LIPITOR- atorvastatin calcium tablet, film coated
PD-Rx Pharmaceuticals, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use LIPITOR safely and effectively. See full prescribing information for LIPITOR.
LIPITOR ® (atorvastatin calcium) tablets, for oral use
Initial U.S. Approval: 1996
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
LIPITOR is an HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to:
Limitations of Use:
LIPITOR has not been studied in Fredrickson Types I and V dyslipidemias ( 1.3).
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 10, 20, 40, and 80 mg of atorvastatin ( 3).
WARNINGS AND PRECAUTIONS
The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with LIPITOR in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (1-800-438-1985 and www.pfizer.com) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due 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 nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, LIPITOR can be started simultaneously with diet.
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:
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:
In adult patients with clinically evident coronary heart disease, LIPITOR is indicated to:
LIPITOR is indicated:
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 10 to 80 mg 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 4 weeks and dosage adjusted accordingly.
The recommended starting dose of LIPITOR is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies (14.6)] . Doses should be individualized according to the recommended goal of therapy [see Indications and Usage (1.2) and Clinical Pharmacology (12)] . Adjustments should be made at intervals of 4 weeks or more.
The dosage of LIPITOR in patients with HoFH is 10 to 80 mg 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.
LIPITOR may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions (5.1) and Drug Interactions (7)] .
Renal disease does not affect the plasma concentrations nor LDL-C reduction of LIPITOR; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .
LIPITOR tablets are white elliptical, film-coated, and are available in four strengths (see Table 1).
|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|
|Interacting Agents||Prescribing Recommendations|
|Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir, letermovir when co-administered with cyclosporine||Avoid atorvastatin|
|Clarithromycin, itraconazole, saquinavir plus ritonavir *, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir||Do not exceed 20 mg atorvastatin daily|
|Nelfinavir||Do not exceed 40 mg atorvastatin daily|
|Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine||Use with caution and lowest dose necessary|
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received LIPITOR in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of LIPITOR.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with LIPITOR and repeated as clinically indicated. There have been rare postmarketing 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 etiology is 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 [see Contraindications (4)] .
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 steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where LIPITOR 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the LIPITOR 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)] .
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
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 16,066 patients (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 patients treated 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 clinical adverse 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.
|Adverse Reaction *||Any dose
|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|
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 [see Clinical Studies (14.1)] 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 [see Clinical Studies (14.1)] 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 [see Clinical Studies (14.1)] 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 LIPITOR 10 mg daily (n=5006) or LIPITOR 80 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 (≥3 × ULN twice within 4–10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 × 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 [see Clinical Studies (14.1)] 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 LIPITOR 80 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 (≥ 3 × ULN twice within 4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 × 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 [see Warnings and Precautions (5.5)] .
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 (17 LIPITOR vs. 18 placebo). 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 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the LIPITOR 80 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 LIPITOR 80 mg group (5.0%) than in the placebo group (4.0%).
Adverse Reactions from Clinical Studies of LIPITOR in Pediatric Patients
In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Special Populations (8.4) and Clinical Studies (14.6)] .
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 not listed 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 statin use [see Warnings and Precautions (5.1)] .
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 are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
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 and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .
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.
Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 80 mg with clarithromycin (500 mg twice daily) compared to that of LIPITOR alone [see Clinical Pharmacology (12.3)] . Therefore, in patients taking clarithromycin, caution should be used when the LIPITOR dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .
Combination of Protease Inhibitors
Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR with several combinations of protease inhibitors [see Clinical Pharmacology (12.3)] . In patients taking tipranavir plus ritonavir or glecaprevir plus pibrentasvir, concomitant use of LIPITOR should be avoided. In patients taking lopinavir plus ritonavir, or simeprevir, use the lowest necessary LIPITOR dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of LIPITOR should not exceed 20 mg. In patients taking nelfinavir the dose of LIPITOR should not exceed 40 mg and close clinical monitoring is recommended [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .
Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)] . Therefore, in patients taking itraconazole, caution should be used when the LIPITOR dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .
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).
Atorvastatin is a substrate of the hepatic transporters. 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 [see Clinical Pharmacology (12.3)] .
The co-administration of LIPITOR with cyclosporine should be avoided [see Warnings and Precautions (5.1)] .
Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29) [see Clinical Pharmacology (12.3)] . Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg LIPITOR daily [see Dosage and Administration (2.6)] .
The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of LIPITOR is not recommended in patients taking letermovir co-administered with cyclosporine.
Concomitant administration of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.
Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministration of LIPITOR in patients receiving concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.
Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of LIPITOR should not exceed 20 mg daily in patients receiving concomitant medications with products containing elbasvir and grazoprevir [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] .
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 [see Warnings and Precautions (5.1)] .
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 [see Warnings and Precautions (5.1)] .
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 [see Warnings and Precautions (5.1)] .
Concomitant administration of LIPITOR with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in 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.
When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)]. Patients taking digoxin should be monitored appropriately.
Co-administration of LIPITOR and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)] . These increases should be considered when selecting an oral contraceptive for a woman taking LIPITOR.
LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
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 [see Contraindications (4)] . 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 malformations at 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/m 2). 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 background 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 15–20%, respectively.
Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports have 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 ≥3 to 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.
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 300 mg/kg/day and 100 mg/kg/day, respectively. 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 at the MRHD based on surface area (mg/m 2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.
In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 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 exposure at the MRHD, based on AUC.
LIPITOR use is contraindicated during breastfeeding [see Contraindications (4)] . 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 atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with LIPITOR.
LIPITOR may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LIPITOR [see Use in Specific Populations (8.1)] .
Heterozygous Familial Hypercholesterolemia (HeFH)
The safety and effectiveness of LIPITOR have been established in pediatric patients, 10 years to 17 years of age, with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels when, after an adequate trial of diet therapy, the following are present:
The long-term efficacy of LIPITOR therapy initiated in childhood 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 80 mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients [see Clinical Studies (14.5)] .
Of the 39,828 patients who received LIPITOR in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, LIPITOR should be prescribed with caution in the elderly.
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 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 (C 33H 34 FN 2O 5) 2Ca∙3H 2O 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 of 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 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.
LIPITOR 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. 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, 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 (2)] .
Absorption: LIPITOR is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. 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 [see Dosage and Administration (2)] .
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 [see Contraindications (4) and Use in Specific Populations (8.2)] .
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 [see Drug Interactions (7.1)] . 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 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 LIPITOR is recovered in urine following oral administration.
Geriatric: Plasma concentrations of LIPITOR 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 Use in Specific Populations (8.5)] .
Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.
Gender: Plasma concentrations of LIPITOR 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 LIPITOR between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of LIPITOR; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)] .
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of LIPITOR since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of LIPITOR 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 (4)] .
Drug Interaction Studies
Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.
|Co-administered drug and dosing regimen||Atorvastatin|
|Dose (mg)||Ratio of AUC *||Ratio of Cmax *|
|†Cyclosporine 5.2 mg/kg/day, stable dose||10 mg QD ‡ for 28 days||8.69||10.66|
|†Tipranavir 500 mg BID §/ritonavir 200 mg BID §, 7 days||10 mg, SD ¶||9.36||8.58|
|†Glecaprevir 400 mg QD ‡/pibrentasvir 120 mg QD ‡, 7 days||10 mg QD ‡ for 7 days||8.28||22.00|
|†Telaprevir 750 mg q8h #, 10 days||20 mg, SD ¶||7.88||10.60|
|†, ÞSaquinavir 400 mg BID §/ ritonavir 400 mg BID §, 15 days||40 mg QD ‡ for 4 days||3.93||4.31|
|†Elbasvir 50 mg QD ‡/grazoprevir 200 mg QD ‡, 13 days||10 mg SD ¶||1.94||4.34|
|†Simeprevir 150 mg QD ‡, 10 days||40 mg SD ¶||2.12||1.70|
|†Clarithromycin 500 mg BID §, 9 days||80 mg QD ‡ for 8 days||4.54||5.38|
|†Darunavir 300 mg BID §/ritonavir 100 mg BID §, 9 days||10 mg QD ‡ for 4 days||3.45||2.25|
|†Itraconazole 200 mg QD ‡, 4 days||40 mg SD ¶||3.32||1.20|
|†Letermovir 480 mg QD ‡, 10 days||20 mg SD ¶||3.29||2.17|
|†Fosamprenavir 700 mg BID §/ritonavir 100 mg BID §, 14 days||10 mg QD ‡ for 4 days||2.53||2.84|
|†Fosamprenavir 1400 mg BID §, 14 days||10 mg QD ‡ for 4 days||2.30||4.04|
|†Nelfinavir 1250 mg BID §, 14 days||10 mg QD ‡ for 28 days||1.74||2.22|
|†Grapefruit Juice, 240 mL QD ‡,ß||40 mg, SD ¶||1.37||1.16|
|Diltiazem 240 mg QD ‡, 28 days||40 mg, SD ¶||1.51||1.00|
|Erythromycin 500 mg QID à, 7 days||10 mg, SD ¶||1.33||1.38|
|Amlodipine 10 mg, single dose||80 mg, SD ¶||1.18||0.91|
|Cimetidine 300 mg QID à, 2 weeks||10 mg QD ‡ for 2 weeks||1.00||0.89|
|Colestipol 10 g BID §, 24 weeks||40 mg QD ‡ for 8 weeks||NA||0.74 è|
|Maalox TC ® 30 mL QID à, 17 days||10 mg QD ‡ for 15 days||0.66||0.67|
|Efavirenz 600 mg QD ‡, 14 days||10 mg for 3 days||0.59||1.01|
|†Rifampin 600 mg QD ‡, 7 days (co-administered) ð||40 mg SD ¶||1.12||2.90|
|†Rifampin 600 mg QD ‡, 5 days (doses separated) ð||40 mg SD ¶||0.20||0.60|
|†Gemfibrozil 600 mg BID §, 7 days||40 mg SD ¶||1.35||1.00|
|†Fenofibrate 160 mg QD ‡, 7 days||40 mg SD ¶||1.03||1.02|
|Boceprevir 800 mg TID ø, 7 days||40 mg SD ¶||2.32||2.66|
|Atorvastatin||Co-administered drug and dosing regimen|
|Drug/Dose (mg)||Ratio of AUC||Ratio of Cmax|
|80 mg QD * for 15 days||Antipyrine, 600 mg SD †||1.03||0.89|
|80 mg QD * for 10 days||‡ Digoxin 0.25 mg QD *, 20 days||1.15||1.20|
|40 mg QD * for 22 days||Oral contraceptive QD
*, 2 months
- norethindrone 1 mg
- ethinyl estradiol 35µg
|10 mg, SD †||Tipranavir 500 mg BID §/ritonavir 200 mg BID §, 7 days||1.08||0.96|
|10 mg QD * for 4 days||Fosamprenavir 1400 mg BID §, 14 days||0.73||0.82|
|10 mg QD * for 4 days||Fosamprenavir 700 mg BID §/ritonavir 100 mg BID §, 14 days||0.99||0.94|
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.
In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on 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 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.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of LIPITOR on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients; <130/80 mm Hg for diabetic patients) and allocated to either LIPITOR 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.
The effect of 10 mg/day of LIPITOR on lipid levels was similar to that seen in previous clinical trials.
LIPITOR significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the LIPITOR group) or non-fatal MI (108 events in the placebo group vs. 60 events in the LIPITOR group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for LIPITOR vs. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of LIPITOR was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive.
LIPITOR also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for LIPITOR and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for LIPITOR and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of LIPITOR on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40–75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either LIPITOR 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA 1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.
The effect of LIPITOR 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
LIPITOR significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the LIPITOR group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of LIPITOR was seen regardless of age, sex, or baseline lipid levels.
LIPITOR significantly reduced the risk of stroke by 48% (21 events in the LIPITOR group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the LIPITOR group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.
There were 61 deaths in the LIPITOR group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).
In the Treating to New Targets Study (TNT), the effect of LIPITOR 80 mg/day vs. LIPITOR 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with LIPITOR 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of LIPITOR and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of LIPITOR and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of LIPITOR.
Treatment with LIPITOR 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 6). The overall risk reduction was consistent regardless of age (<65, ≥65) or gender.
Figure 3: Effect of LIPITOR 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
|HR * (95%CI)|
|HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft
Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
|First major cardiovascular endpoint||548||(10.9)||434||(8.7)||0.78 (0.69, 0.89)|
|Components of the Primary Endpoint|
|CHD death||127||(2.5)||101||(2.0)||0.80 (0.61, 1.03)|
|Non-fatal, non-procedure related MI||308||(6.2)||243||(4.9)||0.78 (0.66, 0.93)|
|Resuscitated cardiac arrest||26||(0.5)||25||(0.5)||0.96 (0.56, 1.67)|
|Stroke (fatal and non-fatal)||155||(3.1)||117||(2.3)||0.75 (0.59, 0.96)|
|SECONDARY ENDPOINTS †|
|First CHF with hospitalization||164||(3.3)||122||(2.4)||0.74 (0.59, 0.94)|
|First PVD endpoint||282||(5.6)||275||(5.5)||0.97 (0.83, 1.15)|
|First CABG or other coronary revascularization procedure ‡||904||(18.1)||667||(13.4)||0.72 (0.65, 0.80)|
|First documented angina endpoint ‡||615||(12.3)||545||(10.9)||0.88 (0.79, 0.99)|
|All-cause mortality||282||(5.6)||284||(5.7)||1.01 (0.85, 1.19)|
|Components of All-Cause Mortality|
|Cardiovascular death||155||(3.1)||126||(2.5)||0.81 (0.64, 1.03)|
|Noncardiovascular death||127||(2.5)||158||(3.2)||1.25 (0.99, 1.57)|
|Cancer death||75||(1.5)||85||(1.7)||1.13 (0.83, 1.55)|
|Other non-CV death||43||(0.9)||58||(1.2)||1.35 (0.91, 2.00)|
|Suicide, homicide, and othertraumatic non-CV death||9||(0.2)||15||(0.3)||1.67 (0.73, 3.82)|
Of the events that comprised the primary efficacy endpoint, treatment with LIPITOR 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 6). Of the predefined secondary endpoints, treatment with LIPITOR 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.
There was no significant difference between the treatment groups for all-cause mortality (Table 6). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the LIPITOR 80 mg group than in the LIPITOR 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the LIPITOR 80 mg group than in the LIPITOR 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with LIPITOR 80 mg/day was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of LIPITOR and 105, 179, 142, 47, and 132 mg/dL during treatment with 20–40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the LIPITOR 80 mg/day group vs. 463 (10.4%) in the simvastatin 20–40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p=0.07.
There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the LIPITOR 80 mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the LIPITOR 80 mg group and the simvastatin 20–40 mg group.
LIPITOR reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb). 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 hyperlipidemia, with and without hypertriglyceridemia, in men and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, 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 7.)
|Dose||N||TC||LDL-C||Apo B||TG||HDL-C||Non-HDL-C/ HDL-C|
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25 th and 75 th percentile) percent changes from baseline in HDL-C for LIPITOR 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 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 hyperlipidemia, LIPITOR was compared to other statins. After randomization, patients were treated for 16 weeks with either LIPITOR 10 mg per day or a fixed dose of the comparative agent (Table 8).
|N||Total-C||LDL-C||Apo B||TG||HDL-C||Non-HDL-C/ HDL-C|
|LIPITOR 10 mg||707||-27 *||-36 *||-28 *||-17 *||+7||-37 *|
|Lovastatin 20 mg||191||-19||-27||-20||-6||+7||-28|
|95% CI for Diff †||-9.2, -6.5||-10.7, -7.1||-10.0, -6.5||-15.2, -7.1||-1.7, 2.0||-11.1, -7.1|
|LIPITOR 10 mg||222||-25 ‡||-35 ‡||-27 ‡||-17 ‡||+6||-36 ‡|
|Pravastatin 20 mg||77||-17||-23||-17||-9||+8||-28|
|95% CI for Diff †||-10.8, -6.1||-14.5, -8.2||-13.4, -7.4||-14.1, -0.7||-4.9, 1.6||-11.5, -4.1|
|LIPITOR 10 mg||132||-29 §||-37 §||-34 §||-23 §||+7||-39 §|
|Simvastatin 10 mg||45||-24||-30||-30||-15||+7||-33|
|95% CI for Diff †||-8.7, -2.7||-10.1, -2.6||-8.0, -1.1||-15.1, -0.7||-4.3, 3.9||-9.6, -1.9|
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 8 is not known. Table 8 does not contain data comparing the effects of LIPITOR 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.
The response to LIPITOR in 64 patients with isolated hypertriglyceridemia ( Fredrickson Type IV) treated across several clinical trials is shown in the table below (Table 9). For the LIPITOR-treated patients, median (min, max) baseline TG level was 565 (267–1502).
|LIPITOR 10 mg
|LIPITOR 20 mg
|LIPITOR 80 mg
|Triglycerides||-12.4 (-36.6, 82.7)||-41.0 (-76.2, 49.4)||-38.7 (-62.7, 29.5)||-51.8 (-82.8, 41.3)|
|Total-C||-2.3 (-15.5, 24.4)||-28.2 (-44.9, -6.8)||-34.9 (-49.6, -15.2)||-44.4 (-63.5, -3.8)|
|LDL-C||3.6 (-31.3, 31.6)||-26.5 (-57.7, 9.8)||-30.4 (-53.9, 0.3)||-40.5 (-60.6, -13.8)|
|HDL-C||3.8 (-18.6, 13.4)||13.8 (-9.7, 61.5)||11.0 (-3.2, 25.2)||7.5 (-10.8, 37.2)|
|VLDL-C||-1.0 (-31.9, 53.2)||-48.8 (-85.8, 57.3)||-44.6 (-62.2, -10.8)||-62.0 (-88.2, 37.6)|
|non-HDL-C||-2.8 (-17.6, 30.0)||-33.0 (-52.1, -13.3)||-42.7 (-53.7, -17.4)||-51.5 (-72.9, -4.3)|
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 10).
|Median % Change (min, max)|
|Median (min, max) at Baseline (mg/dL)||LIPITOR 10 mg||LIPITOR 80 mg|
|Total-C||442 (225, 1320)||-37 (-85, 17)||-58 (-90, -31)|
|Triglycerides||678 (273, 5990)||-39 (-92, -8)||-53 (-95, -30)|
|IDL-C + VLDL-C||215 (111, 613)||-32 (-76, 9)||-63 (-90, -8)|
|non-HDL-C||411 (218, 1272)||-43 (-87, -19)||-64 (-92, -36)|
In a study without a concurrent control group, 29 patients ages 6 years to 37 years with HoFH 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%.
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to LIPITOR (n=140) or placebo (n=47) for 26 weeks and then all received LIPITOR for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5–385.0 mg/dL) in the LIPITOR group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL) in the placebo group. The dosage of LIPITOR (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of LIPITOR-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).
LIPITOR significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 11).
The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0–242.0 mg/dL) in the LIPITOR group compared to 228.5 mg/dL (range: 152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were Caucasian, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of < 130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical studies in both adult and pediatric placebo-controlled trials.
The long-term efficacy of LIPITOR therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
10 mg tablets (10 mg of atorvastatin): coded "PD 155" on one side and "10" on the other.
NDC 55289-870-30 bottles of 30
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Patients taking LIPITOR should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with atorvastatin [see Warnings and Precautions (5.1)] . Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking LIPITOR.
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 (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.
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.
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 [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].
Read the Patient Information that comes with LIPITOR before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment.
If you have any questions about LIPITOR, ask your doctor or pharmacist.
What is LIPITOR?
LIPITOR is a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C ("bad" cholesterol) and triglycerides in your blood. It can raise your HDL-C ("good" cholesterol) as well. LIPITOR is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.
LIPITOR can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as:
LIPITOR can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as:
LIPITOR starts to work in about 2 weeks.
What is Cholesterol?
Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides can clog your blood vessels. It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your family.
Who Should Not Take LIPITOR?
Do not take LIPITOR if you:
LIPITOR dosing has not been established in children under 10 years of age.
Before You Start LIPITOR
Tell your doctor if you:
Some medicines should not be taken with LIPITOR. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. LIPITOR and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for:
Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist.
How Should I Take LIPITOR?
What Should I Avoid While Taking LIPITOR?
What are the Possible Side Effects of LIPITOR?
LIPITOR can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or LIPITOR is stopped. These serious side effects include:
Call your doctor right away if you have:
In clinical studies, patients reported the following common side effects while taking LIPITOR: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been reported with LIPITOR:
tiredness, tendon problems, memory loss, and confusion.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of LIPITOR. Ask your doctor or pharmacist for a complete list.
How do I store LIPITOR
General Information About LIPITOR
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use LIPITOR for a condition for which it was not prescribed. Do not give LIPITOR to other people, even if they have the same problem you have. It may harm them.
This leaflet summarizes the most important information about LIPITOR. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about LIPITOR that is written for health professionals. Or you can go to the LIPITOR website at www.lipitor.com.
What are the Ingredients in LIPITOR?
Active Ingredient: atorvastatin calcium
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 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.
atorvastatin calcium tablet, film coated
|Labeler - PD-Rx Pharmaceuticals, Inc. (156893695)|
|Registrant - PD-Rx Pharmaceuticals, Inc. (156893695)|
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