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 is indicated:

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

• •
  Take orally once daily with or without food ( 2.1).
• •
  Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( 2.1).
• •
  Adults( 2.2):
  • o
    Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily.
  • o
    Patients requiring LDL-C reduction >45% may start at 40 mg once daily.
• •
  Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily ( 2.3).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily ( 2.4).
• •
  See full prescribing information for Atorvastatin calcium tablets dosage modifications due to drug interactions ( 2.5).

Atorvastatin calcium tablets are supplied as follows:

Storage

Store at controlled room temperature 20°C - 25°C (68°F - 77°F)

• •
  Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3)]
• •
  Hypersensitivity to atorvastatin or any excipients in atorvastatin calcium tablets. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions ( 6.2)].

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

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is C ₆₆H ₆₈CaF ₂N ₄O ₁₀.3H ₂O and its molecular weight is 1209.42. Its structural formula is:

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

Atorvastatin calcium tablets, USP for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.359 mg, 20.718 mg, 41.436 mg, or 82.872 mg atorvastatin calcium trihydrate) and the following inactive ingredients: Croscarmellose sodium, NF; Hydroxy propyl cellulose, NF; , Lactose monohydrate, NF; Magnesium stearate, NF; , Microcrystalline cellulose, NF; Polysorbate 80, NF; Precipitated calcium carbonate, NF; Hypromellose; Macrogol; Talc and Titanium dioxide.

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

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

Myopathy and Rhabdomyolysis

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

Hepatic Dysfunction

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

Increases in HbA1c and Fasting Serum Glucose Levels

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

Pregnancy

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

Lactation

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

Missed Doses

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

Manufactured by:

Umedica Laboratories Pvt. Ltd.

Plot No. 221 and 221/1, GIDC, II ^ndPhase,

Vapi, Gujarat 396195, INDIA (IND)

Manufactured for:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827 USA

Toll free number: 1-877-977-0687

April 2024; V-06

Repackaged By: Preferred Pharmaceuticals Inc.                      

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

• •
  Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1)]
• •
  Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2)]
• •
  Hepatic Dysfunction [see Warnings and Precautions ( 5.3)]
• •
  Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4)]

No specific antidotes for atorvastatin calcium tablets are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance.

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% women; 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.

Figure 1: Effect of atorvastatin calcium tablets 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)

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

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium tablets on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 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 HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.

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

Atorvastatin calcium tablets significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 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).

Figure 2: Effect of atorvastatin calcium tablets 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS

In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium tablets 80 mg/day vs. atorvastatin calcium tablets 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level<130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium tablets 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium tablets and followed for a median duration of 4.9 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 Table7). The overall risk reduction was consistent regardless of age (<65, ≥ 65) or sex.

Figure 3: Effect of atorvastatin calcium tablets 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)

^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 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 (Table7).  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 (Table7). 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 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 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.)

^aResults are pooled from 2 dose-response trials.

In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin calcium tablets was 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: Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials)

¹A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium tablets for all except HDL-C, for which a positive value favors atorvastatin calcium tablets. If the range does not include 0, this indicates a statistically significant difference.

^aSignificantly different from lovastatin, ANCOVA, p ≤ 0.05

^bSignificantly different from  pravastatin, ANCOVA,  p  ≤ 0.05

^cSignificantly different from simvastatin, ANCOVA,  p  ≤ 0.05

Table 9 does not contain data comparing the effects of atorvastatin calcium tablets 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the 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 -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 (Table11).

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 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 study followed by an open-label phase, 187  boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Black or African American, 1.6% Asians, 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 -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.

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

This Patient Package Information has been approved by the U.S. Food and Drug Administration                                                                                         April 2024; V-06               

Repackaged By: Preferred Pharmaceuticals Inc.                      

Atorvastatin calcium tablets:

• •
  10 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "10" on other side.
• •
  20 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "20" on other side.
• •
  40 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "40" on other side.
• •
  80 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "80" on other side.

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

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

Atorvastatin Calcium Tablets, USP 10 mg NDC 75834-255-90 - 90s Bottle Label

Atorvastatin calcium tablets is indicated:

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

• •
  Take orally once daily with or without food ( 2.1).
• •
  Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( 2.1).
• •
  Adults( 2.2):
  • o
    Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily.
  • o
    Patients requiring LDL-C reduction >45% may start at 40 mg once daily.
• •
  Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily ( 2.3).
• •
  Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily ( 2.4).
• •
  See full prescribing information for Atorvastatin calcium tablets dosage modifications due to drug interactions ( 2.5).

Atorvastatin calcium tablets are supplied as follows:

Storage

Store at controlled room temperature 20°C - 25°C (68°F - 77°F)

• •
  Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3)]
• •
  Hypersensitivity to atorvastatin or any excipients in atorvastatin calcium tablets. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions ( 6.2)].

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

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

Myopathy and Rhabdomyolysis

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

Hepatic Dysfunction

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

Increases in HbA1c and Fasting Serum Glucose Levels

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

Pregnancy

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

Lactation

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

Missed Doses

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

Manufactured by:

Umedica Laboratories Pvt. Ltd.

Plot No. 221 and 221/1, GIDC, II ^ndPhase,

Vapi, Gujarat 396195, INDIA (IND)

Manufactured for:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827 USA

Toll free number: 1-877-977-0687

April 2024; V-06

Repackaged By: Preferred Pharmaceuticals Inc.                      

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

• •
  Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1)]
• •
  Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2)]
• •
  Hepatic Dysfunction [see Warnings and Precautions ( 5.3)]
• •
  Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4)]

No specific antidotes for atorvastatin calcium tablets are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance.

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

Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is C ₆₆H ₆₈CaF ₂N ₄O ₁₀.3H ₂O and its molecular weight is 1209.42. Its structural formula is:

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

Atorvastatin calcium tablets, USP for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.359 mg, 20.718 mg, 41.436 mg, or 82.872 mg atorvastatin calcium trihydrate) and the following inactive ingredients: Croscarmellose sodium, NF; Hydroxy propyl cellulose, NF; , Lactose monohydrate, NF; Magnesium stearate, NF; , Microcrystalline cellulose, NF; Polysorbate 80, NF; Precipitated calcium carbonate, NF; Hypromellose; Macrogol; Talc and Titanium dioxide.

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% women; 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.

Figure 1: Effect of atorvastatin calcium tablets 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)

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

In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium tablets on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 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 HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.

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

Atorvastatin calcium tablets significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 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).

Figure 2: Effect of atorvastatin calcium tablets 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS

In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium tablets 80 mg/day vs. atorvastatin calcium tablets 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level<130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium tablets 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium tablets and followed for a median duration of 4.9 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 Table7). The overall risk reduction was consistent regardless of age (<65, ≥ 65) or sex.

Figure 3: Effect of atorvastatin calcium tablets 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)

^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 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 (Table7).  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 (Table7). 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 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 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.)

^aResults are pooled from 2 dose-response trials.

In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin calcium tablets was 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: Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials)

¹A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium tablets for all except HDL-C, for which a positive value favors atorvastatin calcium tablets. If the range does not include 0, this indicates a statistically significant difference.

^aSignificantly different from lovastatin, ANCOVA, p ≤ 0.05

^bSignificantly different from  pravastatin, ANCOVA,  p  ≤ 0.05

^cSignificantly different from simvastatin, ANCOVA,  p  ≤ 0.05

Table 9 does not contain data comparing the effects of atorvastatin calcium tablets 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the 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 -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 (Table11).

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 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 study followed by an open-label phase, 187  boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Black or African American, 1.6% Asians, 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 -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.

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

This Patient Package Information has been approved by the U.S. Food and Drug Administration                                                                                         April 2024; V-06               

Repackaged By: Preferred Pharmaceuticals Inc.                      

Atorvastatin calcium tablets:

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  10 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "10" on other side.
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  20 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "20" on other side.
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  40 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "40" on other side.
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  80 mg of atorvastatin: White to off-white, film-coated, oval shaped tablets "ATO" debossed on one side and "80" on other side.

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

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

Atorvastatin Calcium Tablets, USP 10 mg NDC 75834-255-90 - 90s Bottle Label