ATORVASTATIN CALCIUM- atorvastatin calcium_tablet, film coated

Atorvastatin calcium tablets are 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, atorvastatin calcium tablets 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; atorvastatin calcium tablets also reduces LDL production and the number of LDL particles. Atorvastatin calcium tablets, 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: max max [see Dosage and Administration ( 2 ) ] Distribution: [see Contraindications ( 4 ) and Use in Specific Populations ( 8. 2 ] Metabolism: In vitro In vitro [see Drug Interactions ( 7. 1 Excretion: Specific Populations Geriatric: max [see Use in Specific Populations ( 8. 5 ] Pediatric: Gender: max Renal Impairment: [see Dosage and Administration ( 2. 1 ] Hemodialysis: Hepatic Impairment: max max [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. TABLE 6: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin Dose (mg) Ratio of AUC & Ratio of C max & # 10 mg QD a 8. 66 # b b 10 mg, SD c 9. 58 # a a 10 mg QD a 8. 00 # f 20 mg, SD c 7. 60 #,double dagger b b 40 mg QD a 3. 31 # a a 10 mg SD c 1. 34 # a 40 mg SD c 2. 70 # b 80 mg QD a 4. 38 # b b 10 mg QD a 3. 25 # a 40 mg SD c 3. 20 #Letermovir 480 mg QD a 20 mg SD c 3. 17 # b b 10 mg QD a 2. 84 # b 10 mg QD a 2. 04 # b 10 mg QD a 1. 22 # a,* 40 mg, SD c 1. 16 Diltiazem 240 mg QD a 40 mg, SD c 1. 00 Erythromycin 500 mg QID e 10 mg, SD c 1. 38 Amlodipine 10 mg, single dose 80 mg, SD c 1. 91 Cimetidine 300 mg QID e 10 mg QD a 1. 89 Colestipol 10 g BID b 40 mg QD a NA 0. 74** Maalox TC registered e 10 mg QD a 0. 67 Efavirenz 600 mg QD a 10 mg for 3 days 0. 01 # a dagger 40 mg SD c 1. 90 # a dagger 40 mg SD c 0. 60 # b 40 mg SD c 1. 00 # a 40 mg SD c 1. 02 Boceprevir 800 mg TID d 40 mg SD c 2. 1 7 * max max ** dagger Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. double dagger The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a b c d e f TABLE 7: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of C max 80 mg QD a Antipyrine, 600 mg SD c 1. 89 80 mg QD a # a 1. 20 40 mg QD a Oral contraceptive QD a - norethindrone 1 mg - ethinyl estradiol 35mug 1. 23 10 mg, SD c Tipranavir 500 mg BID b b 1. 96 10 mg QD a Fosamprenavir 1400 mg BID b 0. 82 10 mg QD a Fosamprenavir 700 mg BID b b 0. 94 # 7 a b c Atorvastatin calcium tablets had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

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, atorvastatin calcium tablets can be started simultaneously with diet. Atorvastatin calcium tablets are an HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to: Reduce the risk of MI, stroke, revascularization procedures, and angina in adult patients without CHD, but with multiple risk factors ( 1. 1 Reduce the risk of MI and stroke in adult patients with type 2 diabetes without CHD, but with multiple risk factors ( 1. 1 Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in adult patients with CHD ( 1. 1 Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( 1. 2 Reduce elevated TG in adult patients with hypertriglyceridemia and primary dysbetalipoproteinemia ( 1. 2 Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) ( 1. 2 Reduce elevated total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) after failing an adequate trial of diet therapy ( 1. 2 Limitations of Use: Atorvastatin calcium tablets have not been studied in Fredrickson 1. 3 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, atorvastatin calcium tablets are 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, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial 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 Atorvastatin calcium tablets are indicated: As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson As an adjunct to diet for the treatment of adult patients with elevated serum TG levels ( Fredrickson For the treatment of adult patients with primary dysbetalipoproteinemia ( Fredrickson To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e. , 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: a. LDL-C remains >= 190 mg/dL or b. 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 Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson.

Dose range: 10 to 80 mg once daily ( 2. 1 Recommended start dose: 10 or 20 mg once daily ( 2. 1 Patients requiring large LDL-C reduction (>45%) may start at 40 mg once daily ( 2. 1 Pediatric patients with HeFH: starting dose: 10 mg once daily; dose range: 10 to 20 mg/day for patients 10 years to 17 years of age ( 2. 2 The recommended starting dose of atorvastatin calcium tablets 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 atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies ( 14. 6 [see Indications and Usage ( 1. 2 ( 12 ] The dosage of atorvastatin calcium tablets in patients with HoFH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e. , LDL apheresis) in these patients or if such treatments are unavailable. Atorvastatin calcium tablets 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 7 ) ] Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions ( 5. 1 ) and Clinical Pharmacology ( 12. 3 ) ] In patients taking cyclosporine or the HIV protease inhibitor tipranavir plus ritonavir or the hepatitis C virus (HCV) protease inhibitor glecaprevir plus pibrentasvir or letermovir when co-administered with cyclosporine, therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin calcium tablets. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir or letermovir therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin calcium tablets should be limited to 40 mg [see Warnings and Precautions ( 5.

The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5. 1 ) ] Liver enzyme abnormalities [see Warnings and Precautions ( 5. 3 ) ] Most common adverse reactions (incidence >= 2%) in patients treated with atorvastatin calcium tablets 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 Lannett Company, Inc. at (1-844-834-0530) or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 practice. In the atorvastatin calcium tablets placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium tablets vs. 7311 placebo; age range 10en dash93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9. 7% of patients on atorvastatin calcium tablets 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 atorvastatin calcium tablets 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. The most commonly reported adverse reactions (incidence >= 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin calcium tablets 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. Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in >= 2% and at a rate greater than placebo in patients treated with atorvastatin calcium tablets (n=8755), from seventeen placebo-controlled trials. Table 2: Clinical Adverse Reactions Occurring in >= 2% in Patients Treated with any Dose of Atorvastatin Calcium Tablets 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. 2 Arthralgia 6. 5 Diarrhea 6. 3 Pain in extremity 6. 9 Urinary tract infection 5. 6 Dyspepsia 4. 5 Musculoskeletal pain 3. 6 Muscle Spasms 3. 0 Myalgia 3. 1 Insomnia 3. 9 Pharyngolaryngeal pain 2. 1 * Adverse Reaction >= 2% in any dose greater than placebo Other adverse reactions reported in placebo-controlled studies include: Body as a whole Digestive system: Musculoskeletal system Metabolic and nutritional system Nervous system Respiratory system: Skin and appendages Special senses Urogenital system: Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) In ASCOT [see Clinical Studies ( 14. 1 ) ] Collaborative Atorvastatin Diabetes Study (CARDS) In CARDS [see Clinical Studies ( 14. 1 ) ] Treating to New Targets Study (TNT) In TNT [see Clinical Studies ( 14. 1 ) ] Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL) In IDEAL [see Clinical Studies ( 14. 1 ) ] Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4731 subjects (age range 21en dash92 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 atorvastatin calcium tablets 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 x ULN twice within 4en dash 10 days) in the atorvastatin group (0. 9%) compared to placebo (0. Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0. 1%) compared to placebo (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. 6 ) ] In a post-hoc analysis, atorvastatin calcium tablets 80 mg reduced the incidence of ischemic stroke (218/2365, 9. 274/2366, 11. 6%) and increased the incidence of hemorrhagic stroke (55/2365, 2. 4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium tablets 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%) atorvastatin calcium tablets vs. 2 (4%) placebo]. There were no significant differences between the treatment groups for all-cause mortality: 216 (9. 1%) in the atorvastatin calcium tablets 80 mg/day group vs. 9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin calcium tablets 80 mg group (3. 3%) than in the placebo group (4. The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin calcium tablets 80 mg group (5. 0%) than in the placebo group (4. Adverse Reactions from Clinical Studies of A torvastatin Calcium Tablets 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 atorvastatin calcium tablets 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 atorvastatin calcium tablets. 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 atorvastatin calcium tablets 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. 2 )] There have been rare postmarketing reports of cognitive impairment (e. , 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).

Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels Hypersensitivity to Any Component of This Medication Pregnancy [see Use in Specific Populations ( 8. 3 Lactation [see Use in Specific Populations ( 8. 2 Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 Hypersensitivity to any component of this medication ( 4 Pregnancy ( 4 8. 3 Lactation ( 4 8.

Hepatic impairment: Plasma concentrations markedly increased in patients with chronic alcoholic liver disease ( 8. 3 Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with Atorvastatin calcium tablets ( 8. 3 Risk Summary Atorvastatin calcium tablets are 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, atorvastatin calcium tablets may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium tablets should be discontinued as soon as pregnancy is recognized [see Contraindications ( 4 2 (see Data) The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data 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. 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 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 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 (rotarod 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. Risk Summary Atorvastatin calcium tablets use is contraindicated during breastfeeding [see Contraindications ( 4 Contraception Atorvastatin calcium tablets may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with atorvastatin calcium tablets [see Use in Specific Populations ( 8. 1 Heterozygous Familial Hypercholesterolemia (HeFH) The safety and effectiveness of atorvastatin calcium tablets has 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: 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 atorvastatin calcium tablets for this indication is supported by evidence from [see Dosage and Administration ( 2. 6 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 or 20 mg daily atorvastatin calcium tablets 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. Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations ( 8. 3 The long-term efficacy of atorvastatin calcium tablets therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established. The safety and efficacy of atorvastatin calcium tablets has not been established in pediatric patients younger than 10 years of age with HeFH. Additional pediatric use information is approved for Pfizer’s LIPITOR registered Homozygous Familial Hypercholesterolemia (HoFH) Clinical efficacy of atorvastatin calcium tablets 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 atorvastatin calcium tablets 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, atorvastatin calcium tablets should be prescribed with caution in the elderly. Atorvastatin calcium tablets are contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications ( 4 and Clinical Pharmacology ( 12.

Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets ( 2. 3 Interacting Agents Prescribing Recommendations Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir 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 Consider the risk/benefit of concomitant use with atorvastatin Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (>=1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin calcium tablets ( 7 Rifampin should be simultaneously co-administered with atorvastatin calcium tablets ( 7. 2 Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased ( 7. 3 Digoxin: Patients should be monitored appropriately ( 7. 3 Atorvastatin calcium tablets are a substrate of CYP3A4 and transporters (e. , OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium tablets plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to Lipitor and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions ( 5. 3 Table 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology ( 12. 3 Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium tablets is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e. , BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology ( 12. 3 Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium tablets is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium tablets 20 mg. In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg [see Dosage and Administration ( 2. 6 Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium tablets. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology ( 12. 3 Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium tablets 20 mg [see Dosage and Administration ( 2. 6 Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (>1 gram/day niacin) with atorvastatin calcium tablets. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin calcium tablets. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin calcium tablets outweighs the increased risk of myopathy and rhabdomyolysis. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin calcium tablets. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium tablets. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1. 2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1. 2 liters daily, when taking atorvastatin calcium tablets. Table 4 presents drug interactions that may decrease exposure to atorvastatin calcium tablets and instructions for preventing or managing them. Table 4: Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Tablets Rifampin Clinical Impact: Concomitant administration of atorvastatin calcium tablets with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin calcium tablets after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin calcium tablets and rifampin simultaneously. Table 5 presents atorvastatin calcium tablets’ effect on other drugs and instructions for preventing or managing them. Table 5: Atorvastatin Calcium Tablets Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin calcium tablets and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology ( 12. 3 Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin calcium tablets. Digoxin Clinical Impact: When multiple doses of atorvastatin calcium tablets and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology ( 12. 3 Intervention: Monitor patients taking digoxin appropriately.

OVERDOSAGE
There is no specific treatment for atorvastatin calcium tablets overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium tablets clearance.
NONCLINICAL TOXICOLOGY
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 (0en dash24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, Salmonella typhimurium Escherichia coli, in vivo 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.
CLINICAL STUDIES
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium tablets 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. 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. 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 atorvastatin calcium tablets 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. The effect of 10 mg/day of atorvastatin calcium tablets on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium tablets significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium tablets group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium tablets group)] with a relative risk reduction of 36% [(based on incidences of 1. 9% for atorvastatin calcium tablets vs. 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 atorvastatin calcium tablets was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive. Figure 1: Effect of Atorvastatin Calcium Tablets 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium tablets also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1. 4% for atorvastatin calcium tablets 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 atorvastatin calcium tablets 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. In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium tablets 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 atorvastatin calcium tablets 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3. 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 HbA1c 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 atorvastatin calcium tablets 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium tablets significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0. 63, 95% CI (0. 001) (see Figure 2). An effect of atorvastatin calcium tablets was seen regardless of age, sex, or baseline lipid levels. Atorvastatin calcium tablets significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium tablets group vs. 39 events in the placebo group), HR 0. 52, 95% CI (0. 016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium tablets group vs. 64 events in the placebo group), HR 0. There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin calcium tablets group vs. 82 deaths in the placebo group (HR 0. Figure 2: Effect of Atorvastatin Calcium Tablets 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium tablets 80 mg/day vs. atorvastatin calcium tablets 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 atorvastatin calcium tablets 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium tablets and followed for a median duration of 4. 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 atorvastatin calcium tablets and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium tablets. Treatment with atorvastatin calcium tablets 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. 0002 (see Figure 3 and Table 9). The overall risk reduction was consistent regardless of age (<65, >=65) or gender. Figure 3: Effect of Atorvastatin Calcium Tablets 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) TABLE 8: Overview of Efficacy Results in TNT Endpoint Atorvastatin Atorvastatin HR a a b * 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 PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10. 89) Components of the Primary Endpoint CHD death 127 (2. 03) Non-fatal, non-procedure related MI 308 (6. 93) Resuscitated cardiac arrest 26 (0. 67) Stroke (fatal and non-fatal) 155 (3. 96) SECONDARY ENDPOINTS * First CHF with hospitalization 164 (3. 94) First PVD endpoint 282 (5. 15) First CABG or other coronary revascularization procedure b 904 (18. 80) First documented angina endpoint b 615 (12. 99) All-cause mortality 282 (5. 19) Components of All-Cause Mortality Cardiovascular death 155 (3. 03) Noncardiovascular death 127 (2. 57) Cancer death 75 (1. 55) Other non-CV death 43 (0. 00) Suicide, homicide, and other traumatic non-CV death 9 (0. 82) Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium tablets 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 8). Of the predefined secondary endpoints, treatment with atorvastatin calcium tablets 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 8). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group. In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin calcium tablets 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. 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 atorvastatin calcium tablets 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 atorvastatin calcium tablets 80 mg/day group vs. 4%) in the simvastatin 20-40 mg/day group, HR 0. 89, 95% CI ( 0. There were no significant differences between the treatment groups for all-cause mortality: 366 (8. 2%) in the atorvastatin calcium tablets 80 mg/day group vs. 4%) in the simvastatin 20-40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the atorvastatin calcium tablets 80 mg group and the simvastatin 20-40 mg group. Figure 1 Figure 2 Figure 3 Atorvastatin calcium tablets reduce 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 Atorvastatin calcium tablets are 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, atorvastatin calcium tablets given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 9. ) TABLE 9: Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a Dose N TC LDL-C Apo B TG HDL-C Non-HDL- Placebo 21 4 4 3 10 -3 7 10 22 -29 -39 -32 -19 6 -34 20 20 -33 -43 -35 -26 9 -41 40 21 -37 -50 -42 -29 6 -45 80 23 -45 -60 -50 -37 5 -53 a In patients with Fredrickson th th In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin calcium tablets were compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium tablets 10 mg per day or a fixed dose of the comparative agent (Table 10). TABLE 10: Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) Treatment N Total-C LDL-C Apo B TG HDL-C Non-HDL-C/ Study 1 707 -27 a -36 a -28 a -17 a +7 -37 a Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28 95% CI for Diff 1 -9. 1 Study 2 222 -25 b -35 b -27 b -17 b +6 -36 b Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28 95% CI for Diff 1 -10. 1 Study 3 132 -29 c -37 c -34 c -23 c +7 -39 c Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33 95% CI for Diff 1 -8. 9 1 a b c The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 10 is not known. Table 10 does not contain data comparing the effects of atorvastatin calcium tablets 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 atorvastatin calcium tablets in 64 patients with isolated hypertriglyceridemia ( Fredrickson TABLE 11: Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo Atorvastatin Calcium Tablets Atorvastatin Calcium Tablets Atorvastatin Calcium Tablets Triglycerides -12. 3) Total-C -2. 2) VLDL-C -1. 6) non-HDL-C -2. 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 TABLE 12: Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia ( Fredrickson Median % Change (min, max) Median (min, max) at Baseline (mg/dL) Atorvastatin Calcium Tablets Atorvastatin Calcium Tablets 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 atorvastatin calcium tablets. 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 atorvastatin calcium tablets (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium tablets 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. 5en dash385. 0 mg/dL) in the atorvastatin calcium tablets group compared to 230. 0 mg/dL (range: 160. 0en dash324. 5 mg/dL) in the placebo group. The dosage of atorvastatin calcium tablets (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 atorvastatin calcium tablets-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55. Atorvastatin calcium tablets significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 13). TABLE 13: Lipid-altering Effects of Atorvastatin Calcium Tablets in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1. 7 Atorvastatin Calcium Tablets 140 -31. 0 The mean achieved LDL-C value was 130. 7 mg/dL (range: 70. 0en dash242. 0 mg/dL) in the atorvastatin calcium tablets group compared to 228. 5 mg/dL (range: 152. 0en dash385. 0 mg/dL) in the placebo group during the 26-week double-blind phase. The long-term efficacy of atorvastatin calcium tablets therapy in childhood to reduce morbidity and mortality in adulthood has not been established. Additional pediatric use information is approved for Pfizer’s LIPITOR registered.
PATIENT INFORMATION
Dispense with Patient Information Leaflet available at: www.lannett.com/patient-info/atorvastatin Atorvastatin Calcium (a tor" va stat'' in kal'' see um) Tablets Read the Patient Information that comes with Atorvastatin Calcium Tablets 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 Atorvastatin Calcium Tablets, ask your doctor or pharmacist. What are Atorvastatin Calcium Tablets? Atorvastatin Calcium Tablets are 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. Atorvastatin Calcium Tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone. Atorvastatin Calcium Tablets 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: ∙ age, smoking, high blood pressure, low HDL-C, heart disease in the family. Atorvastatin Calcium Tablets can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: ∙ eye problems, kidney problems, smoking, or high blood pressure. Atorvastatin Calcium Tablets start 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 Atorvastatin Calcium Tablets? Do not take Atorvastatin Calcium Tablets if you: are pregnant or think you may be pregnant, or are planning to become pregnant. Atorvastatin Calcium Tablets may harm your unborn baby. If you get pregnant, stop taking Atorvastatin Calcium Tablets and call your doctor right away. are breast feeding. Atorvastatin Calcium Tablets can pass into your breast milk and may harm your baby. have liver problems. are allergic to Atorvastatin Calcium Tablets or any of its ingredients. The active ingredient is atorvastatin. See the end of this leaflet for a complete list of ingredients in Atorvastatin Calcium Tablets. Atorvastatin Calcium Tablets dosing has not been established in children under 10 years of age. Before You Start Atorvastatin Calcium Tablets Tell your doctor if you: have muscle aches or weakness drink more than 2 glasses of alcohol daily have diabetes have a thyroid problem have kidney problems Some medicines should not be taken with Atorvastatin Calcium Tablets. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin Calcium Tablets and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for: your immune system cholesterol infections birth control heart failure HIV or AIDS hepatitis C virus anti-virals Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist. How Should I Take Atorvastatin Calcium Tablets? Take Atorvastatin Calcium Tablets exactly as prescribed by your doctor. Do not change your dose or stop Atorvastatin Calcium Tablets without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during your treatment with Atorvastatin Calcium Tablets. Your dose of Atorvastatin Calcium Tablets may be changed based on these blood test results. Take Atorvastatin Calcium Tablets each day at any time of day at about the same time each day. Atorvastatin Calcium Tablets can be taken with or without food. Don''t break Atorvastatin Calcium Tablets before taking. Your doctor should start you on a low-fat diet before giving you Atorvastatin Calcium Tablets. Stay on this low-fat diet when you take Atorvastatin Calcium Tablets. If you miss a dose of Atorvastatin Calcium Tablets, take it as soon as you remember. Do not take Atorvastatin Calcium Tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of Atorvastatin Calcium Tablets at the same time. If you take too much Atorvastatin Calcium Tablets or overdose, call your doctor or Poison Control Center right away. Or go to the nearest emergency room. What Should I Avoid While Taking Atorvastatin Calcium Tablets? Talk to your doctor before you start any new medicines. This includes prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin Calcium Tablets and certain other medicines can interact causing serious side effects. Do not get pregnant. If you get pregnant, stop taking Atorvastatin Calcium Tablets right away and call your doctor. What are the Possible Side Effects of Atorvastatin Calcium Tablets? Atorvastatin Calcium Tablets 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 Atorvastatin Calcium Tablets are stopped. These serious side effects include: Muscle problems. Liver problems. feel tired or weak loss of appetite upper belly pain dark amber colored urine yellowing of your skin or the whites of your eyes Call your doctor right away if you have: muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have a fever or feel more tired than usual. This may be an early sign of a rare muscle problem. muscle problems that do not go away even after your doctor has advised you to stop taking Atorvastatin Calcium Tablets. Your doctor may do further tests to diagnose the cause of your muscle problems. allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away. nausea and vomiting. passing brown or dark-colored urine. you feel more tired than usual. your skin and whites of your eyes get yellow. stomach pain. allergic skin reactions. In clinical studies, patients reported the following common side effects while taking Atorvastatin Calcium Tablets: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests. The following additional side effects have been reported with Atorvastatin Calcium Tablets: 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 Atorvastatin Calcium Tablets. Ask your doctor or pharmacist for a complete list. How do I store Atorvastatin Calcium Tablets? Store Atorvastatin Calcium Tablets at room temperature, 68 to 77°F (20 to 25°C). Do not keep medicine that is out of date or that you no longer need. Keep Atorvastatin Calcium Tablets and all medicines out of the reach of children. General Information About Atorvastatin Calcium Tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Atorvastatin Calcium Tablets for a condition for which it was not prescribed. Do not give Atorvastatin Calcium Tablets to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about Atorvastatin Calcium Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Atorvastatin Calcium Tablets that is written for health professionals. Or you can call 1-844-834-0530. What are the Ingredients in Atorvastatin Calcium Tablets? Active Ingredient: Inactive Ingredients:

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ATORVASTATIN CALCIUM- atorvastatin calcium_tablet, film coated Product manual source documgent