Lipitor®
`(Atorvastatin Calcium) Tablets
`
`DESCRIPTION
`Lipitor® (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)-ß, δ-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
`(C33H34 FN2O5)2Ca(cid:127)3H2O and its molecular weight is 1209.42. Its structural formula is:
`
`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.
`Lipitor tablets for oral administration contain 10, 20, 40, or 80 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.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-
`limiting enzyme that converts 3-hydroxy-3-methylglutaryl-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.
`
`Spec # 0155G247-2
`
`1
`
`CFAD Exhibit 1050
`
`

`
`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, Lipitor 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;
`Lipitor also reduces LDL production and the number of LDL particles. Lipitor 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.
`Lipitor reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous
`FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Lipitor also
`reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein
`A-1. Lipitor reduces total-C, LDL-C, VLDL-C, apo B, TG, and
`non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Lipitor
`reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with
`dysbetalipoproteinemia. The effect of Lipitor on cardiovascular morbidity and mortality
`has not been determined.
`Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL,
`intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis.
`Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and
`small LDL particles, as well as in association with non-lipid metabolic risk factors for
`coronary heart disease. As such, total plasma TG has not consistently been shown to be
`an independent risk factor for CHD. Furthermore, the independent effect of raising HDL
`or lowering TG on the risk of coronary and 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
`
`Spec # 0155G247-2
`
`2
`
`

`
`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 14% 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 381 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 isozyme (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 extra-hepatic 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.
`Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly
`patient population compared to younger adults (see PRECAUTIONS section; Geriatric
`Use subsection).
`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
`
`Spec # 0155G247-2
`
`3
`
`

`
`clinically significant difference in LDL-C reduction with Lipitor 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)
`Lipitor 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.
`Lipitor 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, Lipitor 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
`TC
`LDL-C
`ApoB
`TG
`
`Dose
`
`N
`
`HDL-C
`
`Non-HDL-C/
`HDL-C
` 7
`–34
`–41
`–45
`–53
`
` 4
` 4
`21
`Placebo
`–39
`–29
`22
`10
`–43
`–33
`20
`20
`–50
`–37
`21
`40
`–60
`–45
`23
`80
`aResults are pooled from 2 dose-response studies
`
` 3
`–32
`–35
`–42
`–50
`
` 10
`–19
`–26
`–29
`–37
`
`-3
` 6
` 9
` 6
` 5
`
`In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24
`controlled trials, the median (25th and 75th percentile) percent changes from baseline in
`HDL-C for atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16),
`and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated
`
`Spec # 0155G247-2
`
`4
`
`

`
`consistent and significant decreases in total-C , LDL-C, TG, total-C/HDL-C, and LDL-
`C/HDL-C.
`In three multicenter, double-blind studies in patients with hypercholesterolemia, Lipitor
`was compared to other HMG-CoA reductase inhibitors. After randomization, patients
`were treated for 16 weeks with either Lipitor 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)
`Total-C
`LDL-C
`ApoB
`TG
`
`HDL-C
`
`Non-HDL-C/
`HDL-C
`
`N
`
`Treatment
`(Daily Dose)
`Study 1
`Atorvastatin 10 mg
`Lovastatin 20 mg
`95% CI for Diff1
`Study 2
`Atorvastatin 10 mg
`Pravastatin 20 mg
`95% CI for Diff1
`Study 3
`-39c
`-23c
`-34c
`-37c
`-29c
`+7
`Atorvastatin 10 mg
`+7
`Simvastatin 10 mg
`–33
`–15
`–30
`–30
`–24
`–4.3,3.9
`95% CI for Diff1
`–9.6,-1.9
`–15.1,-0.7
`–8.0,-1.1
`–10.1,-2.6
`–8.7,-2.7
`1A 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.
`aSignificantly different from lovastatin, ANCOVA, p ≤0.05
`bSignificantly different from pravastatin, ANCOVA, p ≤0.05
`cSignificantly different from simvastatin, ANCOVA, p ≤0.05
`
`-27a
`–19
`–9.2,-6.5
`
`-25b
`–17
`–10.8,-6.1
`
`-36a
`–27
`–10.7,-7.1
`
`-35b
`–23
`–14.5,-8.2
`
`-28a
`–20
`–10.0,-6.5
`
`-27b
`–17
`–13.4,-7.4
`
`707
`191
`
`222
`77
`
`132
`45
`
`-17a
`–6
`–15.2,-7.1
`
`-17b
`–9
`–14.1,-0.7
`
`+7
`+7
`–1.7,2.0
`
`+6
`+8
`–4.9,1.6
`
`-37a
`–28
`–11.1,-7.1
`
`-36b
`–28
`–11.5,-4.1
`
`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 Lipitor 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.
`Hypertriglyceridemia (Fredrickson Type IV)
`The response to Lipitor in 64 patients with isolated hypertriglyceridemia treated across
`several clinical trials is shown in the table below. For the atorvastatin-treated patients,
`median (min, max) baseline TG level was 565 (267-1502).
`
`Spec # 0155G247-2
`
`5
`
`

`
`TABLE 3. Combined Patients With Isolated Elevated TG:
`Median (min, max) Percent Changes From Baseline
`Placebo
`Atorvastatin 10 mg
`Atorvastatin 20 mg
`(N=12)
`(N=37)
`(N=13)
`-12.4 (-36.6, 82.7)
`-41.0 (-76.2, 49.4)
`-38.7 (-62.7, 29.5)
`-2.3 (-15.5, 24.4)
`-28.2 (-44.9, -6.8)
`-34.9 (-49.6, -15.2)
`3.6 (-31.3, 31.6)
`-26.5 (-57.7, 9.8)
`-30.4 (-53.9, 0.3)
`3.8 (-18.6, 13.4)
`13.8 (-9.7, 61.5)
`11.0 (-3.2, 25.2)
`-1.0 (-31.9, 53.2)
`-48.8 (-85.8, 57.3)
`-44.6 (-62.2, -10.8)
`-2.8 (-17.6, 30.0)
`-33.0 (-52.1, -13.3)
`-42.7 (-53.7, -17.4)
`
`Atorvastatin 80 mg
`(N=14)
`-51.8 (-82.8, 41.3)
`-44.4 (-63.5, -3.8)
`-40.5 (-60.6, -13.8)
`7.5 (-10.8, 37.2)
`-62.0 (-88.2, 37.6)
`-51.5 (-72.9, -4.3)
`
`Triglycerides
`Total-C
`LDL-C
`HDL-C
`VLDL-C
`non-HDL-C
`
`Dysbetalipoproteinemia (Fredrickson Type III)
`The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and
`2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III) are shown in the table
`below.
`
`TABLE 4. Open-Label Crossover Study of 16 Patients
`With Dysbetalipoproteinemia (Fredrickson Type III)
`Median % Change (min, max)
`Atorvastatin 10 mg
`Atorvastatin 80 mg
`
`-37 (-85, 17)
`-39 (-92, -8)
`-32 (-76, 9)
`-43 (-87, -19)
`
`-58 (-90, -31)
`-53 (-95, -30)
`-63 (-90, -8)
`-64 (-92, -36)
`
`Median (min, max) at
`Baseline mg/dL)
`442 (225, 1320)
`Total-C
`678 (273, 5990)
`Triglycerides
`215 (111, 613)
`IDL-C + VLDL-C
`411 (218, 1272)
`non-HDL-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 Lipitor. 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
`Lipitor is indicated:
`
`1.
`
`as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and
`to increase HDL-C in patients with primary hypercholesterolemia (heterozygous
`
`Spec # 0155G247-2
`
`6
`
`

`
`familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and
`IIb);
`
`2.
`
`3.
`
`4.
`
`as an adjunct to diet for the treatment of patients with elevated serum TG levels
`(Fredrickson Type IV);
`
`for the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson
`Type III) who do not respond adequately to diet;
`
`to reduce total-C and LDL-C in patients with homozygous familial
`hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL
`apheresis) or if such treatments are unavailable.
`
`Two or More Other
`Risk Factorsb
`No
`
`Yes
`
`Yes or No
`
`Definite
`Atherosclerotic
`Diseasea
`No
`
`No
`
`Yes
`
`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 5).
`TABLE 5. NCEP Guidelines for Lipid Management
`LDL-Cholesterol
`mg/dL (mmol/L)
`Initiation Level
`Minimum Goal
`≥190
`<160
`(≥4.9)
`(<4.1)
`≥160
`<130
`(<3.4)
`(≥4.1)
`≤100
`≥130c
`(≤2.6)
`(≥3.4)
`aCoronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
`bOther 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).
`cIn 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 Lipitor, secondary causes for hypercholesterolemia (eg,
`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.
`
`Spec # 0155G247-2
`
`7
`
`

`
`Lipitor has not been studied in conditions where the major lipoprotein abnormality is
`elevation of chylomicrons (Fredrickson Types I and V).
`
`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 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 both the initiation of therapy and any elevation of dose, and periodically
`(eg, 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.
`
`Spec # 0155G247-2
`
`8
`
`

`
`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
`Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria
`have been reported with atorvastatin and 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 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 (eg,
`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
`
`Spec # 0155G247-2
`
`9
`
`

`
`The risk of myopathy during treatment with 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® 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.
`Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when
`administered to patients receiving chronic warfarin treatment.
`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
`
`Spec # 0155G247-2
`
`10
`
`

`
`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.
`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
`
`Spec # 0155G247-2
`
`11
`
`

`
`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. Lipitor 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 Lipitor, 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 Lipitor should not breast-feed (see CONTRAINDICATIONS).
`Pediatric Use
`Treatment experience in a pediatric population is limited to doses of Lipitor 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
`The safety and efficacy of atorvastatin (10-80 mg) in the geriatric population (>65 years
`of age) was evaluated in the ACCESS study. In this 54-week open-label trial 1,958
`patients initiated therapy with atorvastatin 10 mg. Of these, 835 wer