These Highlights Do Not Include All The Information Needed To Use Atorvastatin Calcium Tablets Safely And Effectively. See Full Prescribing Information For Atorvastatin Calcium Tablets.   

Atorvastatin calcium tablets are indicated:

• •
  To reduce the risk of:
  • o
    Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD
  • o
    MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD
  • o
    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:
  • o
    Adults with primary hyperlipidemia.
  • o
    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:
  • o
    Primary dysbetalipoproteinemia
  • o
    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 (2.1).
• •
  Adults (2.2):
  • o
    Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily.
  • o
    Patients requiring LDL-C reduction >45% may start at 40 mg once daily.
• •
  Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily (2.3).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily (2.4).
• •
  See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions (2.5).

Atorvastatin calcium tablets USP, 10 mg are white to off-white oval shaped, film-coated tablets with ‘C1’ on one side and plain on other side and free from physical defects.

Bottles of 30 NDC 68788-8409-3

Bottles of 60 NDC 68788-8409-6

Bottles of 90 NDC 68788-8409-9

Bottles of 100 NDC 68788-8409- 1

Storage

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

• •
  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)].

Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The molecular formula of atorvastatin calcium is C₆₆H₇₄CaF₂N₄O₁₃and its molecular weight is 1206.408.  Its structural formula is:

Atorvastatin calcium USP is a white to off-white crystalline powder. It is freely soluble in methanol and insoluble in aqueous solutions of pH 4 and below.

Atorvastatin calcium tablets USP, for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.845 mg, 21.69 mg, 43.38 mg, or 86.76 mg of atorvastatin calcium trihydrate) and the following inactive ingredients: calcium carbonate, croscarmellose sodium, hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80. The tablet coating contains hypromellose, polyethylene glycol, talc and titanium dioxide.

Atorvastatin calcium tablets meets USP Dissolution Test 5.

• •
  See full prescribing information for details regarding concomitant use of atorvastatin calcium with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis (2.5, 7.1).
• •
  Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin calcium (7.2).
• •
  Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive (7.3).
• •
  Digoxin: May increase digoxin plasma levels; monitor patients appropriately (7.3).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myopathy and Rhabdomyolysis

Advise patients that atorvastatin calcium tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Hepatic Dysfunction

Inform patients that atorvastatin calcium tablets  may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with atorvastatin calcium tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].

Pregnancy

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if atorvastatin calcium tablets should be discontinued [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium tablets [see Use in Specific Populations (8.2)].

Missed Doses

If a dose is missed, advise patients not to take the missed dose and resume with the nextscheduled dose.

The brands listed are trademarks of their respective owners.

Rx only

Distributor:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540

Made in India

Revised: 04/2024

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 (5.1) and Clinical Pharmacology (12.3)].

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 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.

A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.

In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.

In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years.  

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)]

No specific antidotes for atorvastatin calcium tablets 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 tablets clearance. 

Risk Summary

Discontinue atorvastatin calcium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin calcium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.

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). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.  

Data

Human Data

A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

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/m²). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.  

In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.

• •
  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.

This Patient Package Information has been approved by the U.S. Food and Drug Administration

Revised: 04/2024

Repackaged By: Preferred Pharmaceuticals Inc.

Dispense with Patient Information Sheet available at:

www.drreddys.com/pil/atorvastatintabs.pdf

Atorvastatin calcium tablets USP, 10 mg are white to off-white oval shaped, film-coated tablets with ‘C1’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium tablets USP, 20 mg are white to off-white oval shaped, film-coated tablets with ‘C2’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium tablets USP, 40 mg are white to off-white oval shaped, film-coated tablets with ‘C3’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium tablets USP, 80 mg are white to off-white oval shaped, film-coated tablets with ‘C4’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin 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 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

Atorvastatin calcium tablets are rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin calcium tablets are given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.

Elimination

Metabolism

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium tablets are recovered in urine following oral administration.

• •
  Pregnancy: May cause fetal harm. (8.1).
• •
  Lactation: Breastfeeding not recommended during treatment with atorvastatin calcium tablets (8.2)

•  
  Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin calcium tablets dosage. Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin calcium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing atorvastatin calcium tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever (2.5, 5.1, 7.1, 8.5, 8.6).
•  
  Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue atorvastatin calcium tablets if IMNM is suspected (5.2).
•  
  Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium tablets (5.3).

Atorvastatin Calcium Tablets, 10 mg - Container Label

Risk Summary

There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including atorvastatin calcium tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

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 tablets [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

Data

Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma).

Atorvastatin calcium tablets are indicated:

• •
  To reduce the risk of:
  • o
    Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD
  • o
    MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD
  • o
    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:
  • o
    Adults with primary hyperlipidemia.
  • o
    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:
  • o
    Primary dysbetalipoproteinemia
  • o
    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 (2.1).
• •
  Adults (2.2):
  • o
    Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily.
  • o
    Patients requiring LDL-C reduction >45% may start at 40 mg once daily.
• •
  Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily (2.3).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily (2.4).
• •
  See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions (2.5).

Atorvastatin calcium tablets USP, 10 mg are white to off-white oval shaped, film-coated tablets with ‘C1’ on one side and plain on other side and free from physical defects.

Bottles of 30 NDC 68788-8409-3

Bottles of 60 NDC 68788-8409-6

Bottles of 90 NDC 68788-8409-9

Bottles of 100 NDC 68788-8409- 1

Storage

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

• •
  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)].

• •
  See full prescribing information for details regarding concomitant use of atorvastatin calcium with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis (2.5, 7.1).
• •
  Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin calcium (7.2).
• •
  Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive (7.3).
• •
  Digoxin: May increase digoxin plasma levels; monitor patients appropriately (7.3).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myopathy and Rhabdomyolysis

Advise patients that atorvastatin calcium tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Hepatic Dysfunction

Inform patients that atorvastatin calcium tablets  may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with atorvastatin calcium tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].

Pregnancy

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if atorvastatin calcium tablets should be discontinued [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium tablets [see Use in Specific Populations (8.2)].

Missed Doses

If a dose is missed, advise patients not to take the missed dose and resume with the nextscheduled dose.

The brands listed are trademarks of their respective owners.

Rx only

Distributor:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540

Made in India

Revised: 04/2024

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 (5.1) and Clinical Pharmacology (12.3)].

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 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.

A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.

In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.

In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years.  

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)]

No specific antidotes for atorvastatin calcium tablets 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 tablets clearance. 

Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The molecular formula of atorvastatin calcium is C₆₆H₇₄CaF₂N₄O₁₃and its molecular weight is 1206.408.  Its structural formula is:

Atorvastatin calcium USP is a white to off-white crystalline powder. It is freely soluble in methanol and insoluble in aqueous solutions of pH 4 and below.

Atorvastatin calcium tablets USP, for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.845 mg, 21.69 mg, 43.38 mg, or 86.76 mg of atorvastatin calcium trihydrate) and the following inactive ingredients: calcium carbonate, croscarmellose sodium, hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80. The tablet coating contains hypromellose, polyethylene glycol, talc and titanium dioxide.

Atorvastatin calcium tablets meets USP Dissolution Test 5.

Risk Summary

Discontinue atorvastatin calcium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin calcium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.

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). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.  

Data

Human Data

A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

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/m²). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.  

In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC.

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.

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  Take atorvastatin calcium tablets orally once daily at any time of the day, with or without food.
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  Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust the dosage if necessary.
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  If a dose is missed, advise patients not to take the missed dose and resume with the next scheduled dose.

This Patient Package Information has been approved by the U.S. Food and Drug Administration

Revised: 04/2024

Repackaged By: Preferred Pharmaceuticals Inc.

Dispense with Patient Information Sheet available at:

www.drreddys.com/pil/atorvastatintabs.pdf

Atorvastatin calcium tablets USP, 10 mg are white to off-white oval shaped, film-coated tablets with ‘C1’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium tablets USP, 20 mg are white to off-white oval shaped, film-coated tablets with ‘C2’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium tablets USP, 40 mg are white to off-white oval shaped, film-coated tablets with ‘C3’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium tablets USP, 80 mg are white to off-white oval shaped, film-coated tablets with ‘C4’ on one side and plain on other side and free from physical defects.

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin 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 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

Atorvastatin calcium tablets are rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin calcium tablets are given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Distribution

Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells.

Elimination

Metabolism

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion

Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium tablets are recovered in urine following oral administration.

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  Pregnancy: May cause fetal harm. (8.1).
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  Lactation: Breastfeeding not recommended during treatment with atorvastatin calcium tablets (8.2)

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  Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin calcium tablets dosage. Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin calcium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing atorvastatin calcium tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever (2.5, 5.1, 7.1, 8.5, 8.6).
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  Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue atorvastatin calcium tablets if IMNM is suspected (5.2).
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  Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium tablets (5.3).

Atorvastatin Calcium Tablets, 10 mg - Container Label

Risk Summary

There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including atorvastatin calcium tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

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 tablets [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

Data

Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma).