Atorvastatin calcium tablets are indicated:

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

Atorvastatin Calcium Tablets, USP are available containing atorvastatin calcium, USP equivalent to 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin.

• The 10 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 10on one side of the tablet and blank on the other side.
• The 20 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 20on one side of the tablet and blank on the other side.
• The 40 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 40on one side of the tablet and blank on the other side.
• The 80 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 80on one side of the tablet and blank on the other side.

• 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)] .

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 clearance.

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

Atorvastatin calcium is Calcium ( βR, δR)-2-( p-fluorophenyl)- β, δ-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl) pyrrole-1-heptanoate (1:2), trihydrate. The molecular formula of atorvastatin calcium is C 66H 68CaF 2N 4O 10•3H 2O and its molecular weight is 1209. Its structural formula is:

Atorvastatin calcium, USP is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.

Atorvastatin calcium tablets for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.84 mg, 21.69 mg, 43.38 mg, or 86.75 mg atorvastatin calcium trihydrate) and the following inactive ingredients: anhydrous lactose, anhydrous sodium carbonate, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, L-Arginine, magnesium stearate and microcrystalline cellulose. The film coating of the tablets contains polyvinyl alcohol, talc and titanium dioxide, and may contain polyethylene glycol or lecithin and xanthan gum.

Meets USP Dissolution Test 4.

Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium tablets on fatal and non-fatal coronary heart disease was assessed in 10,305 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 tablets 10 mg daily (n = 5,168) or placebo (n = 5,137), 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 tablets on lipid levels was similar to that seen in previous clinical trials.

Atorvastatin calcium tablets significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium tablets group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium tablets group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium tablets vs. 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 tablets was seen regardless of baseline LDL levels.

Atorvastatin calcium tablets also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium tablets and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p = 0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium tablets and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p = 0.51) or noncardiovascular causes (p = 0.17).

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium tablets 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 40-75 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 tablets 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.

Baseline characteristics of subjects were: mean age of 62 years, mean HbA 1c7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.

The effect of atorvastatin calcium tablets 10 mg/day on lipid levels was similar to that seen in previous clinical trials.

Atorvastatin calcium tablets significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p = 0.001) (see Figure 2). An effect of atorvastatin calcium tablets was seen regardless of age, sex, or baseline lipid levels.

Atorvastatin calcium tablets significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium tablets group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p = 0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium tablets group vs. 64 events in the placebo group), HR 0.58, 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 tablets 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 tablets 80 mg/day vs. atorvastatin calcium tablets 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% White, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level < 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium tablets 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium tablets and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium tablets and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium tablets.

Treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p = 0.0002 (see Figure 3 and Table 7). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or sex.

Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary endpoints, treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.

There was no significant difference between the treatment groups for all-cause mortality (Table 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 tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group.

Primary Hyperlipidemia in Adults

Atorvastatin calcium tablets reduce total-C, LDL-C, apo B, and TG, and increase 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 tablets given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 8.)

In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin calcium tablets were compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium tablets 10 mg per day or a fixed dose of the comparative agent (Table 9).

Table 9 does not contain data comparing the effects of atorvastatin calcium tablets 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 tablets in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 10). For the atorvastatin calcium tablet-treated patients, median (min, max) baseline TG level was 565 (267-1502).

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).

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 to 80 mg of atorvastatin calcium tablets. 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 tablets (n = 140) or placebo (n = 47) for 26 weeks and then all received atorvastatin calcium tablets 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: 139-385 mg/dL) in the atorvastatin calcium tablets group compared to 230 mg/dL (range: 160-325 mg/dL) in the placebo group. The dosage of atorvastatin calcium tablets (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium tablet-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%).

Atorvastatin calcium tablets significantly decreased plasma levels of total-C, LDL-C, TG, and apolipoprotein B during the 26-week double-blind phase (see Table 12).

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin calcium tablets 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.

Atorvastatin Calcium Tablets, USP are available containing atorvastatin calcium, USP equivalent to 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin.

The 10 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 10on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-208-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 20 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 20on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-209-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 40 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 40on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-210-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 80 mg tablets are white to off-white, film-coated, oval, unscored tablets debossed with 80on one side of the tablet and blank on the other side. They are available as follows:

NDC 51079-211-03 – Unit dose blister packages of 30 (5 cards of 6 tablets each).

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

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 next scheduled dose.

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

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured by:
Mylan Laboratories Limited
Hyderabad — 500 096, India

Distributed by:
Mylan Institutional Inc.
Rockford, IL 61103 U.S.A.

S-11992 R11
8/24

NDC 51079-208-20

Atorvastatin
Calcium
Tablets, USP
10 mg*

100 Tablets (10 x 10)

*Each film-coated tablet contains
atorvastatin calcium, USP
equivalent to 10 mg of atorvastatin.

Usual Dosage:See accompanying
prescribing information.

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

Code No.: MP/DRUGS/25/1/2014

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Rx only

S-13013

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

NDC 51079-209-20

Atorvastatin
Calcium
Tablets, USP
20 mg*

100 Tablets (10 x 10)

*Each film-coated tablet contains
atorvastatin calcium, USP
equivalent to 20 mg of atorvastatin.

Usual Dosage:See accompanying
prescribing information.

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

Code No.: MP/DRUGS/25/1/2014

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Rx only

S-13014

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

NDC 51079-210-20

Atorvastatin
Calcium
Tablets, USP
40 mg*

100 Tablets (10 x 10)

*Each film-coated tablet contains
atorvastatin calcium, USP
equivalent to 40 mg of atorvastatin.

Usual Dosage:See accompanying
prescribing information.

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

Code No.: MP/DRUGS/25/1/2014

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Rx only

S-13015

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

NDC 51079-211-03

Atorvastatin
Calcium
Tablets, USP
80 mg*

30 Tablets (5 x 6)

*Each film-coated tablet contains
atorvastatin calcium, USP
equivalent to 80 mg of atorvastatin.

Usual Dosage:See accompanying
prescribing information.

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

Code No.: MP/DRUGS/25/1/2014

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Rx only

S-13008

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.