-C, for which a positive value favors
atorvastatin. If the range does not include 0, this indicates a statistically
significant difference.
(a) Significantly different from lovastatin, ANCOVA, p(=)0.05
(b) Significantly different from pravastatin, ANCOVA, p(=)0.05
(c) Significantly different from simvastatin, ANCOVA, p(=)0.05
The impact on clinical outcomes of the differences in lipid-altering effects
between treatments shown in Table 2 is not known. Table 2 does not contain data
comparing the effects of atorvastatin 10 mg and higher doses of lovastatin,
pravastatin, and simvastatin. The drugs compared in the studies summarized in
the table are not necessarily interchangeable.
In a large clinical study, the number of patients meeting their National
Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) II target LDL-C
levels on 10 mg of ATORLIP daily was assessed. After 16 weeks, 156/167 (93%) of
patients with less than 2 risk factors for CHD and baseline LDL-C (>/=)190 mg/dL
reached a target of (=)160 mg/dL; 141/218 (65%) of patients with 2 or more
risk factors for CHD and LDL-C (>/=)160 mg/dL achieved a level of (=)130 mg/dL
LDL-C, and 21/113 (19%) of patients with CHD and LDL-C (>/=)130 mg/dL reached a
target level of (=)100 mg/dL LDL-C.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
In a study without a concurrent control group, 29 patients ages 6 to 37 years
with homozygous FH received maximum daily doses of 20 to 80 mg of ATORLIP. The
mean LDL-C reduction in this study was 18%. Twenty-five patients with a
reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of
24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29
patients had absent LDL-receptor function. Of these, 2 patients also had a
portacaval shunt and had no significant reduction in LDL-C. The remaining 3
receptor-negative patients had a mean LDL-C reduction of 22%.
INDICATIONS AND USAGE:
ATORLIP is indicated as an adjunct to diet to reduce elevated total-C, LDL-C,
apo B, and TG levels in patients with primary hypercholesterolemia (heterozygous
familial and nonfamilial) and mixed dyslipidemia (FREDRICKSON Types IIa and
IIb).
ATORLIP is also indicated to reduce total-C and LDL-C in patients with
homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering
treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Therapy with lipid-altering agents should be a component of multiple-risk-factor
intervention in individuals at increased risk for atherosclerotic vascular
disease due to hypercholesterolemia. Lipid-altering agents should be used in
addition to a diet restricted in saturated fat and cholesterol only when the
response to diet and other nonpharmacological measures has been inadequate (see
NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP) GUIDELINES, summarized in Table
3).
TABLE 3. NCEP GUIDELINES FOR LIPID MANAGEMENT
Definite LDL-Cholesterol
Atherosclerotic Two or More Other MG/DL (MMOL/L)
Disease(a) Risk Factors(b) Initiation Minimum
Level Goal
No No >/=190 <160
(>/=4.9) (<4.1)
No Yes >/=160 <130
(>/=4.1) (<3.4)
Yes Yes or No >/=130(c) =100
(>/=3.4) (=2.6)
(a) Coronary heart disease or peripheral vascular disease (including
symptomatic carotid artery disease).
(b) Other risk factors for coronary heart disease (CHD) include: age (males:
(>/=)45 years; females: (>/=)55 years or premature menopause without estrogen
replacement therapy); family history of premature CHD; current cigarette
smoking; hypertension; confirmed HDL-C <35 mg/dL (<0.91 mmol/L); and diabetes
mellitus. Subtract 1 risk factor if HDL-C is (>/=)60 mg/dL ((>/=)1.6 mmol/L).
(c) In CHD patients with LDL-C levels 100 to 129 mg/dL, the physician should
exercise clinical judgment in deciding whether to initiate drug treatment.
At the time of hospitalization for an acute coronary event, consideration can be
given to initiating drug therapy at discharge if the LDL-C level is (>/=)130
mg/dL (NCEP-ATP II).
Prior to initiating therapy with ATORLIP, secondary causes for
hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism,
nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug
therapy, and alcoholism) should be excluded, and a lipid profile performed to
measure total-C, LDL-C, HDL-C, and TG. For patients with TG <400 mg/dL (<4.5
mmol/L), LDL-C can be estimated using the following equation: LDL-C = total-C -
(0.20 X (TG) + HDL-C). For TG levels >400 mg/dL (>4.5 mmol/L), this equation is
less accurate and LDL-C concentrations should be determined by
ultracentrifugation.
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 (including 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%,
0.2%, 0.6%, AND 2.3% FOR 10, 20, 40, AND 80MG, 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 BEFORE THE INITIATION
OF TREATMENT, AT 6 AND 12 WEEKS AFTER INITIATION OF THERAPY OR ELEVATION IN
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 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. 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 occurrence 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 PATIENTS
Patients should be advised to report promptly unexplained muscle pain,
tenderness, or weakness, particularly if accompanied by malaise or fever.
DRUG INTERACTIONS
The risk of myopathy during treatment with other drugs of this class is
increased with concurrent administration of cyclosporine, fibric acid
derivatives, niacin (nicotinic acid), erythromycin, azole antifungals (see
WARNINGS, (Skeletal Muscle)).
ANTACID: When atorvastatin and Maalox(R) TC suspension were coadministered,
plasma concentrations of atorvastatin decreased approximately 35%. However, LDL-
C reduction was not altered.
ANTIPYRINE: Because atorvastatin does not affect the pharmacokinetics of
antipyrine, interactions with other drugs metabolized via the same cytochrome
isozymes are not expected.
COLESTIPOL: Plasma concentrations of atorvastatin decreased approximately 25%
when colestipol and atorvastatin were coadministered. However, LDL-C reduction
was greater when atorvastatin and colestipol were coadministered than when
either drug was given alone.
CIMETIDINE: Atorvastatin plasma concentrations and LDL-C reduction were not
altered by coadministration of cimetidine.
DIGOXIN: When multiple doses of atorvastatin and digoxin were coadministered,
steady-state plasma digoxin concentrations increased by approximately 20%.
Patients taking digoxin should be monitored appropriately.
ERYTHROMYCIN: In healthy individuals, plasma concentrations of atorvastatin
increased approximately 40% with coadministration of atorvastatin and
erythromycin, a known inhibitor of cytochrome P450 3A4 (see WARNINGS, Skeletal
Muscle)).
ORAL CONTRACEPTIVES: Coadministration of atorvastatin and an oral contraceptive
increased AUC values for norethindrone and ethinyl estradiol by approximately
30% and 20%. These increases should be considered when selecting an oral
contraceptive for a woman taking atorvastatin.
TERFENADINE: Coadministration of atorvastatin and terfenadine did not produce a
clinically significant effect on the pharmacokinetics of terfenadine.
WARFARIN: Atorvastatin had no clinically significant effect on prothrombin time
when administered to patients receiving chronic warfarin treatment.
OTHER CONCOMITANT THERAPY: In clinical studies, atorvastatin was used
concomitantly with antihypertensive agents and estrogen replacement therapy
without evidence of clinically significant adverse interactions. Interaction
studies with specific agents have not been conducted.
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 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 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, 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 two years.
PREGNANCY
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/m(squared)).
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. ATORLIP
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 ATORLIP, 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 ATORLIP should not breast-feed (see
CONTRAINDICATIONS).
PEDIATRIC USE
Treatment experience in a pediatric population is limited to doses of ATORLIP 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 (>/=)70 years with doses of ATORLIP up to 80
mg/day has been evaluated in 221 patients. The safety and efficacy of ATORLIP in
this population were similar to those of patients <70 years of age.
DRUG INTERACTIONS:
The risk of myopathy during treatment with other drugs of this class is
increased with concurrent administration of cyclosporine, fibric acid
derivatives, niacin (nicotinic acid), erythromycin, azole antifungals (see
WARNINGS, (Skeletal Muscle)).
ANTACID: When atorvastatin and Maalox(R) TC suspension were coadministered,
plasma concentrations of atorvastatin decreased approximately 35%. However, LDL-
C reduction was not altered.
ANTIPYRINE: Because atorvastatin does not affect the pharmacokinetics of
antipyrine, interactions with other drugs metabolized via the same cytochrome
isozymes are not expected.
COLESTIPOL: Plasma concentrations of atorvastatin decreased approximately 25%
when colestipol and atorvastatin were coadministered. However, LDL-C reduction
was greater when atorvastatin and colestipol were coadministered than when
either drug was given alone.
CIMETIDINE: Atorvastatin plasma concentrations and LDL-C reduction were not
altered by coadministration of cimetidine.
DIGOXIN: When multiple doses of atorvastatin and digoxin were coadministered,
steady-state plasma digoxin concentrations increased by approximately 20%.
Patients taking digoxin should be monitored appropriately.
ERYTHROMYCIN: In healthy individuals, plasma concentrations of atorvastatin
increased approximately 40% with coadministration of atorvastatin and
erythromycin, a known inhibitor of cytochrome P450 3A4 (see WARNINGS, Skeletal
Muscle)).
ORAL CONTRACEPTIVES: Coadministration of atorvastatin and an oral contraceptive
increased AUC values for norethindrone and ethinyl estradiol by approximately
30% and 20%. These increases should be considered when selecting an oral
contraceptive for a woman taking atorvastatin.
TERFENADINE: Coadministration of atorvastatin and terfenadine did not produce a
clinically significant effect on the pharmacokinetics of terfenadine.
WARFARIN: Atorvastatin had no clinically significant effect on prothrombin time
when administered to patients receiving chronic warfarin treatment.
OTHER CONCOMITANT THERAPY: In clinical studies, atorvastatin was used
concomitantly with antihypertensive agents and estrogen replacement therapy
without evidence of clinically significant adverse interactions. Interaction
studies with specific agents have not been conducted.
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 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 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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
ATORLIP is generally well-tolerated. Adverse reactions have usually been mild
and transient. In controlled clinical studies of 2502 patients, <2% of patients
were discontinued due to adverse experiences attributable to atorvastatin. The
most frequent adverse events thought to be related to atorvastatin were
constipation, flatulence, dyspepsia, and abdominal pain.
CLINICAL ADVERSE EXPERIENCES
Adverse experiences reported in (>/=)2% of patients in placebo-controlled
clinical studies of atorvastatin, regardless of causality assessment, are shown
in Table 4.
TABLE 4. ADVERSE EVENTS IN PLACEBO-CONTROLLED STUDIES
(% OF PATIENTS)
BODY SYSTEM/ Placebo Atorvastatin Atorvastatin Atorvastatin Atorvastatin
Adverse Event 10 mg 20 mg 40 mg 80 mg
N270 N=863 N=36 N=79 N=94
BODY AS A WHOLE
Infection 10.0 10.3 2.8 10.1 7.4
Headache 7.0 5.4 16.7 2.5 6.4
Accidental Injury 3.7 4.2 0.0 1.3 3.2
Flu Syndrome 1.9 2.2 0.0 2.5 3.2
Abdominal Pain 0.7 2.8 0.0 3.8 2.1
Back Pain 3.0 2.8 0.0 3.8 1.1
Allergic Reaction 2.6 0.9 2.8 1.3 0.0
Asthenia 1.9 2.2 0.0 3.8 0.0
DIGESTIVE SYSTEM
Constipation 1.8 2.1 0.0 2.5 1.1
Diarrhea 1.5 2.7 0.0 3.8 5.3
Dyspepsia 4.1 2.3 2.8 1.3 2.1
Flatulence 3.3 2.1 2.8 1.3 1.1
RESPIRATORY SYSTEM
Sinusitis 2.6 2.8 0.0 2.5 6.4
Pharyngitis 1.5 2.5 0.0 1.3 2.1
SKIN AND APPENDAGES
Rash 0.7 3.9 2.8 3.8 1.1
MUSCULOSKELETAL SYSTEM
Arthralgia 1.5 2.0 0.0 5.1 0.0
Myalgia 1.1 3.2 5.6 1.3 0.0
The following adverse events were reported, regardless of causality assessment
in patients treated with atorvastatin in clinical trials. The events in italics
occurred in (>/=)2% of patients and the events in plain type occurred in <2% of
patients.
BODY AS A WHOLE: CHEST PAIN, face edema, fever, neck rigidity, malaise,
photosensitivity reaction, generalized edema.
DIGESTIVE SYSTEM: NAUSEA, gastroenteritis, liver function tests abnormal,
colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis,
eructation, glossitis, mouth ulceration, anorexia, increased appetite,
stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis,
melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis,
hepatitis, pancreatitis, cholestatic jaundice.
RESPIRATORY SYSTEM: BRONCHITIS, RHINITIS, pneumonia, dyspnea, asthma, epistaxis.
NERVOUS SYSTEM: INSOMNIA, DIZZINESS, paresthesia, somnolence, amnesia, abnormal
dreams, libido decreased, emotional lability, incoordination, peripheral
neuropathy, torticollis, facial paralysis, hyperkinesia, depression,
hypesthesia, hypertonia.
MUSCULOSKELETAL SYSTEM: ARTHRITIS, leg cramps, bursitis, tenosynovitis,
myasthenia, tendinous contracture, myositis.
SKIN AND APPENDAGES: Pruritus, contact dermatitis, alopecia, dry skin, sweating,
acne, urticaria, eczema, seborrhea, skin ulcer.
UROGENITAL SYSTEM: URINARY TRACT INFECTION, urinary frequency, cystitis,
hematuria, impotence, dysuria, kidney calculus, nocturia, epididymitis,
fibrocystic breast, vaginal hemorrhage, albuminuria, breast enlargement,
metrorrhagia, nephritis, urinary incontinence, urinary retention, urinary
urgency, abnormal ejaculation, uterine hemorrhage.
SPECIAL SENSES: Amblyopia, tinnitus, dry eyes, refraction disorder, eye
hemorrhage, deafness, glaucoma, parosmia, taste loss, taste perversion.
CARDIOVASCULAR SYSTEM: Palpitation, vasodilation, syncope, migraine, postural
hypotension, phlebitis, arrhythmia, angina pectoris, hypertension.
METABOLIC AND NUTRITIONAL DISORDERS: PERIPHERAL EDEMA, hyperglycemia, creatine
phosphokinase increased, gout, weight gain, hypoglycemia.
HEMIC AND LYMPHATIC SYSTEM: Ecchymosis, anemia, lymphadenopathy,
thrombocytopenia, petechia.
POSTINTRODUCTION REPORTS
Adverse events associated with ATORLIP that have been received since market
introduction, that are not listed above, and that may have no causal
relationship to drug include the following: angioneurotic edema.
OVERDOSAGE:
There is no specific treatment for atorvastatin overdosage. In the event of an
overdose, the patient should be treated symptomatically, and supportive measures
instituted as required. Due to extensive drug binding to plasma proteins,
hemodialysis is not expected to significantly enhance atorvastatin clearance.
DOSAGE AND ADMINISTRATION:
The patient should be placed on a standard cholesterol-lowering diet before
receiving ATORLIP and should continue on this diet during treatment with
ATORLIP.
HYPERCHOLESTEROLEMIA (HETEROZYGOUS FAMILIAL AND NONFAMILIAL) AND MIXED
DYSLIPIDEMIA (FREDRICKSON TYPES IIA AND IIB)
The recommended starting dose of ATORLIP is 10 mg once daily. The dosage range
is 10 to 80 mg once daily. ATORLIP can be administered as a single dose at any
time of the day, with or without food. Therapy should be individualized
according to goal of therapy and response (see NCEP GUIDELINES, summarized in
Table 3). After initiation and/or upon titration of ATORLIP, lipid levels should
be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C
levels be used to initiate and assess treatment response. Only if LDL-C levels
are not available, should total-C be used to monitor therapy.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
The dosage of ATORLIP in patients with homozygous FH is 10 to 80 mg daily.
ATORLIP should be used as an adjunct to other lipid-lowering treatments (e.g.,
LDL apheresis) in these patients or if such treatments are unavailable.
CONCOMITANT THERAPY
Atorvastatin may be used in combination with a bile acid binding resin for
additive effect. The combination of HMG-CoA reductase inhibitors and fibrates
should generally be avoided (see WARNINGS, Skeletal Muscle, and PRECAUTIONS,
Drug Interactions for other drug-drug interactions).
DOSAGE IN PATIENTS WITH RENAL INSUFFICIENCY
Renal disease does not affect the plasma concentrations nor LDL-C reduction of
atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not
necessary.
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