ATORVASTATIN CALCIUM- atorvastatin calcium_tablet, film coated

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium 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 also reduces LDL production and the number of LDL particles. Atorvastatin calcium, 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 Distribution Elimination Metabolism In vitro In vitro [see Drug Interactions (7. 1) Excretion Specific Populations Geriatric max Pediatric Gender max Renal Impairment [see Use in Specific Populations (8. 6) While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment max max [see Use in Specific Populations (8. 7) Drug Interactions 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 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosage 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 # 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. 66 & # Sections 5. 1 7 * max max ** dagger double dagger a b c d e f Table 6. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosage regimen Drug/Dosage (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 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 b b 0. 94 # Section 7 a b c Atorvastatin Calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Atorvastatin Calcium Tablets are indicated: To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia Hypertriglyceridemia Atorvastatin calcium tablet is an HMG-CoA reductase inhibitor (statin) indicated ( 1 To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia. As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia.

Take orally once daily with or without food ( 2. 1 Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( 2. 2 Recommended starting dosage is 10 mg or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. Patients requiring LDL-C reduction >45% may start at 40 mg once daily. Pediatric Patients Aged 10 Years of Age and Older with HeFH: 2. 3 Pediatric Patients Aged 10 Years of Age and Older with HoFH: 2. 4 See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions ( 2. 5 Take atorvastatin calcium tablets orally once daily at any time of the day, with or without food. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust the dosage if necessary. If a dose is missed, advise patients not to take the missed dose and resume with the next scheduled dose. The recommended starting dosage of atorvastatin calcium tablets is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. The recommended starting dosage of atorvastatin calcium tablets is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. Concomitant use of atorvastatin calcium tablets with the following drugs requires dosage modification of atorvastatin calcium tablets [see Warnings and Precautions (5. 1) and Drug Interactions (7. 1) Anti-Viral Medications In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium 20 mg once daily. In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium tablets 20 mg once daily. For additional recommendations regarding concomitant use of atorvastatin calcium tablets with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions (7.

The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5. 1) Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5. 2) Hepatic Dysfunction [see Warnings and Precautions (5. 3) Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5. 4) Most common adverse reactions (incidence >=5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at (1-855-724-3436) 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 placebo-controlled clinical trial database of 16,066 patients (8,755 Atorvastatin Calcium vs. 7,311 placebo; age range 10 years to 93 years, 39% female, 91% White, 3% Black or African American, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin calcium 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. Table 1 summarizes adverse reactions reported in >= 2% and at a rate greater than placebo in patients treated with Atorvastatin Calcium (n=8,755), from seventeen placebo-controlled trials. Table 1: Adverse Reactions Occurring in >= 2% in Patients Atorvastatin calcium -Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo % 10 mg % 20 mg % 40 mg % 80 mg % Any dose Nasopharyngitis 8. 3 Arthralgia 6. 9 Diarrhea 6. 8 Pain in extremity 5. 0 Urinary tract infection 5. 7 Dyspepsia 4. 0 Musculoskeletal pain 3. 8 Muscle Spasms 3. 6 Myalgia 3. 5 Insomnia 2. 0 Pharyngolaryngeal pain 2. 3 Other adverse reactions reported in placebo-controlled trials include: Body as a whole Digestive system: Musculoskeletal system Metabolic and nutritional system Nervous system Respiratory system: Skin and appendages: Special senses Urogenital system: Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0. 7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0. 3% for 10mg, 20mg, 40mg, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests 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 liver enzyme elevations continued treatment with a reduced dose of atorvastatin calcium. Treating to New Targets Study (TNT) [see Clinical Studies (14. 1) Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (9. 6%) and increased the incidence of hemorrhagic stroke (2. 4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 Atorvastatin Calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin calcium group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% Atorvastatin calcium vs. 4% placebo). Adverse Reactions from Clinical Studies of atorvastatin calcium in Pediatric Patients with HeFH [see Use in Specific Populations (8. 4) Clinical Studies (14. 6) The following adverse reactions have been identified during post-approval use of atorvastatin calcium. 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. Gastrointestinal disorders: General disorders: Hepatobiliary Disorders: Immune system disorders: Injury: Musculoskeletal and connective tissue disorders: Nervous system disorders: Psychiatric disorders: Respiratory disorders: Skin and subcutaneous tissue disorders:.

Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5. 3) Hypersensitivity to atorvastatin or any excipients in atorvastatin calcium tablets. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6. 2) Acute liver failure or decompensated cirrhosis ( 4 Hypersensitivity to atorvastatin or any excipient in atorvastatin calcium tablets ( 4.

Pregnancy: 8. 1 Lactation: 8. 2 Risk Summary [see Clinical Pharmacology (12. 1) Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin calcium use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data 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% to 4% and 15% to 20%, respectively. Data Human Data Animal Data 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 mg/kg/day, 100 mg/kg/day, 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. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Risk Summary (see Data Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium [see Use in Specific Populations (8. 1) Clinical Pharmacology (12. 1) Data The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of LIPITOR for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females. The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14) The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH). Of the total number of atorvastatin calcium-treated patients in clinical trials, 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 patients and younger patients. Advanced age (>=65 years) is a risk factor for atorvastatin calcium-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions (5. 3) Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of atorvastatin calcium, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5. 3) In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max max [see Contraindications (4).

See full prescribing information for details regarding concomitant use of atorvastatin calcium tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2. 1 Rifampin 7. 2 Oral Contraceptives: 7. 3 Digoxin: 7. 3 Atorvastatin calcium is a substrate of CYP3A4 and transporters (e. , OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin calcium and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5. 1) Clinical Pharmacology (12. 3) Table 2: 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 and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12. 3) Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium 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 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 20 mg. In patients taking nelfinavir, do not exceed atorvastatin calcium 40 mg [see Dosage and Administration (2. 5) Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium. 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 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 20 mg [see Dosage and Administration (2. 5) 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. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium 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. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin calcium 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. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium. 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. Table 3 presents drug interactions that may decrease exposure to atorvastatin calcium and instructions for preventing or managing them. Table 3: Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Tablets Rifampin Clinical Impact: Concomitant administration of atorvastatin calcium 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 after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin calcium and rifampin simultaneously. Table 4 presents atorvastatin calcium’s effect on other drugs and instructions for preventing or managing them. Table 4: Atorvastatin Calcium Tablets Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin calcium 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. Digoxin Clinical Impact: When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12. 3) Intervention: Monitor patients taking digoxin appropriately.

OVERDOSAGE
No specific antidotes for atorvastatin calcium are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance.
NONCLINICAL TOXICOLOGY
In a 2-year carcinogenicity study in rats at dose levels of 10 mg/kg/day, 30 mg/kg/day, 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 to 24) A 2-year carcinogenicity study in mice given 100 mg/kg/day, 200 mg/kg/day, 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 to 24) In vitro Salmonella typhimurium Escherichia coli 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 mg/kg 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 mg/kg, 40 mg/kg, or 120 mg/kg for two years.
CLINICAL STUDIES
Prevention of Cardiovascular Disease The effect of 10 mg/day of atorvastatin calcium on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium 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 group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1. 9% for atorvastatin calcium vs. 0% for placebo), p=0. 0005 (see Figure 1 Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infraction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1. 4% for atorvastatin calcium 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 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 on cardiovascular disease (CVD) endpoints was assessed in 2,838 subjects (94% white, 2% Black or African American, 2% South Asian, 1% other; 68% male), ages 40 to75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL <= 160 mg/dL and triglycerides (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 trial. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1,429) or placebo (1,411) 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 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium 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 Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium 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 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 group vs. 82 deaths in the placebo group (HR 0. Figure 2: Effect of Atorvastatin Calcium 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 80 mg/day vs. atorvastatin calcium 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 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium 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 mg/dL, 145 mg/dL, 128 mg/dL, 98 mg/dL, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99 mg/dL, 177 mg/dL, 152 mg/dL, 129 mg/dL, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium. Treatment with atorvastatin calcium 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 Table 7 Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) Table 7. Overview of Efficacy Results in TNT Endpoint Atorvastatin Atorvastatin HR a 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) 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 Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 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 7). Of the predefined secondary endpoints, treatment with atorvastatin calcium 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 7). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. Primary Hyperlipidemia in Adults Atorvastatin Calcium reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. In two multicenter, placebo-controlled, dose-response trials in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 8. ) Table 8: Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a Dose N TC LDL-C Apo B TG HDL-C Placebo 21 4 4 3 10 -3 10 22 -29 -39 -32 -19 6 20 20 -33 -43 -35 -26 9 40 21 -37 -50 -42 -29 6 80 23 -45 -60 -50 -37 5 a In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin calcium was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 9). Table 9: Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) 1 a b c Treatment N Total-C LDL-C Apo B TG HDL-C Trial 1 Atorvastatin calcium 10 mg 707 -27 a -36 a -28 a -17 a +7 Lovastatin 20 mg 191 -19 -27 -20 -6 +7 95% CI for Diff1 -9. 0 Trial 2 Atorvastatin calcium 10 mg 222 -25 b -35 b -27 b -17 b +6 Pravastatin 20 mg 77 -17 -23 -17 -9 +8 95% CI for Diff1 -10. 6 Trial 3 Atorvastatin calcium 10 mg 132 -29 c -37 c -34 c -23 c +7 Simvastatin 10 mg 45 -24 -30 -30 -15 +7 95% CI for Diff1 -8. 9 Table 9 does not contain data comparing the effects of atorvastatin calcium 10 mg and higher dosages of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily exchangeable. Hypertriglyceridemia in Adults The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 10). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267-1502). Table 10: Combined Patients with Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo Atorvastatin Calcium 10 mg Atorvastatin Calcium 20 mg Atorvastatin Calcium 80 mg TG -12. 3) Total-C -2. 2) non-HDL-C -2. 3) Dysbetalipoproteinemia in Adults The results of an open-label crossover trial of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 11). Table 11: Open-Label Crossover Trial of 16 Patients with Dysbetalipoproteinemia Median % Change (min, max) Median (min, max) at Atorvastatin Calcium Atorvastatin Calcium Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) TG 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) HoFH in Adults and Pediatric Patients In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% <18 years) with HoFH received maximum daily doses of 20 mg to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this trial 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%. HeFH in Pediatric Patients In a double-blind, placebo-controlled trial followed by an open-label phase, 187 males and post-menarchal females 10 years to 17 years of age (mean age 14. 1 years; 31% female; 92% White, 1. 6% Black or African American, 1. 6% Asian, 4. 8% other) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the trial 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 219 mg/dL (range: 139 mg/dL to 385 mg/dL) in the atorvastatin calcium group compared to 230 mg/dL (range: 160 mg/dL to 325 mg/dL) in the placebo group. The dosage of atorvastatin calcium (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-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%). Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, TG, and apolipoprotein B during the 26-week double-blind phase (see Table 12 Table 12: Lipid-altering Effects of Atorvastatin Calcium in Adolescent Males and Females 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 140 -31. 0 The mean achieved LDL-C value was 130. 7 mg/dL (range: 70. 0 mg/dL) in the atorvastatin calcium group compared to 228. 5 mg/dL (range: 152. 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 males and 81 females). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black, African American 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 trials in both adult and pediatric placebo-controlled trials. Figure-01 Figure-02 Figure-03.

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