ATORVASTATIN: 79,519 Adverse Event Reports & Safety Profile

Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. 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).The empirical formula of atorvastatin calcium is C 66 H 68 Ca F 2 N 4 O 10 and its molecular weight is 1155.36. Its structural formula is: Atorvastatin calcium is a white to off-white colored powder free from visible extraneous matter. Atorvastatin calcium is soluble in dimethyl sulphoxide, slightly soluble in alcohol, very slightly soluble in water, in pH 7.4 phosphate buffer and in acetonitrile and practically insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium tablets for oral administration contain 10, 20, 40, 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; lecitihin, polyvinyl alcohol part hydrolyzed, talc, titanium dioxide, xanthan gum and iron oxide yellow. Figure-01 Figure-02 Figure-03 chemical-structure

AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet. Atorvastatin calcium tablets are HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to:

• Reduce the risk of MI, stroke, revascularization procedures, and angina in adult patients without CHD, but with multiple risk factors (1.1).
• Reduce the risk of MI, stroke, revascularization procedures, and angina in adult patients without CHD, but with multiple risk factors (1.1).
• Reduce the risk of MI and stroke in adult patients with type 2 diabetes without CHD, but with multiple risk factors (1.1).
• Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in adult patients with CHD (1.1).
• Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (1.2).
• Reduce elevated TG in adult patients with hypertriglyceridemia and primary dysbetalipoproteinemia (1.2).
• Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) (1.2).
• Reduce elevated total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) after failing an adequate trial of diet therapy (1.2). Limitations of Use Atorvastatin calcium tablets have not been studied in Fredrickson Types I and V dyslipidemias (1.3).

1.1 Prevention of Cardiovascular Disease in Adults In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to:

• Reduce the risk of myocardial infarction
• Reduce the risk of stroke
• Reduce the risk for revascularization procedures and angina In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:
• Reduce the risk of myocardial infarction
• Reduce the risk of stroke In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:
• Reduce the risk of non-fatal myocardial infarction
• Reduce the risk of fatal and non-fatal stroke
• Reduce the risk for revascularization procedures
• Reduce the risk of hospitalization for CHF
• Reduce the risk of angina

1.2 Hyperlipidemia Atorvastatin calcium tablets are indicated:

• As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb);
• As an adjunct to diet for the treatment of adult patients with elevated serum TG levels ( Fredrickson Type IV);•For the treatment of adult patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet;
• To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable;
• As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present:
• LDL-C remains ≥ 190 mg/dL or
• LDL-C remains ≥ 160 mg/dL and:
• there is a positive family history of premature cardiovascular disease or
• two or more other CVD risk factors are present in the pediatric patient

1.3 Limitations of Use Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson Types I and V).

AND ADMINISTRATION Dose range: 10 to 80 mg once daily ( 2.1 ). Recommended start dose: 10 or 20 mg once daily ( 2.1 ). Patients requiring large LDL-C reduction (>45%) may start at 40 mg once daily ( 2.1 ). Pediatric patients with HeFH: starting dose: 10 mg once daily; dose range: 10 to 20 mg/day for patients 10 years to 17 years of age ( 2.2 ).

2.1 Hyperlipidemia and Mixed Dyslipidemia The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 Years to17 Years of Age) The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [ see Clinical Studies (14.6 )]. Doses should be individualized according to the recommended goal of therapy [ see Indications and Usage (1.2) and Clinical Pharmacology (12) ]. Adjustments should be made at intervals of 4 weeks or more.

2.3 Homozygous Familial Hypercholesterolemia The dosage of atorvastatin calcium tablets in patients with HoFH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

2.4 Concomitant Lipid-Lowering Therapy Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [ see Warnings and Precautions (5.1) and Drug Interactions (7) ].

2.5 Dosage in Patients with Renal Impairment Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors In tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin calcium tablets. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin calcium tablets should be limited to 40 mg. When co-prescribing atorvastatin with other protease inhibitors, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used In patients taking cyclosporine or the HIV protease inhibitor tipranavir plus ritonavir or the hepatitis C virus (HCV) protease inhibitor glecaprevir plus pibrentasvir, therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin calcium tablets. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin calcium tablets should be limited to 40 mg. When co-prescribing atorvastatin with other protease inhibitors, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used [ see Warnings and Precautions (5.1) and Drug Interactions (7)].

Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( Error! Hyperlink reference not valid. ). Women who are pregnant or may become pregnant ( 4.3 ). Nursing mothers ( 4.4 ). Hypersensitivity to any component of this medication ( Error! Hyperlink reference not valid. ).

4.1 Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels

4.2 Hypersensitivity to any Component of this Medication

4.3 Pregnancy Women who are pregnant or may become pregnant. Atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of atorvastatin calcium use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. ATORVASTATIN CALCIUM SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin calcium should be discontinued immediately and the patient apprised of the potential hazard to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

4.4 Nursing mothers It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require atorvastatin calcium treatment should not breastfeed their infants <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span> .

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 )] 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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 to 93 years, 39% female, 91% White, 3% Black or African American, 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=7,311 %10 mg N=3,908 %20 mg N=188 %40 mg N=604 %80 mg N=4,055 % Any dose N=8,755 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 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 atorvastatin calcium. Treating to New Targets Study (TNT) In TNT, <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span> 10,001 patients (age range 29 to 78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin 10 mg daily (n=5006) or atorvastatin 80 mg daily (n=4995). 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 to 10 days) occurred in 1.3% of individuals with atorvastatin 80 mg and in 0.2% of individuals with atorvastatin 10 mg. Elevations of CK (≥10 x ULN) were higher in the high-dose atorvastatin group (0.3%) compared to the low-dose atorvastatin group (0.1%).

Stroke

Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4,731 patients (age range 21 to 92 years, 40% female; 93% White, 3% Black or African American, 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 80 mg (n=2,365) or placebo (n=2,366) 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 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group. In a post-hoc analysis, atorvastatin 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 vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin 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% Black or African American, 1.6% Asian, 4.8% other), the safety and tolerability profile of atorvastatin calcium 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 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). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

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)

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 to 93 years, 39% female, 91% White, 3% Black or African American, 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=7,311 %10 mg N=3,908 %20 mg N=188 %40 mg N=604 %80 mg N=4,055 % Any dose N=8,755 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 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 atorvastatin calcium. Treating to New Targets Study (TNT) In TNT, <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span> 10,001 patients (age range 29 to 78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin 10 mg daily (n=5006) or atorvastatin 80 mg daily (n=4995). 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 to 10 days) occurred in 1.3% of individuals with atorvastatin 80 mg and in 0.2% of individuals with atorvastatin 10 mg. Elevations of CK (≥10 x ULN) were higher in the high-dose atorvastatin group (0.3%) compared to the low-dose atorvastatin group (0.1%).

Stroke

Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4,731 patients (age range 21 to 92 years, 40% female; 93% White, 3% Black or African American, 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 80 mg (n=2,365) or placebo (n=2,366) 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 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group. In a post-hoc analysis, atorvastatin 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 vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin 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% Black or African American, 1.6% Asian, 4.8% other), the safety and tolerability profile of atorvastatin calcium 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 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). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

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)

AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected ( 2.6 , 5.1 , 8.5 ). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.2 ). A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs. placebo ( 5.5 ).

5.1 Skeletal Muscle A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values &gt;10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy(IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of the drugs listed in Table 2. Physicians considering combined therapy of atorvastatin with any of these drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the afore mentioned drugs Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 2 Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values &gt;10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy(IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of the drugs listed in Table 2. Physicians considering combined therapy of atorvastatin with any of these drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the afore mentioned drugs <span class="opacity-50 text-xs">[see Drug Interactions (7)]</span>. Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 2 [ see Dosage and Administration (2.6), Drug Interactions (7) , and Clinical Pharmacology (12.3)].

Table

2.

Drug Interactions

Associated with Increased Risk of Myopathy/ Rhabdomyolysis Interacting Agents Prescribing Recommendations Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin,itraconazole, saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Use with caution and lowest dose necessary *Use the lowest dose necessary ( ) *Use the lowest dose necessary ( 12.3 ) Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

5.2 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (&gt;3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases 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 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) 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 LFT elevations continued treatment with a reduced dose of atorvastatin. It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin [ see Contraindications (4) ].

5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

5.4 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses upto 280 mg/kg/day.

The

120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retino geniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin 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 nonfatal hemorrhagic stroke was significantly higher in the atorvastatin 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 group [ see Adverse Reactions (6.1) ].

INTERACTIONS

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

7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin 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 atorvastatin 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 Atorvastatin Calcium Tablets Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets 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 atorvastatin calcium tablets. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium tablets is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets 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 atorvastatin calcium tablets. Intervention:

• Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium tablets 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 atorvastatin calcium tablets 20 mg.
• In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg [see Dosage and Administration (2.5) ] .
• Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium tablets.
• 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 atorvastatin calcium tablets 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 atorvastatin calcium tablets 20 mg [see Dosage and Administration (2.5) ] . Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin calcium tablets. 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 atorvastatin calcium tablets. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium tablets 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 atorvastatin calcium tablets. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin calcium tablets 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 atorvastatin calcium tablets. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium tablets. 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 atorvastatin calcium tablets.

7.2 Drug Interactions that may Decrease Exposure to Atorvastatin Table 3 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them.

Table

3: Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin calcium tablets 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 atorvastatin calcium tablets after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin calcium tablets and rifampin simultaneously.

7.3 Atorvastatin Effects on Other Drugs Table 4 presents atorvastatin’s effect on other drugs and instructions for preventing or managing them.

Table

4: Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin calcium tablets 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 atorvastatin calcium tablets.

Digoxin Clinical

Impact: When multiple doses of atorvastatin calcium tablets and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3) ] . Intervention: Monitor patients taking digoxin appropriately.

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 dosage regimen Atorvastatin Dosage (mg) Ratio of AUC Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). Ratio of C max See Sections 5.1 and 7 for clinical significance.

Cyclosporine

5.2 mg/kg/day, stable dose 10 mg QD Once daily for 28 days 8.69

10.66 Tipranavir 500 mg BID Twice daily /ritonavir 200 mg BID , 7 days 10 mg SD Single dosage 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 Every 8 hours , 10 days 20 mg SD 7.88 10.60 , 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.

Saquinavir

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 a 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 , 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). 40 mg SD 1.37

1.16 Diltiazem 240 mg QD , 28 days 40 mg SD 1.51

1.00 Erythromycin 500 mg QID Four times daily , 7 days 10 mg SD 1.33

1.38 Amlodipine 10 mg, single dose 80 mg SD 1.18

0.91 Cimetidine 300 mg QID , 2 weeks 10 mg QD for 2 weeks 1.00

0.89 Colestipol 10 g BID , 24 weeks 40 mg QD for 8 weeks NA

0.74 Ratio based on a single sample taken 8-16 h post dose. Maalox TC ® 30 mL QID , 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) 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. 40 mg SD 1.12

2.90 Rifampin 600 mg QD , 5 days (doses separated) 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 TID Three times daily , 7 days 40 mg SD 2.32

2.66 Table 6: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosage regimen Drug/Dosage (mg) Ratio of AUC Ratio of C max 80 mg QD Once daily for 15 days Antipyrine, 600 mg SD Single dosage 1.03 0.89 80 mg QD for 10 days See Section 7 for clinical significance.

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 Twice daily /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 Atorvastatin calcium tablets had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.