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 ( Error! Hyperlink reference not valid.).
• •
  Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( Error! Hyperlink reference not valid.).
• •
  Adults( Error! Hyperlink reference not valid.):
  • o
    Recommended starting dosage is 10 mg 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 mg to 20 mg once daily ( Error! Hyperlink reference not valid.).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH:
  
  Recommended starting dosage is 10 mg to 20 mg once daily; dosage range is 10 mg to 80 mg once daily ( Error! Hyperlink reference not valid.).
• •
  See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions ( Error! Hyperlink reference not valid.).

Atorvastatin Calcium Tablets, USP are supplied as follows:

Atorvastatin Calcium Tablets 20mg are, Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 153 on other side.

Bottles of 30 Tablets NDC 68788-8613-3

Bottles of 60 Tablets NDC 68788-8613-6

Bottles of 90 Tablets NDC 68788-8613-9

Bottles of 100 Tablets NDC 68788-8613-1

Storage

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, child-resistant container.

• •
  Acute liver failure or decompensated cirrhosis [see Error! Hyperlink reference not valid. ] .
• •
  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 Error! Hyperlink reference not valid. ] .

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

Atorvastatin calcium, USP is [R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C ₃₃H ₃₄FN ₂O ₅) ₂Ca•3H ₂O and its molecular weight is 1209.42. Its structural formula is:

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

Atorvastatin calcium tablets, USP for oral administration contain 10 mg, 20 mg, 40 mg, or 80 mg atorvastatin and the following inactive ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; hypromellose, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow.

This product meets the requirements of USP DissolutionTest-2.

• •
  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 ( Error! Hyperlink reference not valid., Error! Hyperlink reference not valid.).
• •
  Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin calcium tablets ( Error! Hyperlink reference not valid.).
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  Oral Contraceptives:May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( Error! Hyperlink reference not valid.).
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  Digoxin:May increase digoxin plasma levels; monitor patients appropriately ( Error! Hyperlink reference not valid.).

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

Myopathy and Rhabdomyolysis

Advise patients that atorvastatin calcium 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 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. 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 should be discontinued [see Use in Specific Populations (8.1)] .

Lactation

Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium [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 next scheduled dose.

Manufactured by:

ScieGen Pharmaceuticals, Inc.

Hauppauge, NY 11788 USA

Dispense the Patient Information available at: https://sciegenpharm.com/medication-guide/

Rev: 5/2024

Repackaged By: Preferred Pharmaceuticals Inc.

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 Error! Hyperlink reference not valid. ] .

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 Error! Hyperlink reference not valid. and Error! Hyperlink reference not valid. ] .

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)}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 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)}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 typhimuriumand 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 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.

The following important adverse reactions are described below and elsewhere in the labeling:

• •
  Myopathy and Rhabdomyolysis [see Error! Hyperlink reference not valid. ]
• •
  Immune-Mediated Necrotizing Myopathy [see Error! Hyperlink reference not valid. ]
• •
  Hepatic Dysfunction [see Error! Hyperlink reference not valid. ]
• •
  Increases in HbA1c and Fasting Serum Glucose Levels [see Error! Hyperlink reference not valid. ]

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.

Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% female; 95% White, 3% Black or African American, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age >55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for patients without diabetes; <130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.

The effect of 10 mg/day of 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. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels.

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=0.17).

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 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.

Baseline characteristics of subjects were: mean age of 62 years, mean 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 (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels.

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 (0.31, 0.89) (p=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 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.

There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).

In the Treating to New Targets Study (TNT), the effect of 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 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73 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 (0.69, 0.89), p=0.0002 (see Figure 3and Table 7). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or sex.

^aAtorvastatin 80 mg: atorvastatin 10 mg

^bComponent of other secondary endpoints

^*Secondary endpoints not included in primary endpoint

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

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

^aResults are pooled from 2 dose-response trials.

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)

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

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

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)

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26-week double-blind phase.

Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 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.

Risk Summary

Discontinue atorvastatin calcium when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin calcium may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Error! Hyperlink reference not valid. ] . 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 times and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m ²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development 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/m ²). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 mg/kg/day 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 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.

• •
  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.

Repackaged By: Preferred Pharmaceuticals Inc.

Atorvastatin Calcium Tablets, USP:

• •
  10 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “152” on the other
• •
  20 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “153” on the other
• •
  40 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “154” on the other
• •
  80 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “155” on the other

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

Atorvastatin calcium is 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 C _maxand AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C _maxand 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 calcium is approximately 381 liters. Atorvastatin calcium 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 calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitroinhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitrostudies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium 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 calcium 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 calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 hours to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration.

Specific Populations

Geriatric

Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C _maxand 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults.

Pediatric

Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

Gender

Plasma concentrations of atorvastatin calcium in females differ from those in males (approximately 20% higher for C _maxand 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between males and females.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Error! Hyperlink reference not valid. ] .

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

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C _maxand AUC are each 4-fold greater in patients with Childs-Pugh A disease. C _maxand AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [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.

^&Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).

^#See Error! Hyperlink reference not valid.and Error! Hyperlink reference not valid.for clinical significance.

^*Greater increases in AUC (ratio of AUC up to 2.5) and/or C _max(ratio of C _maxup to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

^**Ratio based on a single sample taken 8 to 16 h post dose.

^†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.

^‡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.

^aOnce daily

^bTwice daily

^cSingle dose

^dThree times daily

^eFour times daily

^fEvery 8 hours

^#See Error! Hyperlink reference not valid.for clinical significance.

^aOnce daily

^bTwice daily

^cSingle Dosage

Atorvastatin Calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

• •
  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 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).

NDC 687888-8613

Atorvastatin Calcium

Tablets, USP

20 mg.

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, 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 [see Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ] .

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 ( Error! Hyperlink reference not valid.).
• •
  Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( Error! Hyperlink reference not valid.).
• •
  Adults( Error! Hyperlink reference not valid.):
  • o
    Recommended starting dosage is 10 mg 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 mg to 20 mg once daily ( Error! Hyperlink reference not valid.).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH:
  
  Recommended starting dosage is 10 mg to 20 mg once daily; dosage range is 10 mg to 80 mg once daily ( Error! Hyperlink reference not valid.).
• •
  See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions ( Error! Hyperlink reference not valid.).

Atorvastatin Calcium Tablets, USP are supplied as follows:

Atorvastatin Calcium Tablets 20mg are, Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 153 on other side.

Bottles of 30 Tablets NDC 68788-8613-3

Bottles of 60 Tablets NDC 68788-8613-6

Bottles of 90 Tablets NDC 68788-8613-9

Bottles of 100 Tablets NDC 68788-8613-1

Storage

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, child-resistant container.

• •
  Acute liver failure or decompensated cirrhosis [see Error! Hyperlink reference not valid. ] .
• •
  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 Error! Hyperlink reference not valid. ] .

• •
  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 ( Error! Hyperlink reference not valid., Error! Hyperlink reference not valid.).
• •
  Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin calcium tablets ( Error! Hyperlink reference not valid.).
• •
  Oral Contraceptives:May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( Error! Hyperlink reference not valid.).
• •
  Digoxin:May increase digoxin plasma levels; monitor patients appropriately ( Error! Hyperlink reference not valid.).

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

Myopathy and Rhabdomyolysis

Advise patients that atorvastatin calcium 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 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. 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 should be discontinued [see Use in Specific Populations (8.1)] .

Lactation

Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium [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 next scheduled dose.

Manufactured by:

ScieGen Pharmaceuticals, Inc.

Hauppauge, NY 11788 USA

Dispense the Patient Information available at: https://sciegenpharm.com/medication-guide/

Rev: 5/2024

Repackaged By: Preferred Pharmaceuticals Inc.

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 Error! Hyperlink reference not valid. ] .

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 Error! Hyperlink reference not valid. and Error! Hyperlink reference not valid. ] .

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)}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 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)}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 typhimuriumand 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 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.

The following important adverse reactions are described below and elsewhere in the labeling:

• •
  Myopathy and Rhabdomyolysis [see Error! Hyperlink reference not valid. ]
• •
  Immune-Mediated Necrotizing Myopathy [see Error! Hyperlink reference not valid. ]
• •
  Hepatic Dysfunction [see Error! Hyperlink reference not valid. ]
• •
  Increases in HbA1c and Fasting Serum Glucose Levels [see Error! Hyperlink reference not valid. ]

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.

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

Atorvastatin calcium, USP is [R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C ₃₃H ₃₄FN ₂O ₅) ₂Ca•3H ₂O and its molecular weight is 1209.42. Its structural formula is:

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

Atorvastatin calcium tablets, USP for oral administration contain 10 mg, 20 mg, 40 mg, or 80 mg atorvastatin and the following inactive ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; hypromellose, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow.

This product meets the requirements of USP DissolutionTest-2.

Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% female; 95% White, 3% Black or African American, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age >55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for patients without diabetes; <130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.

The effect of 10 mg/day of 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. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels.

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=0.17).

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 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.

Baseline characteristics of subjects were: mean age of 62 years, mean 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 (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels.

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 (0.31, 0.89) (p=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 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.

There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).

In the Treating to New Targets Study (TNT), the effect of 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 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73 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 (0.69, 0.89), p=0.0002 (see Figure 3and Table 7). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or sex.

^aAtorvastatin 80 mg: atorvastatin 10 mg

^bComponent of other secondary endpoints

^*Secondary endpoints not included in primary endpoint

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

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

^aResults are pooled from 2 dose-response trials.

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)

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

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

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)

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26-week double-blind phase.

Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 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.

Risk Summary

Discontinue atorvastatin calcium when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin calcium may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Error! Hyperlink reference not valid. ] . 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 times and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m ²). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development 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/m ²). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 mg/kg/day 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 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.

• •
  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.

Repackaged By: Preferred Pharmaceuticals Inc.

Atorvastatin Calcium Tablets, USP:

• •
  10 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “152” on the other
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  20 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “153” on the other
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  40 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “154” on the other
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  80 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “155” on the other

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

Atorvastatin calcium is 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 C _maxand AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C _maxand 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 calcium is approximately 381 liters. Atorvastatin calcium 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 calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitroinhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitrostudies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium 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 calcium 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 calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 hours to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration.

Specific Populations

Geriatric

Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C _maxand 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults.

Pediatric

Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.

Gender

Plasma concentrations of atorvastatin calcium in females differ from those in males (approximately 20% higher for C _maxand 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between males and females.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Error! Hyperlink reference not valid. ] .

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

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C _maxand AUC are each 4-fold greater in patients with Childs-Pugh A disease. C _maxand AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [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.

^&Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).

^#See Error! Hyperlink reference not valid.and Error! Hyperlink reference not valid.for clinical significance.

^*Greater increases in AUC (ratio of AUC up to 2.5) and/or C _max(ratio of C _maxup to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).

^**Ratio based on a single sample taken 8 to 16 h post dose.

^†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.

^‡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.

^aOnce daily

^bTwice daily

^cSingle dose

^dThree times daily

^eFour times daily

^fEvery 8 hours

^#See Error! Hyperlink reference not valid.for clinical significance.

^aOnce daily

^bTwice daily

^cSingle Dosage

Atorvastatin Calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

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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 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).

NDC 687888-8613

Atorvastatin Calcium

Tablets, USP

20 mg.

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, 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 [see Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ] .

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).