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2. What you need to know before you take Crestor

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Warnings and precautions

[..]

• If you have ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after taking Crestor or other related medicines.

[..]

• Do not take Crestor 40 mg (the highest dose) and check with your doctor or pharmacist before you actually start taking any dose of Crestor.

Serious skin reactions including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with Crestor treatment. Stop using Crestor and seek medical attention immediately if you notice any of the symptoms described in section 4.

[..]

4. Possible side effects

[..]

Stop taking Crestor and seek medical help immediately if you have any of the following allergic reactions:

[..]

• Reddish non-elevated, target-like or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These serious skin rashes can be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome).
• Widespread rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).

[..]

Side effects of unknown frequency may include:

• Diarrhoea (loose stools), Stevens-Johnson syndrome (serious blistering condition of the skin, mouth, eyes and genitals), cough, shortness of breath, oedema (swelling), sleep disturbances, including insomnia and nightmares, sexual difficulties, depression, breathing problems, including persistent cough and/or shortness of breath or fever, tendon injury and muscle weakness that is constant.

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This leaflet was last revised in JulyMay 2021.

CV 21 002012

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4.4 Special warnings and precautions for use

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Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appear, Crestor should be discontinued immediately and an alternative treatment should be considered.

If the patient has developed a serious reaction such as SJS or DRESS with the use of Crestor, treatment with Crestor must not be restarted in this patient at any time.

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4.8 Undesirable effects

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Table 2. Adverse reactions based on data from clinical studies and post-marketing experience

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10. DATE OF REVISION OF THE TEXT

29^th September 2020 02 September 2021

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4.3 Contraindications

Crestor is contraindicated:

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• in patients receiving concomitant combination of sofosbuvir/velpatasvir/voxilaprevir (see section 4.5)

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4.5 Interaction with other medicinal products and other forms of interaction

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If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the Crestor dose above 20 mg.

The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration: Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing.

[..]

4.8 Undesirable effects

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HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

In section 4.8 Undesirable effects, Lupus-like syndrome and Muscle rupture have been added as Rare side effects in  Table 2. Adverse reactions based on data from clinical studies and post-marketing experience. Revision date has been updated form February 2019 to September 2019. 

Added text

Deleted text

4) Possible side effects

…..

Also, stop taking Crestor and talk to your doctor immediately:

• If you have any unusual aches or pains in your muscles which go on for longer than you might expect. Muscle symptoms are more common in children and adolescents than in adults. As with other statins, a very small number of people have experienced unpleasant muscle effects and rarely these have gone on to become a potentially life threatening muscle damage known as rhabdomyolysis.
• If you experience muscle rupture.
• If you have lupus-like disease syndrome (including rash, joint disorders and effects on blood cells).
• If you experience muscle rupture.
  …..
  Rare possible side effects (these may affect between 1 in 1,000 and 1 in 10,000 patients):

• …..
• Lupus-like disease syndrome (including rash, joint disorders and effects on blood cells).

This leaflet was last revised in February May 2019.

Update to section 4.5 Update to table 1, effect of co-administrered medicinal products on rosuvastatin exposure

Update to section 7 – Change of MAH

Update to section 8 – Update to marketing authorisation numbers

Update to section 10 – Update to date of revision of text

Update to section 4.8 – Update to adverse reaction reporting details.

Update to section 5.1 – Update to paediatric population section

Update to section 10 – Update to date of revision of text.

Change to section 4.1 – inclusion of indication and posology details regarding Homozygous familial hypercholesterolaemia

Change to section 4.3 – editorial and formatting changes

Change to section 4.4 – inclusion of paragraph regarding fusidic acid warning/contraindication

Change to section 4.5 - inclusion of paragraph regarding fusidic acid warning/contraindication

Change to section 5.1 – inclusion of summary of HYRDA study results

Minor editorial and formatting changes made throughout.

Section 5.2 update to special population – age and sex

Section 10 date of revision

Section 4.5 Drug interaction – new protease inhibitor information

Section 4.8 SE reproting – update to HPRA address

Section 10 – date of revision

- Section 4.1 Treatment age group changed to 6 years of older for treatment of hypercholesterolaemia

- Section 4.2 Change to Paediatric population age range – 10years changed down to 6 years

- Section 4.4 Update to Paediatric population age range

- Section 5.1 Addition of information to paediatric studies

- Section 5.2 Update to Paediatric population

- Section 10 date of revision

- Section 4.4 addition of Fusidic acid interaction

- Section 4.5 addition of clopidogrel information and addition of fusidic acid information

- Section 4.8 updating AE address for IMB

- Section 10 date of revision

- Section 4.8 addition of Peripheral neuropathy and change in frequency of side effect

- Section 4.8 section 4.8 AE reporting statement

- Section 5.1 updating of subheading (improving readability)

- Section 10  date of revision

- Section 4.2 addition of genetic polymorphism

- Section 4.2 addition on concomitant therapy
- Section 4.3 clarification of immune-mediated necrotising myopathy occurrence

- Section 4.3 exposure effects during use with protease inhibitors

- Section 4.5 effect of co-administered medicinal products on rosuvastatin clarified.

- Section 4.5 explanations on interactions requiring rosuvastatin dose adjustments

- Section 4.8 adverse events table re-formatted and section update

- Section 5.2 addition of information related to genetic polymorphism

- Section 6.4 storage precautions clarified regarding storage to prevent ingress of moisture

- Section 6.6 clarification of disposal mechanism

- Section 10 Updated date of revision

Section 4.4

Information re necrotizing myopathy added.

Update to Diabetes Mellitus information.

Section 4.8

Footnote 1 re diabetes mellitus updated.

Post Marketing Experience updated re necrotizing myopathy.

Section 10

Date of revision amended to 5^th September 2012

Section 4.4

Addition of imposed amended wording for new onset diabetes mellitus.

Section 4.8

 Addition of imposed wording for gynaecomastia.

Section 10

Date of revision amended to 27th April 2012.

Section 4.2 and 4.4 - Addition of reference ‘(see Section 4.3)'

Section 4.8 - Add Tendon disorder

Section 10 Date of revision changed to 20th December 2011

Section 4.1

Includes paediatric information.

Additional text:

Prevention of Cardiovascular Events

Prevention of major cardiovascular events in patients who are estimated to have a high risk for a first cardiovascular event (see Section 5.1), as an adjunct to correction of other risk factors.

Section 4.2

Additional text:

Crestor may be given at any time of day, with or without food.

Additional text:

Prevention of Cardiovascular Events

In the cardiovascular events risk reduction study, the dose used was 20 mg daily (see Section 5.1).

Section 4.2 includes Paediatric information

Section 4.4

Section 4.4

Addition of paragraph on Lactose Intolerance:

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Section 5.3

Replacement of paragraph:

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows:  In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

Section 10

Change of date:

4.4 Special warnings and special precautions for use

Addition of text after the Race paragraph

Protease inhibitors

The concomitant use with protease inhibitors is not recommended (see Section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Addition of text after Gemfibrozil and other lipid-lowering products paragraph

Protease inhibitors:  Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure.  In a pharmacokinetic study, co-administration of 20 mg rosuvastatin and a combination product of two protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers was associated with an approximately two-fold and five-fold increase in rosuvastatin steady-state AUC_(0-24) and Cmax respectively.  Therefore, concomitant use of rosuvastatin in HIV patients receiving protease inhibitors is not recommended (see also Section 4.4).

5.1 Pharmacodynamic properties

Addition of text last paragraph in section

In a multi-centre, double-blind, placebo-controlled clinical study (METEOR), 984 patients between 45 and 70 years of age and at low risk for coronary heart disease (defined as Framingham risk <10% over 10 years), with a mean LDL-C of 4.0 mmol/l (154.5 mg/dL), but with subclinical atherosclerosis (detected by Carotid Intima Media Thickness) were randomised to 40 mg rosuvastatin once daily or placebo for 2 years.  Rosuvastatin significantly slowed the rate of progression of the maximum CIMT for the 12 carotid artery sites compared to placebo by -0.0145 mm/year [95% confidence interval -0.0196, -0.0093; p<0.0001].  The change from baseline was -0.0014 mm/year (-0.12%/year (non-significant)) for rosuvastatin compared to a progression of +0.0131 mm/year (1.12%/year (p<0.0001)) for placebo.  No direct correlation between CIMT decrease and reduction of the risk of cardiovascular events has yet been demonstrated.  The population studied in METEOR is low risk for coronary heart disease and does not represent the target population of Crestor 40mg.  The 40mg dose should only be prescribed in patients with severe hypercholesterolaemia at high cardiovascular risk (see Section 4.2). 

10 Date of revision of the text

16^th August 2007