Crestor

General Dosage and Administration Information

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Administer CRESTOR orally as a single dose at any time of day, with or without food. The tablet should be swallowed whole.

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Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating CRESTOR, and adjust the dosage if necessary.

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If a dose is missed, advise patients not take an extra dose. Resume treatment with the next dose.

Recommended Dosage in Adult Patients

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The dosage range for CRESTOR is 5 to 40 mg orally once daily.

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The recommended dose of CRESTOR depends on a patient’s indication for usage, LDL-C, and individual risk for cardiovascular events.

Recommended 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.

Dosing in Asian Patients

Initiate CRESTOR at 5 mg once daily due to increased rosuvastatin plasma concentrations. Consider the risks and benefits of CRESTOR when treating Asian patients not adequately controlled at doses up to 20 mg once daily [see Warnings and Precautions (5.1), Use in Specific Populations (8.8), and Clinical Pharmacology (12.3)].

Recommended 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 once daily and should not exceed 10 mg once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

There are no dosage adjustment recommendations for patients with mild and moderate renal impairment.

Dosage and Administration Modifications Due to Drug Interactions

CRESTOR Dosage Modifications Due to Drug Interactions

Table 1 displays dosage modifications for CRESTOR due to drug interactions [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

CRESTOR Administration Modifications Due to Drug Interactions

When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, administer CRESTOR at least 2 hours before the antacid [see Drug Interactions (7.2)].

Pregnancy

Lactation

Risk Summary

Limited data from case reports in published literature indicate that CRESTOR is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including CRESTOR, 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 CRESTOR [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

Pediatric Use

The safety and effectiveness of CRESTOR as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of CRESTOR for this indication is based on one 12-week controlled trial with a 40-week open-label extension period in 176 pediatric patients 10 years of age and older with HeFH and one 2-year open-label, uncontrolled trial in 175 pediatric patients 8 years of age and older with HeFH [see Clinical Studies (14)]. In the 1-year trial with a 12-week controlled phase, there was no detectable effect of CRESTOR on growth, weight, BMI (body mass index), or sexual maturation in patients aged 10 to 17 years.

The safety and effectiveness of CRESTOR as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 7 years of age and older with HoFH. Use of CRESTOR for this indication is based on a randomized, placebo-controlled, cross-over study in 14 pediatric patients 7 years of age and older with HoFH [see Clinical Studies (14)].

The safety and effectiveness of CRESTOR have not been established in pediatric patients younger than 8 years of age with HeFH, younger than 7 years of age with HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

Geriatric Use

Of the total number of CRESTOR-treated patients in clinical studies, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Advanced age (≥65 years) is a risk factor for CRESTOR-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 CRESTOR for the increased risk of myopathy [see Warnings and Precautions (5.1)].

Renal Impairment

Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m2). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) who are not receiving hemodialysis [see Clinical Pharmacology (12.3)].

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment not on hemodialysis, the recommended starting dosage is 5 mg daily and should not exceed 10 mg daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].

Hepatic Impairment

CRESTOR is contraindicated in patients with acute liver failure or decompensated cirrhosis. Chronic alcohol liver disease is known to increase rosuvastatin exposure. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Contraindications (4), Warning and Precautions (5.3) and Clinical Pharmacology (12.3)].

Asian Patients

Pharmacokinetic studies have demonstrated an approximate 2‑fold increase in median exposure to rosuvastatin in Asian subjects when compared with White controls. Adjust the CRESTOR dosage in Asian patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Myopathy 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 [see Drug Interactions (7.1) and Use in Specific Populations (8.8)]. 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 [see Dosage and Administration (2.6)]. Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

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.

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 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.

Hepatic Dysfunction

Increases in serum transaminases have been reported with use of CRESTOR [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. 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 [see Use in Specific Populations (8.7)].

Consider liver enzyme testing before CRESTOR initiation and when clinically indicated thereafter. CRESTOR 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 CRESTOR.

5.4 Proteinuria 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.

Increases 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 [see Adverse Reactions (6.1)]. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

Clinical 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.

Other 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.

In the JUPITER study, patients were treated with CRESTOR 20 mg (n=8901) or placebo (n=8901) 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 [see Clinical Studies (14)].

Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 4.

Pediatric Patients with HeFH

In a 12‑week controlled study in pediatric patients 10 to 17 years of age with HeFH with CRESTOR 5 to 20 mg daily [see Use in Specific Populations (8.4) and Clinical Studies (14)], 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.

Postmarketing 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

Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with CRESTOR

Rosuvastatin is a substrate of CYP2C9 and transporters (such as OATP1B1, BCRP). Rosuvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP2C9 and transporters. Table 5 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with CRESTOR and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Drug Interactions that Decrease the Efficacy of CRESTOR

Table 6 presents drug interactions that may decrease the efficacy of CRESTOR and instructions for preventing or managing them.

CRESTOR Effects on Other Drugs

Table 7 presents CRESTOR’s effect on other drugs and instructions for preventing or managing them.

Mechanism of Action

CRESTOR is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3‑hydroxy‑3‑methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.

Pharmacodynamics

Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of CRESTOR is usually achieved by 4 weeks and is maintained after that.

Pharmacokinetics

Absorption

In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to CRESTOR dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration.

Effect of food

Administration of CRESTOR with food did not affect the AUC of rosuvastatin.

Distribution

Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Elimination

Metabolism

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \\ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG‑CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG‑CoA reductase inhibitory activity is accounted for by the parent compound.

Excretion

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. The elimination half-life of rosuvastatin is approximately 19 hours.

Specific Populations

Geriatric Patients

There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

Pediatric Patients

In a population pharmacokinetic analysis of two pediatric trials involving patients with heterozygous familial hypercholesterolemia 10 to 17 years of age and 8 to 17 years of age, respectively, rosuvastatin exposure appeared comparable to or lower than rosuvastatin exposure in adult patients.

Male and Female Patients

There were no differences in plasma concentrations of rosuvastatin between men and women.

Racial or Ethnic Groups

A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2‑fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group.

Patients with Renal Impairment

Mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3‑fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CLcr >80 mL/min/1.73 m2).

Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

Patients with Hepatic Impairment

In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased.

In patients with Child‑Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child‑Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Drug Interactions Studies

Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent.

Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of CRESTOR with medications that are inhibitors of these transporter proteins (e.g. cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [see Dosage and Administration (2.6) and Drug Interactions (7.1)].

Pharmacogenomics

Disposition of rosuvastatin, involves OATP1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T > C). The frequency of this genotype (i.e., SLCO1B1 521 C/C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism on efficacy and/or safety of CRESTOR has not been clearly established.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6‑month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.