Components:
Method of action:
Treatment option:
Medically reviewed by Oliinyk Elizabeth Ivanovna, PharmD. Last updated on 06.04.2022
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Dosage Forms And Strengths
LIPITOR tablets are white elliptical, film-coated, and are available in four strengths (see Table 1).
Table 1: LIPITOR Tablet
Strengths and Identifying Features
Tablet Strength | Identifying Features |
10 mg of atorvastatin | “PD 155” on one side and “10” on the other |
20 mg of atorvastatin | “PD 156” on one side and “20” on the other. |
40 mg of atorvastatin | “PD 157’ on one side and “40” on the other |
80 mg of atorvastatin | “PD 158” on one side and “80” on the other |
Storage And Handling
10 mg tablets (10 mg of atorvastatin):coded “PD 155” on one side and “10” on the other.
NDC 0071-0155-23 bottles of 90
NDC 0071-0155-34 bottles of
5000
NDC 0071-0155-40 10 x 10 unit
dose blisters
NDC 0071-0155-10 bottles of
1000
20 mg tablets (20 mg of atorvastatin): coded “PD 156” on one side and “20” on the other.
NDC 0071-0156-23 bottles of 90
NDC 0071-0156-40 10 x 10 unit dose
blisters
NDC 0071-0156-94 bottles of
5000
NDC 0071-0156-10 bottles of
1000
40 mg tablets (40 mg of atorvastatin): coded “PD 157” on oneside and “40” on the other.
NDC 0071-0157-23 bottles of 90
NDC 0071-0157-73 bottles of 500
NDC 0071-0157-88 bottles of
2500
NDC 0071-0157-40 10 x 10 unit dose
blisters
80 mg tablets (80 mg of atorvastatin): coded “PD 158” on one side and “80” on the other.
NDC 0071-0158-23 bottles of 90
NDC 0071-0158-73 bottles of 500
NDC 0071-0158-88 bottles of
2500
NDC 0071-0158-92 8 x 8 unit dose
blisters
Storage
Store at controlled room temperature 20 -25°C (68-77°F).
Distributed by: Parke-Davis, Division of Pfizer Inc., NY, NY 10017. Revised: May 2017
Therapy with lipid-alteringagents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular diseasedue to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, LIPITOR can be started simultaneously with diet.
Prevention Of Cardiovascular Disease In Adults
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, LIPITOR is indicated to:
- Reduce the risk of myocardial infarction
- Reduce the risk of stroke
- Reduce the risk for revascularization procedures and angina
In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, LIPITOR is indicated to:
- Reduce the risk of myocardial infarction
- Reduce the risk of stroke
In adult patients with clinically evident coronary heart disease, LIPITOR is indicated to:
- Reduce the risk of non-fatalmyocardial infarction
- Reduce the risk of fatal and non-fatal stroke
- Reduce the risk for revascularization procedures
- Reduce the risk of hospitalization for CHF
- Reduce the risk of angina
Hyperlipidemia
LIPITOR is indicated:
- As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TGlevels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and non familial) and mixed dyslipidemia(Fredrickson Types IIa and IIb);
- As an adjunct to diet for the treatment of adult patients with elevated serum TG levels (Fredrickson Type IV);
- For the treatment of adult patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
- To reduce total-C and LDL-Cin patients with homozygous familial hypercholesterolemia(HoFH)as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable;
- As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH)if after an adequate trial of diet therapy the following findings are present:
- LDL-C remains ≥ 190 mg/dL or
- LDL-C remains ≥ 160 mg/dL and:
- there is a positive family history of premature cardiovascular disease or
- two or more other CVD risk factors are present in the pediatric patient
Limitations Of Use
LIPITOR has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons(Fredrickson Types I and V).
Hyperlipidemia And Mixed Dyslipidemia
The recommended starting dose of LIPITOR is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of LIPITOR is 10to 80mg once daily. LIPITOR can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of LIPITOR should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of LIPITOR, lipid levels should be analyzed within 2 to 4weeks and dosage adjusted accordingly.
Heterozygous Familial Hypercholesterolemia In Pediatric Patients (10Years to17Years of Age)
The recommended starting dose of LIPITOR is 10 mg/day; the usual dose range is 10 to 20mg orally once daily. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.
Homozygous Familial Hypercholesterolemia
The dosage of LIPITOR in patients with HoFH is 10to 80mg daily. LIPITOR 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 Lipid-Lowering Therapy
LIPITOR may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution.
Dosage In Patients With Renal Impairment
Renal disease does not affect the plasma concentrations nor LDL-Creduction of LIPITOR; thus, dosage adjustment in patients with renal dysfunction is not necessary.
Dosage In Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Or Certain Protease Inhibitors
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with LIPITOR should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing LIPITOR and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with LIPITOR should be limited to20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed. In patients taking the HIV protease inhibitornelfinaviror the hepatitis C protease inhibitor boceprevir, therapy with LIPITOR should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed.
- Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels
- Hypersensitivity to Any Component of This Medication
- Pregnancy .
- Lactation.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
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.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximalmuscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
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 or if muscle signs and symptoms persist after discontinuing LIPITOR. 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, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavirplus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with LIPITOR and fibric acid derivatives, erythromycin, clarithromycin, a combination ofsaquinavir plusritonavir, lopinavir plus ritonavir, darunavir plusritonavir, fosamprenavir, or fosamprenavir plus ritonavir,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. 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 Table2.
Table 2: Drug Interactions
Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents | Prescribing Recommendations |
Cyclosporine, HIVprotease inhibitors (tipranavir plus ritonavir), hepatitis Cprotease inhibitor (telaprevir) | Avoid atorvastatin |
HIV pro tease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
Clarithromycin, itraconazole, HIV pro tease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fo s amprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
HIV pro tease inhibitor (nelfinavir) Hepatitis Cprotease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
*Use with caution and with the lowest dose necessary |
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatinco-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
LIPITOR therapy should be temporarily withheld or discontinued in any patient with anacute, 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 ( > 3times 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, and80 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 enzyme tests be obtained prior to initiating therapy with LIPITOR and repeated as clinically indicated. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIPITOR, promptly interrupt therapy. If an alternate etiologyis not found, do not restart LIPITOR.
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.
Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIPITOR.
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 steroidhormones, 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 120mg/kg doseresulted in a systemic exposure approximately 16times 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 2years at doses up to 400 mg/kg/day or in rats at doses upto 100 mg/kg/day. These doses were 6 to 11times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum recommended human dose of 80mg/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 4,731subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the LIPITOR80mg 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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Patients taking LIPITOR shouldbe 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. Patients should also be advised to in for mother 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 particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing LIPITOR. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities ( > 1liter) 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 enzyme tests be performed before the initiation of LIPITOR and if signs or symptoms of liver injury occur. All patients treated with LIPITOR should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Embryofetal Toxicity
Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment and to inform their healthcare provider of a known or suspected pregnancy.
Lactation
Advise women not to breastfeed during treatment with LIPITOR.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and100mg/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 16times the mean human plasma drug exposure after an 80 mg oraldose.
A 2-year carcinogenicity studyin 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 6times 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 negativein the in vivo mouse micronucleus test.
In female rats, atorvastatinat doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effectson fertility. Studies in male 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 10rats treated with 100 mg/kg/dayof atorvastatinfor 3 months (16 times the human AUC at the 80mg dose); testis weights were significantly lower at 30 and 100mg/kg and epididymal weight was lower at 100mg/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.
Use In Specific Populations
Pregnancy
Risk Summary
LIPITOR is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, LIPITOR may cause fetal harm when administered to a pregnant woman. LIPITOR should be discontinued as soon as pregnancy is recognized. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformation sat doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD)of 80 mg, based on body surface area (mg/m²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥ 6 times the MRHD (see Data).
The estimated back ground risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 1520%, respectively.
Data
Human Data
Limited published data on atorvastatin calcium from observational studies, meta-analyses and case report shave not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥ 3to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Animal Data
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300mg/kg/day and 100mg/kg/day, respectively. Atorvastatin was notteratogenic in rats at doses up to 300mg/kg/day or in rabbits at doses up to 100mg/kg/day. These doses resulted in multiples of about 30 times (rat) or20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m²).In rats, the maternally toxic dose of 300mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100mg/kg/day in rabbits, there was increased post-implantation loss, and at 100mg/kg/day fetal body weights were decreased.
In a study inpregnantratsadministered20, 100, or 225 mg/kg/day from gestation day7 through to lactation day20(weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21at 100 mg/kg/day, and through postnatal day91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22times (225 mg/kg) the human exposure at the MRHD, based on AUC.
Lactation
Risk Summary
LIPITOR use is contraindicated during breastfeeding. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. It is not known whether at orvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and at orvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfedinfant, advise women that breastfeeding is not recommended during treatment with LIPITOR.
Females And Males Of Reproductive Potential
Contraception
LIPITOR may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LIPITOR.
Pediatric Use
Heterozygous Familial Hypercholesterolemia(HeFH)
The safety and effectiveness of LIPITOR have been established in pediatric patients,10years to 17 years of age, with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apoB levels when, after an adequate trial of diet therapy, the following are present:
- LDL-C ≥ 190 mg/dL, or
- LDL-C ≥ 160 mg/Dl and
- A positive family history of FH, or premature CVD in a first, or second-degree relative, or
- two or more other CVD risk factors are present.
Use of LIPITOR for this indication is supported by evidence from:
- A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls,10 years to 17 years of age. Patients treated with 10 mg or20 mg daily LIPITOR had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls.
- A three year open-label uncontrolled trial that included163 pediatric patients 10 to 15years of age with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of LIPITOR in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design
Advise postmenarchal girls of contraception recommendations, if appropriate for the patient.
The long-term efficacy of LIPITOR therapy initiated inchild hood to reduce morbidity and mortality in adulthood has not been established.
The safety and efficacy of LIPITOR have not been established in pediatric patients younger than 10 years of age with HeFH.
Homozygous Familial Hypercholesterolemia (HoFH)
Clinical efficacy of LIPITOR with dosages up to 80mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients.
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 someolder 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.
SIDE EFFECTS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy
Liver enzyme abnormalities
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In the LIPITOR placebo-controlled clinical trial database of 16,066patients (8755 LIPITOR vs. 7311 placebo; age range 10-93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other)with a median treatment duration of 53 weeks, 9.7% of patients on LIPITOR and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with LIPITOR that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).
The most commonly reported adverse reactions(incidence ≥ 2%and greater than placebo) regardless of causality, in patient streated with LIPITOR in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 3 summarizes the frequency of clinicaladverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with LIPITOR (n=8755), from seventeen placebo-controlled trials.
Table 3: Clinical adverse
reactions occurring in ≥ 2% in patients treated with any dose of LIPITOR and at an incidence
greater than placebo regardless of causality (% of patients).
Adverse Reaction* | Any dose N=8755 |
10 mg N=3908 |
20 mg N=188 |
40 mg N=604 |
80 mg N=4055 |
Placebo N=7311 |
Nasopharyngitis | 8.3 | 12.9 | 5.3 | 7.0 | 4.2 | 8.2 |
Arthralgia | 6.9 | 8.9 | 11.7 | 10.6 | 4.3 | 6.5 |
Diarrhea | 6.8 | 7.3 | 6.4 | 14.1 | 5.2 | 6.3 |
Pain in extremity | 6.0 | 8.5 | 3.7 | 9.3 | 3.1 | 5.9 |
Urinary tract infection | 5.7 | 6.9 | 6.4 | 8.0 | 4.1 | 5.6 |
Dyspepsia | 4.7 | 5.9 | 3.2 | 6.0 | 3.3 | 4.3 |
Nausea | 4.0 | 3.7 | 3.7 | 7.1 | 3.8 | 3.5 |
Musculoskeletal pain | 3.8 | 5.2 | 3.2 | 5.1 | 2.3 | 3.6 |
Muscle Spasms | 3.6 | 4.6 | 4.8 | 5.1 | 2.4 | 3.0 |
Myalgia | 3.5 | 3.6 | 5.9 | 8.4 | 2.7 | 3.1 |
Insomnia | 3.0 | 2.8 | 1.1 | 5.3 | 2.8 | 2.9 |
Pharyngolaryngeal pain | 2.3 | 3.9 | 1.6 | 2.8 | 0.7 | 2.1 |
*Adverse Reaction ≥ 2% in any dose greater than placebo |
Other Adverse Reactions Reported in Placebo-controlled Studies Include:
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
In ASCOT involving 10,305 participants (age range 40-80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with LIPITOR 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with LIPITOR was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.
Collaborative Atorvastatin Diabetes Study (CARDS)
In CARDS involving 2,838 subjects (age range 39-77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with LIPITOR 10 mg daily(n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.
Treating to New Targets Study(TNT)
In TNT involving 10,001 subjects (age range 29-78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0%Asians, 2.0% other) with clinically evident CHD treated with LIPITOR10mg daily (n=5006) orLIPITOR80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%,respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations ( ≥ 3x ULN twice within 4-10days) occurred in 62 (1.3%) individuals with atorvastatin80mg andinnine(0.2%)individualswithatorvastatin10mg.ElevationsofCK( ≥ 10x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).
Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)
In IDEAL involving 8,888 subjects (age range 26-80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with LIPITOR80 mg/day (n=4439)or simvastatin 20-40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In SPARCL involving 4731 subjects (age range 21-92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with LIPITOR 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations ( ≥ 3xULN twice within 4-10days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK ( > 10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group.
In a post-hoc analysis, LIPITOR 80 mg reduced the incidence of ischemic stroke(218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%)compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17LIPITOR vs. 18placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) LIPITOR vs.2 (4%) placebo].
There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the LIPITOR 80mg/day group vs. 211(8.9%)in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the LIPITOR80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the LIPITOR80 mg group (5.0%) than in the placebo group(4.0%).
Adverse Reactions From Clinical Studies Of LIPITOR In Pediatric Patients
In a 26-weekcontrolled study in boys and postmenarchal girls with HeFH (ages 10years to17 years)(n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR10 to 20mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apoB levels, was generally similar to that of placebo.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of LIPITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with LIPITOR therapy reported since market introduction, that are notlisted above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.
There have been rare reports of immune-mediated necrotizing myopathy associated with stat in use.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports aregenerally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) andsymptom resolution (median of 3 weeks).
DRUG INTERACTIONS
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole).
Strong Inhibitors Of CYP 3A4
LIPITOR is metabolized by cytochrome P450 3A4.Concomitant administration of LIPITOR with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
Clarithromycin
Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 80 mg with clarithromycin (500mg twice daily)compared to that of LIPITOR alone. Therefore, in patients taking clarithromycin, caution should be used when the LIPITOR dose exceeds 20mg.
Combination Of Protease Inhibitors
Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of LIPITOR alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of LIPITOR should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing LIPITOR and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of LIPITOR should not exceed 20 mg and should be used with caution. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of LIPITOR should not exceed 40 mg and close clinical monitoring is recommended.
Itraconazole
Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 40 mg and itraconazole200mg. Therefore, in patients taking itraconazole, caution should be used when the LIPITOR dose exceeds 20 mg .
Grapefruit Juice
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption ( > 1.2 liters per day).
Cyclosporine
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 10 mg and cyclosporine 5.2 mg/kg/day compared to that of LIPITOR alone . The co-administration of LIPITOR with cyclosporine should be avoided.
Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of LIPITOR with gemfibrozil should be avoided.
Other Fibrates
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, LIPITOR should be administered with caution when used concomitantly with other fibrates.
Niacin
The risk of skeletal muscle effects may be enhanced when LIPITOR is used in combination with niacin; a reduction in LIPITOR dosage should be considered in this setting.
Rifampin Or Other Inducers Of Cytochrome P450 3A4
Concomitant administration of LIPITOR with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductionsin plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of LIPITOR with rifampin is recommended, as delayed administration of LIPITOR after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Digoxin
When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients takingdigoxin should be monitored appropriately.
Oral Contraceptives
Co-administration of LIPITOR and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol.These increases should be considered when selecting an oral contraceptive for a woman taking LIPITOR.
Warfarin
LIPITOR had no clinically significant effect onprothrombin time when administered to patients receiving chronic warfarin treatment.
Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported withatorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Risk Summary
LIPITOR is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, LIPITOR may cause fetal harm when administered to a pregnant woman. LIPITOR should be discontinued as soon as pregnancy is recognized. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformation sat doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD)of 80 mg, based on body surface area (mg/m²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥ 6 times the MRHD (see Data).
The estimated back ground risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 1520%, respectively.
Data
Human Data
Limited published data on atorvastatin calcium from observational studies, meta-analyses and case report shave not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥ 3to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Animal Data
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300mg/kg/day and 100mg/kg/day, respectively. Atorvastatin was notteratogenic in rats at doses up to 300mg/kg/day or in rabbits at doses up to 100mg/kg/day. These doses resulted in multiples of about 30 times (rat) or20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m²).In rats, the maternally toxic dose of 300mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100mg/kg/day in rabbits, there was increased post-implantation loss, and at 100mg/kg/day fetal body weights were decreased.
In a study inpregnantratsadministered20, 100, or 225 mg/kg/day from gestation day7 through to lactation day20(weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21at 100 mg/kg/day, and through postnatal day91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22times (225 mg/kg) the human exposure at the MRHD, based on AUC.
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy
Liver enzyme abnormalities
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In the LIPITOR placebo-controlled clinical trial database of 16,066patients (8755 LIPITOR vs. 7311 placebo; age range 10-93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other)with a median treatment duration of 53 weeks, 9.7% of patients on LIPITOR and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with LIPITOR that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).
The most commonly reported adverse reactions(incidence ≥ 2%and greater than placebo) regardless of causality, in patient streated with LIPITOR in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 3 summarizes the frequency of clinicaladverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with LIPITOR (n=8755), from seventeen placebo-controlled trials.
Table 3: Clinical adverse
reactions occurring in ≥ 2% in patients treated with any dose of LIPITOR and at an incidence
greater than placebo regardless of causality (% of patients).
Adverse Reaction* | Any dose N=8755 |
10 mg N=3908 |
20 mg N=188 |
40 mg N=604 |
80 mg N=4055 |
Placebo N=7311 |
Nasopharyngitis | 8.3 | 12.9 | 5.3 | 7.0 | 4.2 | 8.2 |
Arthralgia | 6.9 | 8.9 | 11.7 | 10.6 | 4.3 | 6.5 |
Diarrhea | 6.8 | 7.3 | 6.4 | 14.1 | 5.2 | 6.3 |
Pain in extremity | 6.0 | 8.5 | 3.7 | 9.3 | 3.1 | 5.9 |
Urinary tract infection | 5.7 | 6.9 | 6.4 | 8.0 | 4.1 | 5.6 |
Dyspepsia | 4.7 | 5.9 | 3.2 | 6.0 | 3.3 | 4.3 |
Nausea | 4.0 | 3.7 | 3.7 | 7.1 | 3.8 | 3.5 |
Musculoskeletal pain | 3.8 | 5.2 | 3.2 | 5.1 | 2.3 | 3.6 |
Muscle Spasms | 3.6 | 4.6 | 4.8 | 5.1 | 2.4 | 3.0 |
Myalgia | 3.5 | 3.6 | 5.9 | 8.4 | 2.7 | 3.1 |
Insomnia | 3.0 | 2.8 | 1.1 | 5.3 | 2.8 | 2.9 |
Pharyngolaryngeal pain | 2.3 | 3.9 | 1.6 | 2.8 | 0.7 | 2.1 |
*Adverse Reaction ≥ 2% in any dose greater than placebo |
Other Adverse Reactions Reported in Placebo-controlled Studies Include:
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
In ASCOT involving 10,305 participants (age range 40-80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with LIPITOR 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with LIPITOR was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.
Collaborative Atorvastatin Diabetes Study (CARDS)
In CARDS involving 2,838 subjects (age range 39-77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with LIPITOR 10 mg daily(n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.
Treating to New Targets Study(TNT)
In TNT involving 10,001 subjects (age range 29-78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0%Asians, 2.0% other) with clinically evident CHD treated with LIPITOR10mg daily (n=5006) orLIPITOR80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%,respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations ( ≥ 3x ULN twice within 4-10days) occurred in 62 (1.3%) individuals with atorvastatin80mg andinnine(0.2%)individualswithatorvastatin10mg.ElevationsofCK( ≥ 10x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).
Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)
In IDEAL involving 8,888 subjects (age range 26-80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with LIPITOR80 mg/day (n=4439)or simvastatin 20-40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In SPARCL involving 4731 subjects (age range 21-92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with LIPITOR 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations ( ≥ 3xULN twice within 4-10days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK ( > 10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group.
In a post-hoc analysis, LIPITOR 80 mg reduced the incidence of ischemic stroke(218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%)compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17LIPITOR vs. 18placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) LIPITOR vs.2 (4%) placebo].
There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the LIPITOR 80mg/day group vs. 211(8.9%)in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the LIPITOR80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the LIPITOR80 mg group (5.0%) than in the placebo group(4.0%).
Adverse Reactions From Clinical Studies Of LIPITOR In Pediatric Patients
In a 26-weekcontrolled study in boys and postmenarchal girls with HeFH (ages 10years to17 years)(n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR10 to 20mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apoB levels, was generally similar to that of placebo.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of LIPITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with LIPITOR therapy reported since market introduction, that are notlisted above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.
There have been rare reports of immune-mediated necrotizing myopathy associated with stat in use.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports aregenerally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) andsymptom resolution (median of 3 weeks).
There is no specific treatment for LIPITOR 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 LIPITOR clearance.
LIPITOR, 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.
Absorption
LIPITOR is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2hours. Extent of absorption increases in proportion to LIPITOR 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 LIPITOR is given with or without food. Plasma LIPITOR 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.
Distribution
Mean volume of distribution of LIPITOR is approximately 381 liters. LIPITOR 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, LIPITOR is likely to be secreted in human milk.
Metabolism
LIPITOR 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 LIPITOR. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of LIPITOR metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of LIPITOR in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion
LIPITOR 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 LIPITOR in humans is approximately 14hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30hours due to the contribution of active metabolites. Less than2% of a dose of LIPITOR is recovered in urine following oral administration.