LIPITOR- atorvastatin calcium tablet, film coated 
Parke-Davis Div of Pfizer Inc

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LIPITOR safely and effectively. See full prescribing information for LIPITOR.
 
LIPITOR® (atorvastatin calcium) tablets, for oral use
Initial U.S. Approval: 1996

RECENT MAJOR CHANGES

Contraindications, Pregnancy and Lactation (4)          Removed 12/2022

Warnings and Precautions, CNS Toxicity (5.5)           Removed 12/2022

INDICATIONS AND USAGE

LIPITOR is an HMG-CoA reductase inhibitor (statin) indicated (1):

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 (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 to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia.
As an adjunct to diet for the treatment of adults with:
o
Primary dysbetaliproteinemia.
o
Hypertriglyceridemia.

DOSAGE AND ADMINISTRATION

Take orally once daily with or without food (2.1).
Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LIPITOR, 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 LIPITOR dosage modifications due to drug interactions (2.5).

DOSAGE FORMS AND STRENGTHS

Tablets: 10 mg; 20 mg; 40 mg; 80 mg of atorvastatin (3).

CONTRAINDICATIONS

Acute liver failure or decompensated cirrhosis (4).
Hypersensitivity to atorvastatin or any excipient in LIPITOR (4).

WARNINGS AND PRECAUTIONS

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher LIPITOR dosage. Discontinue LIPITOR if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue LIPITOR 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 LIPITOR 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 LIPITOR 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 LIPITOR (5.3).

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

See full prescribing information for details regarding concomitant use of LIPITOR 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 LIPITOR (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).

USE IN SPECIFIC POPULATIONS

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

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2022

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

2.2 Recommended Dosage in Adult Patients

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

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

2.5 Dosage Modifications Due to Drug Interactions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

5.2 Immune-Mediated Necrotizing Myopathy

5.3 Hepatic Dysfunction

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

5.5 Increased Risk of Hemorrhagic Stroke in Patients on LIPITOR 80 mg with Recent Hemorrhagic Stroke

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR

7.2 Drug Interactions that may Decrease Exposure to LIPITOR

7.3 LIPITOR Effects on Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

LIPITOR 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

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

Take Lipitor 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 LIPITOR, and adjust the dosage if necessary.

2.2 Recommended Dosage in Adult Patients

The recommended starting dosage of LIPITOR 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 LIPITOR 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 LIPITOR 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 LIPITOR with the following drugs requires dosage modification of LIPITOR [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 LIPITOR 20 mg once daily.
In patients taking nelfinavir, do not exceed LIPITOR 40 mg once daily.

Select Azole Antifungals or Macrolide Antibiotics

In patients taking clarithromycin or itraconazole, do not exceed LIPITOR 20 mg once daily.

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

3 DOSAGE FORMS AND STRENGTHS

LIPITOR tablets:

10 mg of atorvastatin: white elliptical, film-coated tablets with “PD 155” on one side and “10” on the other
20 mg of atorvastatin: white elliptical, film-coated tablets with “PD 156” on one side and “20” on the other
40 mg of atorvastatin: white elliptical, film-coated tablets with “PD 157” on one side and “40” on the other
80 mg of atorvastatin: white elliptical, film-coated tablets with “PD 158” on one side and “80” on the other

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

LIPITOR 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 LIPITOR.

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 LIPITOR 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

LIPITOR 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 LIPITOR is not recommended. LIPITOR 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 LIPITOR [see Drug Interactions (7.1)].

Discontinue LIPITOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if LIPITOR is discontinued. Temporarily discontinue LIPITOR 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 LIPITOR 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 LIPITOR if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with use of LIPITOR [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 LIPITOR in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LIPITOR.

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 LIPITOR initiation and when clinically indicated thereafter. LIPITOR 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 LIPITOR.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LIPITOR. 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 LIPITOR 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 LIPITOR 80 mg, a higher incidence of hemorrhagic stroke was seen in the LIPITOR 80 mg group compared to placebo (55, 2.3% LIPITOR 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 LIPITOR 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 LIPITOR group [see Adverse Reactions (6.1)]. Consider the risk/benefit of use of LIPITOR 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 LIPITOR placebo-controlled clinical trial database of 16,066 patients (8755 LIPITOR vs. 7311 placebo; age range 10-93 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 LIPITOR 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 LIPITOR (n=8755), from seventeen placebo-controlled trials.

Table 1: Adverse Reactions Occurring in ≥ 2% in Patients LIPITOR-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 LIPITOR in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, 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 LIPITOR.

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 LIPITOR 10 mg daily (n=5006) or LIPITOR 80 mg daily (n=4995). In the high-dose LIPITOR 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 LIPITOR 80 mg and in 0.2% of individuals with LIPITOR 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose LIPITOR group (0.3%) compared to the low-dose LIPITOR 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 LIPITOR 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 LIPITOR group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the LIPITOR group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the LIPITOR group and 3.8% of subjects in the placebo group.

In a post-hoc analysis, LIPITOR 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 LIPITOR vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the LIPITOR 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% LIPITOR vs. 4% placebo).

Adverse Reactions from Clinical Studies of LIPITOR 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 LIPITOR 10 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 LIPITOR. 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)

7 DRUG INTERACTIONS

7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR

LIPITOR is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). LIPITOR plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to LIPITOR and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR

Cyclosporine or Gemfibrozil

Clinical Impact:

Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3)]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with LIPITOR.

Intervention:

Concomitant use of cyclosporine or gemfibrozil with LIPITOR is not recommended.

Anti-Viral Medications

Clinical Impact:

Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3)]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with LIPITOR.

Intervention:

Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with LIPITOR is not recommended.
In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.
In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed LIPITOR 20 mg.
In patients taking nelfinavir, do not exceed LIPITOR 40 mg [see Dosage and Administration (2.5)].
Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with LIPITOR.
Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Examples:

Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.

Select Azole Antifungals or Macrolide Antibiotics

Clinical Impact:

Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3)].

Intervention:

In patients taking clarithromycin or itraconazole, do not exceed LIPITOR 20 mg [see Dosage and Administration (2.5)]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with LIPITOR. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Examples:

Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

Niacin

Clinical Impact:

Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with LIPITOR.

Intervention:

Consider if the benefit of using lipid modifying dosages of niacin concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Fibrates (other than Gemfibrozil)

Clinical Impact:

Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with LIPITOR.

Intervention:

Consider if the benefit of using fibrates concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Colchicine

Clinical Impact:

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with LIPITOR.

Intervention:

Consider the risk/benefit of concomitant use of colchicine with LIPITOR. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Grapefruit Juice

Clinical Impact:

Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.

Intervention:

Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking LIPITOR.

 

7.2 Drug Interactions that may Decrease Exposure to LIPITOR

Table 3 presents drug interactions that may decrease exposure to LIPITOR and instructions for preventing or managing them.

Table 3: Drug Interactions that may Decrease Exposure to LIPITOR

Rifampin

Clinical Impact:

Concomitant administration of LIPITOR with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of LIPITOR after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Intervention:

Administer LIPITOR and rifampin simultaneously.

 

7.3 LIPITOR Effects on Other Drugs

Table 4 presents LIPITOR’s effect on other drugs and instructions for preventing or managing them.

Table 4: LIPITOR Effects on Other Drugs

Oral Contraceptives

Clinical Impact:

Co-administration of LIPITOR and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)].

Intervention:

Consider this when selecting an oral contraceptive for patients taking LIPITOR.

Digoxin

Clinical Impact:

When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)].

Intervention:

Monitor patients taking digoxin appropriately.

 

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with LIPITOR use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data).

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

Data

Human Data

A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

Animal Data

Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.

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

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

8.2 Lactation

Risk Summary

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

Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LIPITOR [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

Data

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

8.4 Pediatric Use

The safety and effectiveness of LIPITOR as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of LIPITOR for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls.

The safety and effectiveness of LIPITOR as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of LIPITOR for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14)].

The safety and effectiveness of LIPITOR have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

8.5 Geriatric Use

Of the total number of LIPITOR-treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Advanced age (≥65 years) is a risk factor for LIPITOR-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LIPITOR for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of LIPITOR, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of LIPITOR are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. LIPITOR is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)].

10 OVERDOSAGE

No specific antidotes for LIPITOR 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 LIPITOR clearance.

11 DESCRIPTION

LIPITOR (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 (C33H34FN2O5)2Ca•3H2O and its molecular weight is 1209.42. Its structural formula is:

Atorvastatin calcium structural formula

Atorvastatin calcium 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.

LIPITOR tablets for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.36 mg, 20.72 mg, 41.44 mg, or 82.88 mg atorvastatin calcium anhydrous) and the following inactive ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

LIPITOR is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, LIPITOR lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; LIPITOR also reduces LDL production and the number of LDL particles.

12.2 Pharmacodynamics

LIPITOR, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)].

12.3 Pharmacokinetics

Absorption

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

Distribution

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

Elimination

Metabolism

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

Excretion

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

Specific Populations

Geriatric

Plasma concentrations of LIPITOR are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults.

Pediatric

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

Gender

Plasma concentrations of LIPITOR in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with LIPITOR between men and women.

Renal Impairment

Renal disease has no influence on the plasma concentrations or LDL-C reduction of LIPITOR [see Use in Specific Populations (8.6)].

While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of LIPITOR since the drug is extensively bound to plasma proteins.

Hepatic Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of LIPITOR are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations (8.7)].

Drug Interactions

Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and
dosing regimen
Atorvastatin
Dose (mg)Ratio of AUC*Ratio of Cmax*
*
Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).
See Sections 5.1 and 7 for clinical significance.
Once daily
§
Twice daily
Single dose
#
Every 8 hours
Þ
The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.
ß
Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL-1.2 liters per day).
à
Four times daily
è
Ratio based on a single sample taken 8-16 h post dose.
ð
Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
ø
Three times daily

Cyclosporine 5.2 mg/kg/day, stable dose

10 mg QD for 28 days

8.69

10.66

Tipranavir 500 mg BID§/ritonavir 200 mg BID§, 7 days

10 mg SD

9.36

8.58

Glecaprevir 400 mg QD/pibrentasvir 120 mg QD, 7 days

10 mg QD for 7 days

8.28

22.00

Telaprevir 750 mg q8h#, 10 days

20 mg SD

7.88

10.60

, ÞSaquinavir 400 mg BID§/ritonavir 400 mg BID§, 15 days

40 mg QD for 4 days

3.93

4.31

Elbasvir 50 mg QD/grazoprevir 200 mg QD, 13 days

10 mg SD

1.94

4.34

Simeprevir 150 mg QD, 10 days

40 mg SD

2.12

1.70

Clarithromycin 500 mg BID§, 9 days

80 mg QD for 8 days

4.54

5.38

Darunavir 300 mg BID§/ritonavir 100 mg BID§, 9 days

10 mg QD for 4 days

3.45

2.25

Itraconazole 200 mg QD, 4 days

40 mg SD

3.32

1.20

Letermovir 480 mg QD, 10 days

20 mg SD

3.29

2.17

Fosamprenavir 700 mg BID§/ritonavir 100 mg BID§, 14 days

10 mg QD for 4 days

2.53

2.84

Fosamprenavir 1400 mg BID§, 14 days

10 mg QD for 4 days

2.30

4.04

Nelfinavir 1250 mg BID§, 14 days

10 mg QD for 28 days

1.74

2.22

Grapefruit Juice, 240 mL QD,ß

40 mg SD

1.37

1.16

Diltiazem 240 mg QD, 28 days

40 mg SD

1.51

1.00

Erythromycin 500 mg QIDà, 7 days

10 mg SD

1.33

1.38

Amlodipine 10 mg, single dose

80 mg SD

1.18

0.91

Cimetidine 300 mg QIDà, 2 weeks

10 mg QDfor 2 weeks

1.00

0.89

Colestipol 10 g BID§, 24 weeks

40 mg QD for 8 weeks

NA

0.74è

Maalox TC® 30 mL QIDà, 17 days

10 mg QD for 15 days

0.66

0.67

Efavirenz 600 mg QD, 14 days

10 mg for 3 days

0.59

1.01

Rifampin 600 mg QD, 7 days (co‑administered)ð

40 mg SD

1.12

2.90

Rifampin 600 mg QD, 5 days (doses separated)ð

40 mg SD

0.20

0.60

Gemfibrozil 600 mg BID§, 7 days

40 mg SD

1.35

1.00

Fenofibrate 160 mg QD, 7 days

40 mg SD

1.03

1.02

Boceprevir 800 mg TIDø, 7 days

40 mg SD

2.32

2.66

 

Table 6: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
*
Once daily
Single dose
See Section 7 for clinical significance.
§
Twice daily

Atorvastatin

Co-administered drug and dosing regimen

Drug/Dose (mg)

Ratio of AUC

Ratio of Cmax

80 mg QD* for 15 days

Antipyrine, 600 mg SD

1.03

0.89

80 mg QD* for 10 days

Digoxin 0.25 mg QD*, 20 days

1.15

1.20

40 mg QD* for 22 days

Oral contraceptive QD*, 2 months

- norethindrone 1 mg

- ethinyl estradiol 35 µg

1.28

1.19

1.23

1.30

10 mg SD

Tipranavir 500 mg BID§/ritonavir 200 mg BID§, 7 days

1.08

0.96

10 mg QD* for 4 days

Fosamprenavir 1400 mg BID§, 14 days

0.73

0.82

10 mg QD* for 4 days

Fosamprenavir 700 mg BID§/ritonavir 100 mg BID§, 14 days

0.99

0.94

 

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0-24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.

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

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

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

14 CLINICAL STUDIES

Prevention of Cardiovascular Disease

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of LIPITOR 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, 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 LIPITOR 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.

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

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

Effect of LIPITOR 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)

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

LIPITOR also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for LIPITOR 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 LIPITOR 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 LIPITOR on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% White, 2% Black, 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 LIPITOR 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 LIPITOR 10 mg/day on lipid levels was similar to that seen in previous clinical trials.

LIPITOR significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the LIPITOR 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 LIPITOR was seen regardless of age, sex, or baseline lipid levels.

LIPITOR significantly reduced the risk of stroke by 48% (21 events in the LIPITOR 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 LIPITOR 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 LIPITOR group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).

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

Figure 2: Effect of LIPITOR 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 LIPITOR 80 mg/day vs. LIPITOR 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 LIPITOR 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of LIPITOR 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 LIPITOR and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of LIPITOR.

Treatment with LIPITOR 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.

Effect of LIPITOR 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)

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

 

Table 7: Overview of Efficacy Results in TNT
*
Atorvastatin 80 mg: atorvastatin 10 mg
Secondary endpoints not included in primary endpoint
Component of other secondary endpoints

Endpoint

Atorvastatin

10 mg

(N=5006)

Atorvastatin

80 mg

(N=4995)

HR* (95%CI)

PRIMARY ENDPOINT

n

(%)

n

(%)

First major cardiovascular endpoint

548

(10.9)

434

(8.7)

0.78 (0.69, 0.89)

Components of the Primary Endpoint

CHD death

127

(2.5)

101

(2.0)

0.80 (0.61, 1.03)

Non-fatal, non-procedure related MI

308

(6.2)

243

(4.9)

0.78 (0.66, 0.93)

Resuscitated cardiac arrest

26

(0.5)

25

(0.5)

0.96 (0.56, 1.67)

Stroke (fatal and non-fatal)

155

(3.1)

117

(2.3)

0.75 (0.59, 0.96)

SECONDARY ENDPOINTS

First CHF with hospitalization

164

(3.3)

122

(2.4)

0.74 (0.59, 0.94)

First PVD endpoint

282

(5.6)

275

(5.5)

0.97 (0.83, 1.15)

First CABG or other coronary revascularization procedure

904

(18.1)

667

(13.4)

0.72 (0.65, 0.80)

First documented angina endpoint

615

(12.3)

545

(10.9)

0.88 (0.79, 0.99)

All-cause mortality

282

(5.6)

284

(5.7)

1.01 (0.85, 1.19)

Components of All-Cause Mortality

Cardiovascular death

155

(3.1)

126

(2.5)

0.81 (0.64, 1.03)

Noncardiovascular death

127

(2.5)

158

(3.2)

1.25 (0.99, 1.57)

Cancer death

75

(1.5)

85

(1.7)

1.13 (0.83, 1.55)

Other non-CV death

43

(0.9)

58

(1.2)

1.35 (0.91, 2.00)

Suicide, homicide, and other traumatic non-CV death

9

(0.2)

15

(0.3)

1.67 (0.73, 3.82)

 

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 LIPITOR 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 LIPITOR 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 LIPITOR 80 mg group than in the LIPITOR 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the LIPITOR 80 mg group than in the LIPITOR 10 mg treatment group.

Primary Hyperlipidemia in Adults

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

Table 8: Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean % Change From Baseline)*
*
Results are pooled from 2 dose response trials.

Dose

N

TC

LDL‑C

Apo B

TG

HDL‑C

Placebo

21

4

4

3

10

-3

10

22

-29

-39

-32

-19

6

20

20

-33

-43

-35

-26

9

40

21

-37

-50

-42

-29

6

80

23

-45

-60

-50

-37

5

In three multicenter, double-blind trials in patients with hyperlipidemia, LIPITOR was compared to other statins. After randomization, patients were treated for 16 weeks with either LIPITOR 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)
*
Significantly different from lovastatin, ANCOVA, p ≤0.05
A negative value for the 95% CI for the difference between treatments favors LIPITOR for all except HDL-C, for which a positive value favors LIPITOR. If the range does not include 0, this indicates a statistically significant difference.
Significantly different from pravastatin, ANCOVA, p ≤0.05
§
Significantly different from simvastatin, ANCOVA, p ≤0.05

Treatment

(Daily Dose)

N

Total‑C

LDL‑C

Apo B

TG

HDL‑C

Trial 1

LIPITOR 10 mg

707

-27*

-36*

-28*

-17*

+7

Lovastatin 20 mg

191

-19

-27

-20

-6

+7

95% CI for Diff

-9.2, -6.5

-10.7, -7.1

-10.0, -6.5

-15.2, -7.1

-1.7, 2.0

Trial 2

LIPITOR 10 mg

222

-25

-35

-27

-17

+6

Pravastatin 20 mg

77

-17

-23

-17

-9

+8

95% CI for Diff

-10.8, -6.1

-14.5, -8.2

-13.4, -7.4

-14.1, -0.7

-4.9, 1.6

Trial 3

LIPITOR 10 mg

132

-29§

-37§

-34§

-23§

+7

Simvastatin 10 mg

45

-24

-30

-30

-15

+7

95% CI for Diff

-8.7, -2.7

-10.1, -2.6

-8.0, -1.1

-15.1, -0.7

-4.3, 3.9

 

Table 9 does not contain data comparing the effects of LIPITOR 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily interchangeable.

Hypertriglyceridemia in Adults

The response to LIPITOR in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 10). For the LIPITOR-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

Placebo

(N=12)

LIPITOR 10 mg

(N=37)

LIPITOR 20 mg

(N=13)

LIPITOR 80 mg

(N=14)

Triglycerides

-12.4 (-36.6, 82.7)

-41.0 (-76.2, 49.4)

-38.7 (-62.7, 29.5)

-51.8 (-82.8, 41.3)

Total-C

-2.3 (-15.5, 24.4)

-28.2 (-44.9, -6.8)

-34.9 (-49.6, -15.2)

-44.4 (-63.5, -3.8)

LDL-C

3.6 (-31.3, 31.6)

-26.5 (-57.7, 9.8)

-30.4 (-53.9, 0.3)

-40.5 (-60.6, -13.8)

HDL-C

3.8 (-18.6, 13.4)

13.8 (-9.7, 61.5)

11.0 (-3.2, 25.2)

7.5 (-10.8, 37.2)

non-HDL-C

-2.8 (-17.6, 30.0)

-33.0 (-52.1, -13.3)

-42.7 (-53.7, -17.4)

-51.5 (-72.9, -4.3)

 

Dysbetalipoproteinemia in Adults

The results of an open-label crossover trial of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 11).

Table 11: Open-Label Crossover Trial of 16 Patients with Dysbetalipoproteinemia (Fredrickson Type III)

Median % Change (min, max)

Median (min, max) at Baseline (mg/dL)

LIPITOR

10 mg

LIPITOR

80 mg

Total-C

442 (225, 1320)

-37 (-85, 17)

-58 (-90, -31)

Triglycerides

678 (273, 5990)

-39 (-92, -8)

-53 (-95, -30)

IDL-C + VLDL-C

215 (111, 613)

-32 (-76, 9)

-63 (-90, -8)

non-HDL-C

411 (218, 1272)

-43 (-87, -19)

-64 (-92, -36)

 

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 LIPITOR. 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 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to LIPITOR (n=140) or placebo (n=47) for 26 weeks and then all received LIPITOR 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 LIPITOR group compared to 230 mg/dL (range: 160-325 mg/dL) in the placebo group. The dosage of LIPITOR (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 LIPITOR-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%).

LIPITOR significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double‑blind phase (see Table 12).

 

Table 12: Lipid-altering Effects of LIPITOR in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention‑to‑Treat Population)

DOSAGE

N

Total-C

LDL-C

HDL-C

TG

Apolipoprotein B

Placebo

47

-1.5

-0.4

-1.9

1.0

0.7

LIPITOR

140

-31.4

-39.6

2.8

-12.0

-34.0

 

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the LIPITOR 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 boys and 81 girls). 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

LIPITOR tablets are supplied as follows:

Strength

How Supplied

NDC

Tablet Description

10 mg

of atorvastatin

bottles of 90

0071-0155-23

white elliptical, film-coated tablets with “PD 155” on one side and “10” on the other

10 x 10 unit dose blisters

0071-0155-40

20 mg

of atorvastatin

bottles of 90

0071-0156-23

white elliptical, film-coated tablets with “PD 156” on one side and “20” on the other

10 x 10 unit dose blisters

0071-0156-40

40 mg

of atorvastatin

bottles of 90

0071-0157-23

white elliptical, film-coated tablets with “PD 157” on one side and “40” on the other

10 x 10 unit dose blisters

0071-0157-40

80 mg

of atorvastatin

bottles of 90

0071-0158-23

white elliptical, film-coated tablets with “PD 158” on one side and “80” on the other

8 x 8 unit dose blisters

0071-0158-92

 

Storage

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

17 PATIENT COUNSELING INFORMATION

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

Myopathy and Rhabdomyolysis

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

Lactation

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

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.lipitor.com.

Distributed by:
Viatris Specialty LLC
Morgantown, WV 26505 U.S.A.

UPJ:LPTR: RX2

Patient Information

LIPITOR (LIP-ih-tore)
atorvastatin calcium
tablets, for oral use

What is LIPITOR?

LIPITOR is a prescription medicine that contains a cholesterol lowering medicine (statin) called atorvastatin. LIPITOR is used:

to reduce the risk of:
o
heart attack, stroke, certain types of heart surgery and chest pain in adults who do not have heart disease but have other multiple risk factors for heart disease.
o
heart attack and stroke in adults with type 2 diabetes mellitus who do not have heart disease but have other multiple risk factors.
o
heart attack that does not cause death, stroke, certain types of heart surgery, hospitalization for congestive heart failure, and chest pain in adults with heart disease.
along with diet to reduce low density lipoprotein cholesterol (LDL-C) or bad cholesterol:
o
in adults with primary hyperlipidemia.
o
in adults and children aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). This is an inherited condition that causes high levels of bad cholesterol.
along with other cholesterol lowering treatments or alone if such treatments are unavailable in adults and children aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). This is an inherited condition that causes high levels of bad cholesterol.
along with diet for the treatment of adults with:
o
primary dysbetalipoproteinemia (an inherited condition that causes high levels of cholesterol and fat).
o
hypertriglyceridemia.

It is not known if LIPITOR is safe and effective in children younger than 10 years of age with HeFH or HoFH or in children with other types of hyperlipidemias (other than HeFH or HoFH).

Do not take LIPITOR if you:

have liver problems (acute liver failure or decompensated cirrhosis)
are allergic to atorvastatin or any of the ingredients in LIPITOR. Stop using LIPITOR and get medical help right away if you have symptoms of a serious allergic reaction including:
o
swelling of your face, lips, tongue or throat
o
problems breathing or swallowing
o
fainting or feeling dizzy
o
very rapid heartbeat
o
severe skin rash or itching
o
flu-like symptoms including fever, sore throat, cough, tiredness, and joint pain

See the end of this leaflet for a complete list of ingredients in LIPITOR.

Before you take LIPITOR, tell your doctor about all of your medical conditions, including if you:

have unexplained muscle aches or weakness
drink more than 2 glasses of alcohol daily
have diabetes
have thyroid problems
have kidney problems
had a stroke
are pregnant or plan to become pregnant. LIPITOR may harm your unborn baby. If you become pregnant, stop taking LIPITOR and call your doctor right away.
are breastfeeding or plan to breastfeed. You and your doctor should decide if you will take LIPITOR or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take LIPITOR.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. LIPITOR and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your doctor if you take medicines for:

your immune system (cyclosporine)
cholesterol (gemfibrozil)
infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole)
birth control pills
heart failure (digoxin)
gout (colchicine)
niacin
fibrates
viruses that treat HIV, AIDS, or hepatitis C (anti-virals)
o
tipranavir plus ritonavir
o
ledipasvir plus sofosbuvir
o
saquinavir plus ritonavir
o
fosamprenavir
o
elbasvir plus grazoprevir
o
nelfinavir
o
glecaprevir plus pibrentasvir
o
simeprevir
o
darunavir plus ritonavir
o
fosamprenavir plus ritonavir
o
letermovir

Ask your doctor or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take LIPITOR?

Take LIPITOR exactly as your doctor tells you to take it.
Do not change your dose or stop LIPITOR without talking to your doctor.
Your doctor may do blood tests to check your cholesterol levels during your treatment with LIPITOR. Your dose of LIPITOR may be changed based on these blood test results.
Take LIPITOR each day at any time of day. LIPITOR can be taken with or without food.
Your doctor may start you on a cholesterol lowering diet before giving you LIPITOR. Stay on this low-fat diet when you take LIPITOR.
If you miss a dose of LIPITOR, take it as soon as you remember. Do not take LIPITOR if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of LIPITOR at the same time. If you take too much LIPITOR or overdose, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away.

What should I avoid while taking LIPITOR?

Avoid drinking more than 1.2 liters of grapefruit juice each day.

What are the possible side effects of LIPITOR?

LIPITOR may cause serious side effects including:

Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death.
Tell your doctor right away if you have:
o
unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take LIPITOR.
o
muscle problems that do not go away after your doctor has told you to stop taking LIPITOR. Your doctor may do further tests to diagnose the cause of your muscle problems.
 
Your chances of getting muscle problems are higher if you:
o
are taking certain other medicines while you take LIPITOR
o
drink large amounts of grapefruit juice
o
are 65 years of age or older
o
have thyroid problems (hypothyroidism) that are not controlled
o
have kidney problems
o
are taking higher doses of LIPITOR
Liver problems. Your doctor should do blood tests to check your liver before you start taking LIPITOR and if you have symptoms of liver problems while you take LIPITOR. Call your doctor right away if you have the following symptoms of liver problems:
o
feel tired or weak
o
nausea or vomiting
o
loss of appetite
o
upper belly pain
o
dark amber colored urine
o
yellowing of your skin or the whites of your eyes
Increase in blood sugar level. Your blood sugar level may increase while you are taking LIPITOR.
Exercise regularly and make healthy food choices to maintain healthy body weight.

The most common side effects of LIPITOR include:

nasal congestion, sore throat, runny nose
diarrhea
urinary tract infection
nausea
muscle spasms
throat pain
muscle and joint pain
pain in extremity
upset stomach
musculoskeletal pain
trouble sleeping

Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.

These are not all the side effects of LIPITOR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store LIPITOR?

Store LIPITOR at room temperature between 68°F to 77°F (20 C to 25°C).
Do not keep medicine that is out of date or that you no longer need.
Keep LIPITOR and all medicines out of the reach of children.

General information about the safe and effective use of LIPITOR.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LIPITOR for a condition for which it was not prescribed. Do not give LIPITOR to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about LIPITOR, talk with your doctor. You can ask your pharmacist or doctor for information about LIPITOR that is written for health professionals.

What are the ingredients in LIPITOR?

Active Ingredient: atorvastatin calcium

Inactive Ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.

 

Distributed by:

Viatris Specialty LLC

Morgantown, WV 26505   U.S.A.

 

For more information, go to the LIPITOR website at www.lipitor.com

This Patient Package Information has been approved by the U.S. Food and Drug Administration              12/2022

UPJ:PL:LPTR: RX2

PRINCIPAL DISPLAY PANEL – 10 mg

NDC 0071-0155-23

Lipitor®
atorvastatin calcium)
tablets

10 mg*

90 Tablets     Rx only

Store at controlled room
temperature 20-25ºC
(68-77ºF).

Dispense in tight
containers (USP).

DOSAGE AND USE

See package insert
for full prescribing
information.

* Each tablet contains
atorvastatin 10 mg
(equivalent to
10.36 mg atorvastatin
calcium anhydrous).

MADE IN IRELAND

Distributed by
Parke-Davis
Division of Pfizer Inc
NY, NY 10017

Lipitor® 10 mg

PRINCIPAL DISPLAY PANEL – 20 mg

NDC 0071-0156-23

Lipitor®
(atorvastatin calcium)
tablets

20 mg*

90 Tablets     Rx only

Store at controlled room
temperature 20-25ºC
(68-77ºF).

Dispense in tight
containers (USP).

DOSAGE AND USE

See package insert
for full prescribing
information.

* Each tablet contains
atorvastatin 20 mg
(equivalent to
20.72 mg atorvastatin
calcium anhydrous).

MADE IN IRELAND

Distributed by
Parke-Davis
Division of Pfizer Inc
NY, NY 10017

Lipitor® 20 mg

PRINCIPAL DISPLAY PANEL – 40 mg

NDC 0071-0157-23

Lipitor®
(atorvastatin calcium)

40 mg*

tablets

90 Tablets     Rx only

Store at controlled room temperature
20-25ºC (68-77ºF).

Dispense in tight containers (USP).

DOSAGE AND USE
See package insert for full prescribing
information.

* Each tablet contains atorvastatin 40 mg
(equivalent to 41.44 mg atorvastatin
calcium anhydrous).

Distributed by
Parke-Davis
Division of Pfizer Inc
NY, NY 10017

MADE IN IRELAND

Lipitor® 40 mg

PRINCIPAL DISPLAY PANEL – 80 mg

NDC 0071-0158-23

Lipitor®
(atorvastatin calcium)

80 mg*

tablets

90 Tablets Rx only

Store at controlled
room temperature
20-25ºC (68-77ºF).

Dispense in tight
containers (USP).

DOSAGE AND USE
See package insert for full
prescribing information.

* Each tablet contains
atorvastatin 80 mg
(equivalent to 82.88 mg
atorvastatin calcium
anhydrous).

MADE IN IRELAND

Distributed by
Parke-Davis
Division of Pfizer Inc
NY, NY 10017

Lipitor® 80 mg
LIPITOR 
atorvastatin calcium tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0071-0155
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ATORVASTATIN CALCIUM TRIHYDRATE (UNII: 48A5M73Z4Q) (ATORVASTATIN - UNII:A0JWA85V8F) ATORVASTATIN10 mg
Inactive Ingredients
Ingredient NameStrength
CALCIUM CARBONATE (UNII: H0G9379FGK)  
CANDELILLA WAX (UNII: WL0328HX19)  
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
Product Characteristics
ColorWHITEScoreno score
ShapeOVAL (elliptical) Size10mm
FlavorImprint Code PD;155;10
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0071-0155-2390 in 1 BOTTLE; Type 0: Not a Combination Product12/17/1996
2NDC:0071-0155-40100 in 1 CARTON12/17/199603/31/2023
21 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02070212/17/1996
LIPITOR 
atorvastatin calcium tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0071-0156
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ATORVASTATIN CALCIUM TRIHYDRATE (UNII: 48A5M73Z4Q) (ATORVASTATIN - UNII:A0JWA85V8F) ATORVASTATIN20 mg
Inactive Ingredients
Ingredient NameStrength
CALCIUM CARBONATE (UNII: H0G9379FGK)  
CANDELILLA WAX (UNII: WL0328HX19)  
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
Product Characteristics
ColorWHITEScoreno score
ShapeOVAL (elliptical) Size12mm
FlavorImprint Code PD;156;20
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0071-0156-2390 in 1 BOTTLE; Type 0: Not a Combination Product12/17/199609/30/2025
2NDC:0071-0156-40100 in 1 CARTON12/17/199611/30/2023
21 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02070212/17/199609/30/2025
LIPITOR 
atorvastatin calcium tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0071-0157
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ATORVASTATIN CALCIUM TRIHYDRATE (UNII: 48A5M73Z4Q) (ATORVASTATIN - UNII:A0JWA85V8F) ATORVASTATIN40 mg
Inactive Ingredients
Ingredient NameStrength
CALCIUM CARBONATE (UNII: H0G9379FGK)  
CANDELILLA WAX (UNII: WL0328HX19)  
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
Product Characteristics
ColorWHITEScoreno score
ShapeOVAL (elliptical) Size15mm
FlavorImprint Code PD;157;40
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0071-0157-2390 in 1 BOTTLE; Type 0: Not a Combination Product12/17/199603/31/2026
2NDC:0071-0157-40100 in 1 CARTON12/17/199609/30/2023
21 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02070212/17/199603/31/2026
LIPITOR 
atorvastatin calcium tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0071-0158
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ATORVASTATIN CALCIUM TRIHYDRATE (UNII: 48A5M73Z4Q) (ATORVASTATIN - UNII:A0JWA85V8F) ATORVASTATIN80 mg
Inactive Ingredients
Ingredient NameStrength
CALCIUM CARBONATE (UNII: H0G9379FGK)  
CANDELILLA WAX (UNII: WL0328HX19)  
CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
Product Characteristics
ColorWHITEScoreno score
ShapeOVAL (elliptical) Size19mm
FlavorImprint Code PD;158;80
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0071-0158-2390 in 1 BOTTLE; Type 0: Not a Combination Product04/07/2000
2NDC:0071-0158-9264 in 1 CARTON04/07/200007/31/2023
21 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02070204/07/2000
Labeler - Parke-Davis Div of Pfizer Inc (829076962)

Revised: 12/2022
Document Id: f732b1c6-f3ed-4f9a-aa53-da673ce5e220
Set id: c6e131fe-e7df-4876-83f7-9156fc4e8228
Version: 40
Effective Time: 20221201
 
Parke-Davis Div of Pfizer Inc