Crestor

1 INDICATIONS AND USAGE CRESTOR is indicated: • To reduce the risk of major adverse cardiovascular (CV) events (CV death, nonfatal myocardial infarction, nonfatal stroke, or an arterial revascularization procedure) in adults at increased risk for CV events. • As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C): ∘ in adults with hypercholesterolemia. ∘ and slow the progression of atherosclerosis in adults. ∘ in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). ∘ in adults and pediatric patients aged 7 years and older with homozygous familial hypercholesterolemia (HoFH). • As an adjunct to diet for the treatment of adults with: ∘ Primary dysbetalipoproteinemia. ∘ Hypertriglyceridemia. CRESTOR is an HMG Co‑A reductase inhibitor (statin) indicated: • To reduce the risk of major adverse cardiovascular (CV) events (CV death, nonfatal myocardial infarction, nonfatal stroke, or an arterial revascularization procedure) in adults at increased risk for CV events. • As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C): ∘ in adults with primary hypercholesterolemia. ∘ and slow the progression of atherosclerosis in adults. ∘ in adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). ∘ in adults and pediatric patients aged 7 years and older with homozygous familial hypercholesterolemia (HoFH). • As an adjunct to diet for the treatment of adults with: ∘ Primary dysbetalipoproteinemia. ∘ Hypertriglyceridemia.

Take orally with or without food, at any time of day. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating CRESTOR, and adjust dosage if necessary. Adults: Recommended dosage range is 5 to 40 mg once daily. Pediatric Patients with HeFH: Recommended dosage range is 5 to 10 mg once daily for patients aged 8 to less than 10 years of age, and 5 to 20 mg once daily for patients aged 10 years and older. Pediatric Patients with HoFH: Recommended dosage is 20 mg once daily for patients aged 7 years and older. Asian Patients: Initiate at 5 mg once daily. Consider risks and benefits of treatment if not adequately controlled at dosages up to 20 mg once daily. Patients with Severe Renal Impairment (not on hemodialysis): Initiate at 5 mg once daily; do not exceed 10 mg once daily. See full prescribing information for CRESTOR dosage and administration modifications due to drug interactions.

2.1General Dosage and Administration Information

• Administer CRESTOR orally as a single dose at any time of day, with or without food. Swallow the tablets whole. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating CRESTOR, and adjust the dosage if necessary. • If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. • When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, administer CRESTOR at least 2 hours before the antacid .

2.2Recommended Dosage in Adult Patients

• The dosage range for CRESTOR is 5 to 40 mg orally once daily. • The recommended dosage of CRESTOR depends on a patient’s indication for usage, LDL-C, and individual risk for CV events.

2.3Recommended Dosage in Pediatric Patients Dosage

in Pediatric Patients 8 Years of Age and Older with HeFH The recommended dosage range is 5 mg to 10 mg orally once daily in patients aged 8 years to less than 10 years and 5 mg to 20 mg orally once daily in patients aged 10-years and older. Dosage in Pediatric Patients 7 Years of Age and Older with HoFH The recommended dosage is 20 mg orally once daily.

2.4Recommended Dosage in Asian Patients Initiate

CRESTOR at 5 mg orally once daily due to increased rosuvastatin plasma concentrations. Consider the risks and benefits of CRESTOR when treating Asian patients not adequately controlled at dosages up to 20 mg orally once daily .

2.5Recommended Dosage in Patients with Renal Impairment

In patients with severe renal impairment (CLcr less than 30 mL/min/1.73 m2) not on hemodialysis, the recommended starting dosage is 5 mg orally once daily and should not exceed 10 mg orally once daily . There are no dosage adjustment recommendations for patients with mild and moderate renal impairment.

2.6Dosage Modifications Due to Drug Interactions

Table 1 displays dosage modifications for CRESTOR due to drug interactions . Table 1: CRESTOR Dosage Modifications Due to Drug Interactions Concomitantly Used Drug CRESTOR Dosage Modifications Sofosbuvir/velpatasvir/voxilaprevir or Ledipasvir/sofosbuvir Avoid concomitant use. Gemfibrozil Avoid concomitant use. If use is unavoidable, initiate at 5 mg once daily and do not exceed 10 mg once daily.

Tafamidis Avoid concomitant use. If use is unavoidable, initiate at 5 mg once daily and do not exceed 20 mg once daily. Belumosudil Do not exceed 5 mg once daily. Cyclosporine Do not exceed 5 mg once daily. Darolutamide Do not exceed 5 mg once daily. Additional Antiviral Medications ∘ Simeprevir ∘ Dasabuvir/ombitasvir/paritaprevir/ritonavir ∘ Elbasvir/Grazoprevir ∘ Sofosbuvir/Velpatasvir ∘ Glecaprevir/Pibrentasvir ∘ Atazanavir/Ritonavir ∘ Lopinavir/Ritonavir Initiate at 5 mg once daily.

Do not exceed 10 mg once daily. Capmatinib Do not exceed 10 mg once daily. Enasidenib Do not exceed 10 mg once daily. Momelotinib Do not exceed 10 mg once daily. Regorafenib Do not exceed 10 mg once daily. Teriflunomide Do not exceed 10 mg once daily. Ticagrelor Do not exceed 20 mg once daily.

In patients at increased risk for rhabdomyolysis , consider dosages less than 20 mg per day. Febuxostat Do not exceed 20 mg once daily. Fostamatinib Do not exceed 20 mg once daily.

5 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 CRESTOR dosage. Asian patients may be at higher risk for myopathy. Discontinue CRESTOR if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue CRESTOR 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 CRESTOR dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. • Immune-Mediated Necrotizing Myopathy (IMNM) : Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue CRESTOR if IMNM is suspected. • 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 CRESTOR.

5.1Myopathy and Rhabdomyolysis

CRESTOR 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 with statins, including CRESTOR. 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 CRESTOR dosage. Asian patients on CRESTOR may be at higher risk for myopathy . The myopathy risk is greater in patients taking CRESTOR 40 mg daily compared with lower CRESTOR dosages.

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of CRESTOR with cyclosporine or gemfibrozil is not recommended. CRESTOR dosage modifications are recommended for patients taking certain antiviral medications, darolutamide, and regorafenib . Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis . Discontinue CRESTOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if CRESTOR is discontinued.

Temporarily discontinue CRESTOR 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 CRESTOR dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2Immune-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 persist 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 CRESTOR if IMNM is suspected.

5.3Hepatic Dysfunction Increases in

serum transaminases have been reported with use of CRESTOR . 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. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to more than three times the ULN occurred in 1.1% of patients taking CRESTOR versus 0.5% of patients treated with placebo. Marked persistent increases of hepatic transaminases have also occurred with CRESTOR. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including CRESTOR. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury . Consider liver enzyme testing before CRESTOR initiation and when clinically indicated thereafter.

CRESTOR is contraindicated in patients with acute liver failure or decompensated cirrhosis . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue CRESTOR.

5.4Proteinuria and Hematuria In the

CRESTOR clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among CRESTOR treated patients. These findings were more frequent in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator statins, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, consider a dose reduction for patients on CRESTOR therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

5.5Increases in HbA1c and Fasting Serum Glucose

Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including CRESTOR. Based on clinical trial data with CRESTOR, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus . Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

4 CONTRAINDICATIONS CRESTOR is contraindicated in patients with: • Acute liver failure or decompensated cirrhosis . • Hypersensitivity to rosuvastatin or any excipients in CRESTOR. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with CRESTOR . Acute liver failure or decompensated cirrhosis. Hypersensitivity to rosuvastatin or any excipients in CRESTOR.

8.1Pregnancy Risk Summary Discontinue

CRESTOR when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. CRESTOR decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, CRESTOR may cause fetal harm when administered to pregnant patients based on the mechanism of action . In addition, treatment of hypercholesterolemia 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 hypercholesterolemia 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 CRESTOR use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered rosuvastatin during the period of organogenesis at doses that resulted in systemic exposures equivalent to human exposures at the maximum recommended human dose (MRHD) of 40 mg/day, based on AUC and body surface area (mg/m2), respectively . 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 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1,152 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 In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD of 40 mg/day based on AUC). In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area). In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area).

Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. In rabbits, fetal tissue distribution was 25% of maternal plasma concentration after a single oral gavage dose of 1 mg/kg on gestation day 18.

The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis Immune-Mediated Necrotizing Myopathy Hepatic Dysfunction Proteinuria and Hematuria Increases in HbA1c and Fasting Serum Glucose Levels Most frequent adverse reactions (rate ≥2%) are headache, nausea, myalgia, asthenia, and constipation. To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, 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 clinical practice. Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 2. These studies had a treatment duration of up to 12 weeks.

Table 2: Adverse Reactions Reported in ≥2% of Patients Treated with CRESTOR and > Placebo in Placebo-Controlled Trials Adverse Reactions Placebo N=382 % CRESTOR 5 mg N=291 % CRESTOR 10 mg N=283 % CRESTOR 20 mg N=64 % CRESTOR 40 mg N=106 % Total CRESTOR 5 mg ‑ 40 mg N=744 % Headache 5.0 5.5 4.9 3.1 8.5

5.5Nausea

3.1 3.8 3.5 6.3 0

3.4Myalgia

1.3 3.1 2.1 6.3 1.9

2.8Asthenia

2.6 2.4 3.2 4.7 0.9

2.7Constipation

2.4 2.1 2.1 4.7 2.8

2.4Other

adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In the METEOR study, patients were treated with CRESTOR 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years.

Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 3. Table 3: Adverse Reactions Reported in ≥2% of Patients Treated with CRESTOR and > Placebo in the METEOR Trial Adverse Reactions Placebo N=281 % CRESTOR 40 mg N=700 % Myalgia 12.1

12.7Arthralgia

7.1

10.1Headache

5.3

6.4Dizziness

2.8

4.0Increased

CPK 0.7

2.6Abdominal

pain 1.8

2.4ALT

greater than 3x ULN Frequency recorded as abnormal laboratory value. 0.7

2.2In the

JUPITER study, patients were treated with CRESTOR 20 mg (n=8,901) or placebo (n=8,901) for a mean duration of 2 years. In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking CRESTOR (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in CRESTOR-treated patients compared to placebo-treated patients.

The number of patients with a HbA1c >6.5% at the end of the trial was significantly higher in CRESTOR-treated versus placebo-treated patients . Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 4. Table 4: Adverse Reactions Reported in ≥2% of Patients Treated with CRESTOR and > Placebo in the JUPITER Trial Adverse Reactions Placebo N=8901 % CRESTOR 20 mg N=8901 % Myalgia 6.6

7.6Arthralgia

3.2

3.8Constipation

3.0

3.3Diabetes

mellitus 2.3

2.8Nausea

2.3

2.4Pediatric Patients with HeFH In a

12‑week controlled study in pediatric patients 10 to 17 years of age with HeFH with CRESTOR 5 mg to 20 mg daily , elevations in serum CK greater than 10 x ULN were observed more frequently in CRESTOR-treated patients compared with patients receiving placebo. Four of 130 (3%) patients treated with CRESTOR (2 treated with 10 mg and 2 treated with 20 mg) had increased CK greater than 10 x ULN, compared to 0 of 46 patients on placebo.

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval use of CRESTOR. 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. Blood Disorders : thrombocytopenia Hepatobiliary Disorders : hepatitis, jaundice, fatal and non-fatal hepatic failure Musculoskeletal Disorders : arthralgia, rare reports of immune-mediated necrotizing myopathy associated with statin use Nervous System Disorders : peripheral neuropathy, rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with the use of all statins. The reports are 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, sleep disorders (including insomnia and nightmares) Reproductive System and Breast Disorders : gynecomastia Respiratory Disorders : interstitial lung disease Skin and Subcutaneous Tissue Disorders : drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption