1 INDICATIONS AND USAGE

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

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

Atorvastatin Calcium may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin calcium.

Risk Factors for Myopathy
Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher atorvastatin calcium dosage [see Drug Interactions (7.1)and Use in Specific Populations (8.5, 8.6)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
Atorvastatin calcium exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin calcium is not recommended. Atorvastatin calcium dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2.5)] . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co- administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)] .

Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin calcium [see Drug Interactions (7.1)] .

Discontinue atorvastatin calcium if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if atorvastatin calcium is discontinued. Temporarily discontinue atorvastatin calcium in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the atorvastatin calcium dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue atorvastatin calcium if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with use of atorvastatin calcium [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin calcium in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin calcium.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7)].

Consider liver enzyme testing before atorvastatin calcium initiation and when clinically indicated thereafter. atorvastatin calcium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin calcium. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

5.5 Increased Risk of Hemorrhagic Stroke in Patients on atorvastatin

calcium tablets 80 mg with Recent Hemorrhagic Stroke

In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or TIA within the preceding 6 months, were treated with atorvastatin calcium 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin calcium vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin calcium group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin calcium group [see Adverse Reactions (6.1)] . Consider the risk/benefit of use of atorvastatin calcium 80 mg in patients with recent hemorrhagic stroke.

6 ADVERSE REACTIONS

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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8,755 Atorvastatin Calcium vs. 7,311 placebo; age range 10 years to 93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).

Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with Atorvastatin Calcium (n=8,755), from seventeen placebo-controlled trials.

Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin calcium -Treated with any Dose and Greater than Placebo

Adverse Reaction	% Placebo N=7311	% 10 mg N=3908	% 20 mg N=188	% 40 mg N=604	% 80 mg N=4055	% Any dose N=8755
Nasopharyngitis	8.2	12.9	5.3	7.0	4.2	8.3
Arthralgia	6.5	8.9	11.7	10.6	4.3	6.9
Diarrhea	6.3	7.3	6.4	14.1	5.2	6.8
Pain in extremity	5.9	8.5	3.7	9.3	3.1	6.0
Urinary tract infection	5.6	6.9	6.4	8.0	4.1	5.7
Dyspepsia	4.3	5.9	3.2	6.0	3.3	4.7
Nausea	3.5	3.7	3.7	7.1	3.8	4.0
Musculoskeletal pain	3.6	5.2	3.2	5.1	2.3	3.8
Muscle spasms	3.0	4.6	4.8	5.1	2.4	3.6
Myalgia	3.1	3.6	5.9	8.4	2.7	3.5
Insomnia	2.9	2.8	1.1	5.3	2.8	3.0
Pharyngolaryngeal pain	2.1	3.9	1.6	2.8	0.7	2.3

Other adverse reactions reported in placebo-controlled trials include:
Body as a whole: malaise, pyrexia
Digestive system:abdominal discomfort, eructation, flatulence, hepatitis, cholestasis
Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling
Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia
Nervous system: nightmare
Respiratory system:epistaxis Skin and appendages: urticaria
Special senses: vision blurred, tinnitus
Urogenital system:white blood cells urine positive

Elevations in Liver Enzyme Tests
Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10mg, 20mg, 40mg, and 80 mg, respectively.

One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin calcium.

Treating to New Targets Study (TNT)
In TNT, [see Clinical Studies (14.1)] 10,001 patients (age range 29-78 years, 19% women; 94% White, 3% Black, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin calcium 10 mg daily (n=5,006) or atorvastatin calcium 80 mg daily (n=4,995). In the high-dose atorvastatin calcium group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low- dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4-10 days) occurred in 1.3% of individuals with atorvastatin calcium 80 mg and in 0.2% of individuals with atorvastatin calcium 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin calcium group (0.3%) compared to the low-dose atorvastatin calcium group (0.1%).

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In SPARCL, 4731 patients (age range 21-92 years, 40% women; 93% White, 3% Black, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin calcium 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4-10 days) in the atorvastatin calcium group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin calcium group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin calcium group and 3.8% of subjects in the placebo group.

In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 Atorvastatin Calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin calcium group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% Atorvastatin calcium vs. 4% placebo).

Adverse Reactions from Clinical Studies of atorvastatin calcium in Pediatric Patients with HeFH
In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 mg to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (8.4)and Clinical Studies (14.6)] .

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of atorvastatin calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders:pancreatitis
General disorders:fatigue
Hepatobiliary Disorders:fatal and non-fatal hepatic failure
Immune system disorders:anaphylaxis
Injury:tendon rupture
Musculoskeletal and connective tissue disorders:rhabdomyolysis, myositis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
Nervous system disorders:dizziness, peripheral neuropathy.
There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Psychiatric disorders:depression
Respiratory disorders:interstitial lung disease
Skin and subcutaneous tissue disorders:angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

RECENT MAJOR CHANGES

Contraindications, Pregnancy and Lactation ( 4)	Removed 12/2022
Warnings and Precautions, CNS Toxicity ( 5.5)	Removed 12/2022

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

• 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.

2.2 Recommended Dosage in Adult Patients

The recommended starting dosage of atorvastatin calcium tablets is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily.

2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with

HeFH

The recommended starting dosage of atorvastatin calcium tablets is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily.

2.4 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with

HoFH

The recommended starting dosage of atorvastatin calcium tablets is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily.

2.5 Dosage Modifications Due to Drug Interactions

Concomitant use of atorvastatin calcium tablets with the following drugs requires dosage modification of atorvastatin calcium tablets [see Warnings and Precautions (5.1)and Drug Interactions (7.1)] .

Anti-Viral Medications

• In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium 20 mg once daily.
• In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg once daily.

Select Azole Antifungals or Macrolide Antibiotics

• In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium tablets 20 mg once daily.

For additional recommendations regarding concomitant use of atorvastatin calcium tablets with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions (7.1)].

11 DESCRIPTION

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Atorvastatin Calcium Tablets, USP are supplied as follows:

Strength	How Supplied	NDC	Tablet Description
10 mg of atorvastatin	bottles of 90	77771-451-90	Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 152 on other side
bottles of 1,000	77771-451-10
20 mg of atorvastatin	bottles of 90	77771-452-90	Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 153 on other side
bottles of 500	77771-452-05
40 mg of atorvastatin	bottles of 90	77771-453-90	Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 154 on other side
bottles of 1,000	77771-453-10
80 mg of atorvastatin	bottles of 90	77771-454-90	Yellow, oval shape, biconvex, film coated tablets, debossed with SG on one side and 155 on other side
bottles of 500	77771-454-05

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.

17 PATIENT COUNSELING INFORMATION

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)].

Manufactured by:
ScieGen Pharmaceuticals, Inc.
Hauppauge, NY 11788

Distributed by:
Radha Pharmaceuticals, Inc.
Hauppauge, NY 11788 USA

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

Rev: 8/2023