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CRESTOR® (rosuvastatin calcium)



 

Safety

In this section, you can review the safety profile for CRESTOR® (rosuvastatin calcium). This safety profile is in line with other leading statins, as demonstrated by preapproval clinical trials in 10,275 patients and postmarketing experience.1,2,3,4,5,6,7

For a comprehensive, scientific, nonpromotional summary of rosuvastatin clinical trials conducted by AstraZeneca and a summary of postmarketing data for the first five years that rosuvastatin was available (through April 2008), please visit www.rosuvastatininformation.com.

Safety Evidence

  • Extensive clinical trials and postmarketing experience
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  • Variety of patient types enrolled in CRESTOR clinical trials2 Adapted from the Shepherd Publication
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  • Discontinuation rates due to adverse events similar to placebo and other studied statins in fixed-dose controlled trials2 Adapted from the Shepherd Publication
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  • Incidence of myalgia and myopathy with CRESTOR2 Adapted from the Shepherd Publication
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  • Semiannual reporting rates for spontaneous reports of rhabdomyolysis3 Adapted from the Shepherd Publication
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  • Reported incidence of serum transaminase elevations with CRESTOR and other statins2 Adapted from the Shepherd Publication
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  • Serum creatinine changes with long-term CRESTOR treatment14 Adapted from the Shepherd Publication
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  • Estimated glomerular filtration rate (eGFR) with CRESTOR 5 mg to 40 mg14
    Adapted from the Shepherd Publication
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  • Percentage of proteinuria incidence with statin therapies at last visit14 Adapted from the Shepherd Publication
  • > View Chart
  • Urinary albumin excretion (UAE) with CRESTOR15 Adapted from the Sorof Publication
  • > View Chart
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Extensive clinical trials and postmarketing experience

Clinical patient populations during preapproval 1 8 9 10 1 8 9 10

Over 13 million patients worldwide treated with CRESTOR.11

Four completed real-world studies of more than 240,000 patients.4,5,6,7

*CRESTOR (n=42,069), other statins (n=206,634).4,5,6,7

  • Part of an ongoing 9-study pharmacoepidemiologic program12

CRESTOR is approved for use in over 91 countries.11

Over 141 million prescriptions for CRESTOR have been written by health care professionals.11

In total, more than 70,000 patients have taken rosuvastatin in clinical trials (as of April 2008).11

CRESTOR was studied in more patients during preapproval than atorvastatin,simvastatin, and pravastatin combined.1,8,9,10

Through the GALAXY™ Program, AstraZeneca continues to study CRESTOR for a variety of outcomes in a wide range of study populations.

Enlarge Chart 1 8 9 10 1 8 9 10

PUBLICATION: SHEPHERD
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Variety of patient types enrolled in CRESTOR clinical trials*2

Patient types enrolled in CRESTOR clinical trials 2

NO upper age limit† (almost one third were >65 years of age).2,13

NO exclusion for mild-to-moderate renal impairment with serum creatinine up to 2.5 mg/dL.2,13

NO exclusion for ALT <1.5x ULN or CK < 3x ULN at baseline.2,13

10,103 patients were treated for > 48 weeks; 6449 patients were treated for > 96 weeks.2,13

*In phase III trials.13

†In phase II-IV trials.2

Enlarge Chart 2
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Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg. Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis. Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg).2


PUBLICATION: SHEPHERD
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Discontinuation rates due to adverse events similar to placebo and other studied statins in fixed-dose controlled trials2

Statin discontinuation rates due to adverse events
Enlarge Chart
Show/Hide Description

Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg. Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis. Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg). The discontinuation rates due to adverse events presented above were determined from the fixed-dose controlled trials.2


PUBLICATION: SHEPHERD
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Incidence of myalgia and myopathy with CRESTOR2

Incidence of myalgia and myopathy with CRESTOR
Enlarge Chart
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Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg. Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis. Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg).2


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Semiannual reporting rates for spontaneous reports of rhabdomyolysis3

Patients with clinically significant ALT elevations in controlled trials

Reporting rate of rhabdomyolysis for CRESTOR is in line with the reporting rates of other statins.

*All spontaneous reports, including expedited, periodic, and direct reports from the FDA AERS database, are not medically confirmed.

†US reporting rates, based on FDA AERS data, are made available through the Freedom of Information Act divided by US prescribing data supplied by IMS Health Database to the end of February 2007.

‡Cerivastatin reports received after September 1, 2001, are excluded. Due to a change in the way the FDA AERS reports are recorded, AERS data corresponding to the period March 2005 to August 2006 differ from previous data as they may include non-US reports and those of clinical trial origin. For this reason, the data corresponding to this period are joined by dotted lines.

Reports of rhabdomyolysis in postmarketing experience with CRESTOR have been in line with other currently marketed statins and are very rare — less than one report per 10,000 patients. [rosuvastatininformation.com]

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including CRESTOR. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Therapy with CRESTOR should be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (eg, sepsis; hypertension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled seizures).

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PUBLICATION: SHEPHERD
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Reported incidence of serum transaminase elevations with CRESTOR and other statins*2

Serum creatinine changes with long-term CRESTOR treatment 2 2

Reported incidence of serum transaminase elevations with CRESTOR and other statins is low.2

With CRESTOR, in most cases, serum transaminase elevations were transient and resolved and improved on continued therapy or after a brief interruption in therapy.1

Enlarge Chart 2 2
Show/Hide Description

Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg. Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis. Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg). Rates of clinically significant ALT elevations were assessed using data from controlled trials.2


PUBLICATION: SHEPHERD
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Serum creatinine changes with long-term CRESTOR treatment14

eGFR with CRESTOR 5 mg to 40 mg

CRESTOR was not associated with worsening renal function during long-term treatment — even among patients with preexisting kidney disease.2

Renal function was assessed in a diverse group of more than 16,000 patients treated with CRESTOR.14

Patients were treated with CRESTOR 5 mg to 40 mg.14

Dipstick-positive proteinuria and microscopic hematuria were observed among patients treated with CRESTOR. These findings were more frequent in patients taking CRESTOR 40 mg, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, dose reduction should be considered for patients on CRESTOR therapy with unexplained, persistent proteinuria and/or hematuria during routine urinalysis testing.1

Patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not on hemodialysis have demonstrated a threefold increase in plasma concentrations and should be started at 5 mg once daily and not exceed 10 mg once daily.1

Enlarge Chart
Show/Hide Description

Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg.2 Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis.2 Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg).2 The effects on serum creatinine were assessed using data from the all-controlled/uncontrolled pool.14


PUBLICATION: SHEPHERD
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Estimated glomerular filtration rate (eGFR) with CRESTOR 5 mg to 40 mg14

Percentage of proteinuria incidence with statin therapies at last visit

eGFR increases were seen with CRESTOR 5 mg to 40 mg following long-term treatment (>144 weeks).14

*P<.001 vs baseline eGFR at every dose.14

Mean eGFR was predicted from the abbreviated Modification of Diet in Renal Disease equation.14

Enlarge Chart
Show/Hide Description

Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg.2 Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis.2 Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg).2 Estimated glomular filtration rates were assessed using data from the all-controlled/uncontrolled pool.14


PUBLICATION: SHEPHERD
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Percentage of proteinuria incidence with statin therapies at last visit14

Urinary albumin excretion (UAE) with CRESTOR

In controlled clinical trials with CRESTOR and other statins, proteinuria (defined as shift from none or trace at baseline to ≥2+ at last visit) was observed with all studied statins and placebo.14

  • <1.0% occurrence of proteinuria with CRESTOR 5 mg to 20 mg (1.5% with CRESTOR 40 mg).14
  • <1.0% with atorvastatin 10 mg to 80 mg, simvastatin 20 mg to 80 mg, and pravastatin 20 mg to 40 mg.14

Proteinuria, as determined by urinary dipstick, was generally transient and not associated with worsening renal function.1,2

No renal monitoring required in patients taking CRESTOR.1

No modification of dosage necessary for patients with mild-to-moderate renal insufficiency (CLcr <30 mL/min/1.73 m2).1

Enlarge Chart
Show/Hide Description

Shepherd et al evaluated the safety and tolerability of CRESTOR using data from a multinational phase II/III/IIIb/IV program that included 16,876 patients (25,670 patient-years) who received CRESTOR 5 mg to 40 mg.2 Data from 33 clinical trials whose databases were locked up to and including September 16, 2005, were used in the analysis.2 Dose-ranging, fixed-dose, forced-titration, and titration-to-goal trial designs were utilized, as were controlled trials with placebo or comparator statins (atorvastatin 10 mg to 80 mg, simvastatin 10 mg to 80 mg, and pravastatin 10 mg to 40 mg).2 Rates of proteinuria were assessed using data from the all-controlled pool.14


PUBLICATION: SOROF
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Urinary albumin excretion (UAE) with CRESTOR15

Urinary albumin excretion (UAE) with CRESTOR 15 15 15
Enlarge Chart 15 15 15
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Sorof et al was part of the URANUS study.15 URANUS was a 16-week, randomized, double-blind, forced-titration trial comparing CRESTOR and atorvastatin in 465 type 2 diabetics with dyslipidemia.16 Patients were randomized to CRESTOR 10 mg or atorvastatin 10 mg for 4 weeks and then titrated up if goal was not met.16 The primary end point was the percentage change in LDL-C from baseline to 16 weeks.16