Treatment of hypercholesterolaemia
Adults, adolescents and children aged 6 years or older with primary hypercholesterolaemia (type
IIa including heterozygous familial hypercholesterolaemia) or mixed dyslipidaemia (type IIb) as an
adjunct to diet when response to diet and other non-pharmacological treatments (e.g. exercise,
weight reduction) is inadequate.
Adults, adolescents and children aged 6 years or older with homozygous familial
hypercholesterolaemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL
apheresis) or if such treatments are not appropriate.
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.

Posology
Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that
should continue during treatment. The dose should be individualised according to the goal of
therapy and patient response, using current consensus guidelines.
Rosuvastatin may be given at any time of day, with or without food.
Treatment of hypercholesterolaemia
The recommended start dose is 5 or 10 mg orally once daily in both statin-naïve or patients
switched from another HMG CoA reductase inhibitor. The choice of start dose should take into
account the individual patient's cholesterol level and future cardiovascular risk as well as the
potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be
made after 4 weeks, if necessary (see Section 5.1). In light of the increased reporting rate of
adverse reactions with the 40 mg dose compared to lower doses (see Section 4.8), a final titration
to the maximum dose of 40 mg should only be considered in patients with severe
hypercholesterolaemia at high cardiovascular risk (in particular those with familial
hypercholesterolaemia), who do not achieve their treatment goal on 20 mg, and in whom routine
follow-up will be performed (see Section 4.4). Specialist supervision is recommended when the 40
mg dose is initiated.
Prevention of cardiovascular events
In the cardiovascular events risk reduction study, the dose used was 20 mg daily (see Section 5.1).
Paediatric population
Paediatric use should only be carried out by specialists.
Children and adolescents 6 to 17 years of age (Tanner Stage II-V)
Heterozygous familial hypercholesterolaemia
In children and adolescents with heterozygous familial hypercholesterolaemia the usual start dose
is 5 mg daily.
• In children 6 to 9 years of age with heterozygous familial hypercholesterolaemia, the usual dose
range is 5-10 mg orally once daily. Safety and efficacy of doses greater than 10 mg have not been
studied in this population.

• In children 10 to 17 years of age with heterozygous familial hypercholesterolaemia, the usual
dose range is 5-20 mg orally once daily. Safety and efficacy of doses greater than 20 mg have not
been studied in this population.
Titration should be conducted according to the individual response and tolerability in paediatric
patients, as recommended by the paediatric treatment recommendations (see Section 4.4). Children
and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin
treatment initiation; this diet should be continued during rosuvastatin treatment.
Homozygous familial hypercholesterolaemia
In children 6 to 17 years of age with homozygous familial hypercholesterolaemia, the
recommended maximum dose is 20 mg once daily. A starting dose of 5 to 10 mg once daily
depending on age, weight and prior statin use is advised.
Titration to the maximum dose of 20 mg once daily should be conducted according to the
individual response and tolerability in paediatric patients, as recommended by the paediatric
treatment recommendations (see section 4.4).
Children and adolescents should be placed on standard cholesterol-lowering diet before
rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment. There
is limited experience with doses other than 20 mg in this population.
The 40 mg tablet is not suitable for use in paediatric patients.
Children younger than 6 years
The safety and efficacy of use in children younger than 6 years has not been studied. Therefore,
Rosuvastatin is not recommended for use in children younger than 6 years.
Use in the elderly
A start dose of 5 mg is recommended in patients >70 years (see Section 4.4). No other dose
adjustment is necessary in relation to age.

Dosage in patients with renal insufficiency
No dose adjustment is necessary in patients with mild to moderate renal impairment. The
recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance
<60 ml/min). The 40 mg dose is contraindicated in patients with moderate renal impairment. The
use of rosuvastatin in patients with severe renal impairment is contraindicated for all doses (See
sections 4.3 and 5.2).
Dosage in patients with hepatic impairment
There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7
or below. However, increased systemic exposure has been observed in subjects with Child-Pugh
scores of 8 and 9 (see Section 5.2). In these patients an assessment of renal function should be
considered (see Section 4.4). There is no experience in subjects with Child-Pugh scores above 9.
Rosuvastatin is contraindicated in patients with active liver disease (see Section 4.3).
Race
Increased systemic exposure has been seen in Asian subjects (see Section 4.3, 4.4 and 5.2). The
recommended start dose is 5 mg for patients of Asian ancestry.
Genetic polymorphisms
Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin
exposure (see Section 5.2).
For patients who are known to have such specific types of polymorphisms, a lower daily dose of
rosuvastatin is recommended.
Dosage in patients with pre-disposing factors to myopathy
The recommended start dose is 5 mg in patients with predisposing factors to myopathy (see Section
4.4).

Concomitant therapy
Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of
myopathy (including rhabdomyolysis) is increased when rosuvastatin is administered
concomitantly with certain medicinal products that may increase the plasma concentration of
rosuvastatin due to interactions with these transporter proteins (e.g. ciclosporin and certain protease
inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir; see
Sections 4.4 and 4.5). Whenever possible, alternative medications should be considered, and, if
necessary, consider temporarily discontinuing rosuvastatin therapy. In situations where
coadministration of these medicinal products with rosuvastatin is unavoidable, the benefit and the
risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered
(see Section 4.5).

 

Rosuvastatin is contraindicated: - In patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - In patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN). - In patients with severe renal impairment (creatinine clearance <30 ml/min). - In patients with myopathy. - In patients receiving concomitant combination of sofosbuvir/velpatasvir/voxilaprevir (see section 4.5). - In patients receiving concomitant ciclosporin. During pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures. The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy/ rhabdomyolysis. Such factors include: - Moderate renal impairment (creatinine clearance < 60 ml/min) - Hypothyroidism - Personal or family history of hereditary muscular disorders - Previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate - Alcohol abuse - Situations where an increase in plasma levels may occur - Asian patients - Concomitant use of fibrates. (see Sections 4.4, 4.5 and 5.2).

Renal Effects
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients
treated with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent
in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease
(see Section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the
40 mg dose. An assessment of renal function should be considered during routine follow-up of
patients treated with a dose of 40 mg.
Skeletal Muscle Effects
Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported
in rosuvastatin - treated patients with all doses and in particular with doses > 20 mg. Very rare
cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMGCoA
reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see Section 4.5)
and caution should be exercised with their combined use.
As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated
with rosuvastatin in postmarketing use is higher at the 40 mg dose.
Creatine Kinase Measurement
Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a
plausible alternative cause of CK increase which may confound interpretation of the result. If CK
levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out
within 5 – 7 days. If the repeat test confirms a baseline CK>5xULN, treatment should not be
started.
Before Treatment
Rosuvastatin, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in
patients with predisposing factors for myopathy/rhabdomyolysis. Such factors include:
• renal impairment

• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• age >70 years
• situations where an increase in plasma levels may occur (see Sections 4.2, 4.5 and5.2)
• concomitant use of fibrates.
In such patients the risk of treatment should be considered in relation to possible benefit and
clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN)
treatment should not be started.
Whilst on Treatment
Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately,
particularly if associated with malaise or fever. CK levels should be measured in these patients.
Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular
symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5x ULN). If symptoms
resolve and CK levels return to normal, then consideration should be given to re-introducing
rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close
monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There
have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after
treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal
muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of
statin treatment.
In clinical trials, there was no evidence of increased skeletal muscle effects in the small number of
patients dosed with rosuvastatin and concomitant therapy. However, an increase in the incidence of
myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors
together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole
antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of
myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the
combination of Rosuvastatin and gemfibrozil is not recommended. The benefit of further
alterations in lipid levels by the combined use of Rosuvastatin with fibrates or niacin should be
carefully weighed against the potential risks of such combinations. The 40 mg dose is
contraindicated with concomitant use of a fibrate. (See Section 4.5 and 4.8).

Rosuvastatin must not be co-administered with systemic formulations of fusidic acid or within 7
days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is
considered essential, statin treatment should be discontinued throughout the duration of fusidic acid
treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients
receiving fusidic acid and statins in combination (see section 4.5). Patients should be advised to
seek medical advice immediately if they experience any symptoms of muscle weakness, pain or
tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In
exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment
of severe infections, the need for co-administration of Rosuvastatin and fusidic acid should only be
considered on a case by case basis and under close medical supervision.
Rosuvastatin should not be used in any patient with an acute, serious condition suggestive of
myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g.
sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders;
or uncontrolled seizures).

Liver Effects
As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients
who consume excessive quantities of alcohol and/or have a history of liver disease.
It is recommended that liver function tests be carried out prior to, and 3 months following, the
initiation of treatment.
Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is
greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events
(consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg
dose.
In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic
syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin.
Race
Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians
(see Section 4.2, 4.3 and 5.2).
Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin
concomitantly with various protease inhibitors in combination with ritonavir. Consideration should
be given both to the benefit of lipid lowering by use of rosuvastatin in HIV patients receiving
protease inhibitors and the potential for increased Rosuvastatin plasma concentrations when
initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors.
The concomitant use with certain protease inhibitors is not recommended unless the dose of
rosuvastatin is adjusted (see Sections 4.2 and 4.5).
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with
long-term therapy (see Section 4.8). Presenting features can include dyspnoea, non-productive
cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient
has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk
of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is
appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and
therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to
6.9 mmol/L, BMI>30 kg/m2, raised triglycerides, hypertension) should be monitored both
clinically and biochemically according to national guidelines.
In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin
and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/L.
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. 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 appears, Rosuvastatin 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 Rosuvastatin,
treatment with Rosuvastatin must not be restarted in this patient at any time.

Paediatric population
The evaluation of linear growth (height), weight, BMI (body mass index), and secondary
characteristics of sexual maturation by Tanner staging in paediatric patients 6 to 17 years of age
taking rosuvastatin is limited to a two-year period. After two years of study treatment, no effect on
growth, weight, BMI or sexual maturation was detected (see Section 5.1).
In a clinical trial of children and adolescents receiving rosuvastatin for 52 weeks, CK
elevations>10xULN and muscle symptoms following exercise or increased physical activity were
observed more frequently compared to observations in clinical trials in adults (see Section 4.8).
Lactose: This product contains lactose. Patients with rare hereditary problems of galactose
intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this
medicine.
Azo colouring agents: This product also contains azo colouring agents, allura red AC (E129) and
sunset yellow FCF (E110) which may cause allergic reactions.

Effect of coadministered medicinal products on rosuvastatin
Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins
including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant
administration of rosuvastatin with medicinal products that are inhibitors of these transporter
proteins may result in increased rosuvastatin plasma concentrations and an increased risk of
myopathy (see Sections 4.2, 4.4 and 4.5 Table 1).
Ciclosporin: During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC
values were on average 7 times higher than those observed in healthy volunteers (see Table 1).
Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin (see Section 4.3).
Concomitant administration did not affect plasma concentrations of ciclosporin.
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant
protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). For instance, in a
pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two
protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers was associated
with an approximately three--fold and f seven-fold increase in rosuvastatin AUC() and Cmax
respectively. The concomitant use of rosuvastatin and some protease inhibitor combinations may
be considered after careful consideration of rosuvastatin dose adjustments based on the expected
increase in rosuvastatin exposure (see Sections 4.2, 4.4 and 4.5 Table 1).

Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and
gemfibrozil resulted in a 2-fold increase in rosuvastatin C max and AUC (see Section 4.4).
Based on data from specific interaction studies no pharmacokinetic relevant interaction with
fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil,
fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid)
increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors,
probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated
with concomitant use of a fibrate (see Sections 4.3 and 4.4). These patients should also start with
the 5 mg dose.
Ezetimibe: Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold
increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic
interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out (see
Section 4.4).
Antacid: The simultaneous dosing of rosuvastatin with an antacid suspension containing
aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration
of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after
rosuvastatin. The clinical relevance of this interaction has not been studied.
Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in
AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase
in gut motility caused by erythromycin.

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is
neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Therefore, drug interactions
resulting from cytochrome P450 mediated metabolism are not expected. In addition, rosuvastatin is
a poor substrate for these isoenzymes. No clinically relevant interactions have been observed
between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or
ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary
to co-administer rosuvastatin with other medicinal products known to increase exposure to
rosuvastatin, doses of rosuvastatin should be adjusted. Start with a 5 mg once daily dose of
rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The
maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure
would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting
medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase),
and a 10 mg dose of rosuvastatin with combination atazanavir/ritonavir (3.1fold increase).
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 rosuvastatin dose above 20 mg

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is
neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Therefore, drug interactions
resulting from cytochrome P450 mediated metabolism are not expected. In addition, rosuvastatin is
a poor substrate for these isoenzymes. No clinically relevant interactions have been observed
between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or
ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary
to co-administer rosuvastatin with other medicinal products known to increase exposure to
rosuvastatin, doses of rosuvastatin should be adjusted. Start with a 5 mg once daily dose of
rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The
maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure
would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting
medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase),
and a 10 mg dose of rosuvastatin with combination atazanavir/ritonavir (3.1fold increase).
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 rosuvastatin 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.
Effect of rosuvastatin on co-administered medicinal products
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment
or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists
(e.g. warfarin or another coumarin anticoagulant) may result in an increase in International
Normalised Ratio (INR). Discontinuation or down-titration of rosuvastatin may result in a decrease
in INR. In such situations, appropriate monitoring of INR is desirable.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of rosuvastatin and
an oral contraceptive resulted in an increase in ethinylestradiol and norgestrel AUC of 26% and
34%, respectively. These increased plasma levels should be considered when selecting oral
contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant
rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, the combination
has been extensively used in women in clinical trials and was well tolerated.
Other medicinal products:
Digoxin: Based on data from specific interaction studies no clinically relevant interaction with
digoxin is expected.
Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The
risk of myopathy, including rhabdomyolysis may be increased by the concomitant administration
of systemic fusidic acid with statins. The mechanism of this interaction (whether it is
pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of
rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, Rosuvastatin treatment should be discontinued
throughout the duration of the fusidic acid treatment. Also see section 4.4.
Paediatric population
Interaction studies have only been performed in adults. The extent of interactions in the paediatric
population is not known.

Rosuvastatin is contraindicated in pregnancy and lactation.
Women of child bearing potential should use appropriate contraceptive measures.
Since cholesterol and other products of cholesterol biosynthesis are essential for the development
of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of
treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity (see
Section 5.3). If a patient becomes pregnant during use of this product, treatment should be
discontinued immediately.
Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in
humans. (See Section 4.3).

Studies to determine the effect of Rosuvastatin on the ability to drive and use machines have not
been conducted.
However, based on its pharmacodynamic properties, Rosuvastatin is unlikely to affect this ability.
When driving vehicles or operating machines, it should be taken into account that dizziness may
occur during treatment.

The adverse reactions seen with rosuvastatin are generally mild and transient. In controlled
clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse
reactions.
Tabulated list of adverse reactions
Based on data from clinical studies and extensive post-marketing experience, the following table
presents the adverse reaction profile for rosuvastatin. Adverse reactions listed below are classified
according to frequency and system organ class (SOC).
The frequencies of adverse reactions are ranked according to the following convention: Common
(≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare
(<1/10,000); Not known (cannot be estimated from the available data).

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

Common possible side effects: may affect up to 1 in 10 people
• Headache
• Stomach pain
• Constipation
• Feeling sick
• Muscle pain
• Feeling weak
• Dizziness
• An increase in the amount of protein in the urine – this usually returns to normal on its own without
having to stop taking your Rosuvastatin tablets (only Rosuvastatin 40 mg)
• Diabetes. This is more likely if you have high levels of sugars and fats in your blood, are
overweight and have high blood pressure. Your doctor will monitor you while you are taking this
medicine.
Uncommon possible side effects: may affect up to 1 in 100 people
• Rash, itching or other skin reactions
• An increase in the amount of protein in the urine – this usually returns to normal on its own without
having to stop taking your Rosuvastatin tablets (only Rosuvastatin 5 mg, 10 mg and 20 mg).

Rare possible side effects: may affect up to 1 in 1,000 people
• Severe allergic reaction – signs include swelling of the face, lips, tongue and/ or throat, difficulty in
swallowing and breathing, a severe itching of the skin (with raised lumps). If you think you are
having an allergic reaction, then stop taking Rosgan and seek medical help immediately
• Muscle damage in adults – as a precaution, stop taking Rosgan and talk to your doctor
immediately if you have any unusual aches or pains in your muscles which go on for longer
than expected
• A severe stomach pain (inflamed pancreas)
• Increase in liver enzymes in the blood
• Bleeding or bruising more easily than normal due to low level of blood platelets
• Lupus-like disease syndrome (including rash, joint disorders and effects on blood cells).
Very rare possible side effects: may affect up to 1 in 10,000 people
• Jaundice (yellowing of the skin and eyes)
• Hepatitis (an inflamed liver)
• Traces of blood in your urine
• Damage to the nerves of your legs and arms (such as numbness)
• Joint pain
• Memory loss
• Breast enlargement in men (gynaecomastia)
Side effects of not known frequency may include:
• Diarrhoea (loose stools)
• 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
• Muscle weakness that is constant

There is no specific treatment in the event of overdose. In the event of overdose, the patient should
be treated symptomatically and supportive measures instituted as required. Liver function and CK
levels should be monitored.
Haemodialysis is unlikely to be of benefit.

Pharmacotherapeutic group: HMG-CoA reductase inhibitors.
ATC Code: C10A A07
Mechanism of action
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting
enzyme that converts 3- hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for
cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol
lowering.
Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake
and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total
number of VLDL and LDL particles.

Pharmacodynamic effects
Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases
HDL-cholesterol. It also lowers ApoB, non-HDL-C, VLDL-C, VLDL-TG and increases ApoA-I
(see Table3). Rosuvastatin also lowers the LDL-C/HDLC, total C/HDL-C and nonHDL-C/HDL-C
and the ApoB/ApoA-I ratios.
Table 3 Dose response in patients with primary hypercholesterolaemia (type IIa and IIb)
(adjusted mean percent change from baseline)

Dose	N	LDL-C	Total-C	HDL-C	TG	nonHDL-C	ApoB	ApoA-I
Placebo	13	-7	-5	3	-3	-7	-3	0
5	17	-45	-33	13	-35	-44	-38	4
10	17	-52	-36	14	-10	-48	-42	4
20	17	-55	-40	8	-23	-51	-46	5
40	18	-63	-46	10	-28	-60	-54	0

A therapeutic effect is obtained within 1 week following treatment initiation and 90% of
maximum response is achieved in 2 weeks. The maximum response is usually achieved by 4
weeks and is maintained after that.

Clinical efficacy and safety
Rosuvastatin is effective in adults with hypercholesterolaemia, with and without
hypertriglyceridaemia, regardless of race, sex, or age and in special populations such as diabetics,
or patients with familial hypercholesterolaemia.
From pooled phase III data, rosuvastatin has been shown to be effective at treating the majority of
patients with type IIa and IIb hypercholesterolaemia (mean baseline LDL-C about 4.8 mmol/l) to
recognised European Atherosclerosis Society (EAS; 1998) guideline targets; about 80% of
patients treated with 10 mg reached the EAS targets for LDL-C levels (<3 mmol/l).
In a large study, 435 patients with heterozygous familial hypercholesterolaemia were given
rosuvastatin from 20 mg to 80 mg in a force-titration design. All doses showed a beneficial effect
on lipid parameters and treatment to target goals.
Following titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C was reduced by
53%. Thirty three percent (33%) of patients reached EAS guidelines for LDL-C levels (<3
mmol/l).
In a force-titration, open label trial, 42 patients (including 8 paediatric patients) with homozygous
familial hypercholesterolaemia were evaluated for their response to rosuvastatin 20 - 40 mg. In
the overall population, the mean LDL-C reduction was 22%.

In clinical studies with a limited number of patients, rosuvastatin has been shown to have additive
efficacy in lowering triglycerides when used in combination with fenofibrate and in increasing
HDL-C levels when used in combination with niacin (see Section 4.4).
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 (nonsignificant)) 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 rosuvastatin 40mg. The 40mg dose should only be prescribed in patients
with severe hypercholesterolaemia at high cardiovascular risk (see Section 4.2).
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating
Rosuvastatin (JUPITER) study, the effect of rosuvastatin on the occurrence of major
atherosclerotic cardiovascular disease events was assessed in 17,802 men (≥50 years) and women
(≥60 years).
Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily
(n=8901) and were followed for a mean duration of 2 years.
LDL-cholesterol concentration was reduced by 45% (p<0.001) in the rosuvastatin group
compared to the placebo group.
In a post-hoc analysis of a high-risk subgroup of subjects with a baseline Framingham risk
score>20% (1558 subjects) there was a significant reduction in the combined end-point of
cardiovascular death, stroke and myocardial infarction (p=0.028) on rosuvastatin treatment versus
placebo. The absolute risk reduction in the event rate per 1000 patient-years was 8.8. Total
mortality was unchanged in this high risk group (p=0.193). In a post-hoc analysis of a high-risk
subgroup of subjects (9302 subjects total) with a baseline SCORE risk ≥5% (extrapolated to
include subjects above 65 yrs) there was a significant reduction in the combined end-point of
cardiovascular death, stroke and myocardial infarction (p=0.0003) on rosuvastatin treatment
versus placebo. The absolute risk reduction in the event rate was 5.1 per 1000 patient-years. Total
mortality was unchanged in this high risk group (p=0.076).

In the JUPITER trial, there were 6.6% of rosuvastatin and 6.2% of placebo subjects who
discontinued use of study medication due to an adverse event. The most common adverse events
that led to treatment discontinuation were: myalgia (0.3% rosuvastatin, 0.2% placebo), abdominal
pain (0.03% rosuvastatin, 0.02% placebo) and rash (0.02% rosuvastatin, 0.03% placebo). The
most common adverse events at a rate greater than or equal to placebo were urinary tract
infection (8.7% rosuvastatin, 8.6% placebo), nasopharyngitis (7.6% rosuvastatin, 7.2% placebo),
back pain (7.6% rosuvastatin, 6.9% placebo) and myalgia (7.6% rosuvastatin, 6.6% placebo).
Paediatric population
In a double-blind, randomized, multi-centre, placebo-controlled, 12-week study (n=176, 97 male
and 79 female) followed by a 40-week (n=173, 96 male and 77 female), open-label, rosuvastatin
dose-titration phase, patients 10 to17 years of age (Tanner stage II-V, females at least 1 year postmenarche)
with heterozygous familial hypercholesterolaemia received rosuvastatin 5, 10 or 20
mg or placebo daily for 12 weeks and then all received rosuvastatin daily for 40 weeks. At study
entry, approximately 30% of the patients were 10 to13 years and approximately 17%, 18%, 40%,
and 25% were Tanner stage II, III, IV, and V, respectively.
LDL-C was reduced 38.3%, 44.6%, and 50.0% by rosuvastatin 5, 10 and 20 mg, respectively,
compared to 0.7% for placebo.
At the end of the 40-week, open-label, titration to goal, dosing up to a maximum of 20 mg once
daily, 70 of 173 patients (40.5%) had achieved the LDL-C goal of less than 2.8 mmol/l.
After 52 weeks of study treatment, no effect on growth, weight, BMI or sexual maturation was
detected (see Section 4.4). This trial (n=176) was not suited for comparison of rare adverse drug
events.
Rosuvastatin was also studied in a 2-year open-label, titration-to-goal study in 198 children with
heterozygous familial hypercholesterolaemia aged 6 to 17 years (88 male and 110 female, Tanner
stage <II-V). The starting dose for all patients was 5 mg rosuvastatin once daily. Patients aged 6
to 9 years (n=64) could titrate to a maximum dose of 10 mg once daily and patients aged 10 to 17
years (n=134) to a maximum dose of 20 mg once daily.
After 24 months of treatment with rosuvastatin, the LS mean percent reduction from the baseline
value in LDL-C was -43% (Baseline: 236 mg/dL, Month 24: 133 mg/dL). For each age group, the
LS mean percent reductions from baseline values in LDL-C were -43% (Baseline: 234 mg/dL,
Month 24: 124 mg/dL), -45% (Baseline: 234 mg/dL, Month 24: 124 mg/dL ), and -35%
(Baseline: 241 mg/dL, Month 24: 153 mg/dL) in the 6 to <10, 10 to <14, and 14 to <18 age
groups, respectively.

Rosuvastatin 5 mg, 10 mg, and 20 mg also achieved statistically significant mean changes from
baseline for the following secondary lipid and lipoprotein variables: HDL-C, TC, non-HDLC,
LDL-C/HDL-C, TC/HDL-C, TG/HDL-C, non-HDL, C/HDL-C, ApoB, ApoB/ApoA-1. These
changes were each in the direction of improved lipid responses and were sustained over 2 years.
No effect on growth, weight, BMI or sexual maturation was detected after 24 months of treatment
(see Section 4.4).
Rosuvastatin was studied in a randomised, double-blind, placebo-controlled, multicenter, crossover
study with 20 mg once daily versus placebo in 14 children and adolescents (aged from 6 to
17 years) with homozygous familial hypercholesterolaemia. The study included an active 4-week
dietary lead-in phase during which patients were treated with rosuvastatin 10 mg, a cross-over
phase that consisted of a 6-week treatment period with rosuvastatin 20 mg preceded or followed
by a 6-week placebo treatment period, and a 12-week maintenance phase during which all
patients were treated with rosuvastatin 20 mg. Patients who entered the study on ezetimibe or
apheresis therapy continued the treatment throughout the entire study.
A statistically significant (p=0.005) reduction in LDL-C (22.3%, 85.4 mg/dL or 2.2 mmol/L) was
observed following 6 weeks of treatment with rosuvastatin 20 mg versus placebo. Statistically
significant reductions in Total-C (20.1%, p=0.003), non-HDL-C (22.9%, p=0.003), and ApoB
(17.1%, p=0.024) were observed. Reductions were also seen in TG, LDL-C/HDL-C, Total-
C/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-1 following 6 weeks of treatment with
rosuvastatin 20 mg versus placebo. The reduction in LDL-C after 6 weeks of treatment with
rosuvastatin 20 mg following 6 weeks of treatment with placebo was maintained over 12 weeks
of continuous therapy. One patient had a further reduction in LDLC (8.0%), Total-C (6.7%) and
non-HDL-C (7.4%) following 6 weeks of treatment with 40 mg after up-titration. During an
extended open-label treatment in 9 of these patients with 20 mg rosuvastatin for up to 90 weeks,
the LDL-C reduction was maintained in the range of -12.1% to -21.3%.
In the 7 evaluable children and adolescent patients (aged from 8 to 17 years) from the force
titration open-label study with homozygous familial hypercholesterolaemia (see above), the
percent reduction in LDL-C (21.0%), Total-C (19.2%), and non-HDL-C (21.0%) from baseline
following 6 weeks of treatment with rosuvastatin 20 mg was consistent with that observed in the
aforementioned study in children and adolescents with homozygous familial
hypercholesterolaemia.
The European Medicines Agency has waived the obligation to submit the results of studies with
rosuvastatin in all subsets of the paediatric population in the treatment of homozygous familial
hypercholesterolaemia, primary combined (mixed) dyslipidaemia and in the (see section 4.2 for
information on paediatric use).

Absorption
Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral
administration. The absolute bioavailability is approximately 20%.
Distribution
Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis
and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L.
Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.
Biotransformation
Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies
using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based
metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to
a lesser extent. The main metabolites identified are the Ndesmethyl and lactone metabolites. The
N-desmethyl metabolite is approximately 50% less active than Rosuvastatin whereas the lactone
form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the
circulating HMG-CoA reductase inhibitor activity.
Elimination
Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of
absorbed and nonabsorbed active substance) and the remaining part is excreted in urine.
Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is
approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric
mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with
other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane
transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.

Linearity
Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in
pharmacokinetic parameters following multiple daily doses.
Special populations
Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of
rosuvastatin in adults. The exposure in in children and adolescents with heterozygous familial
hypercholesterolaemia appears to be similar to or lower than that in adult patients with
dyslipidaemia (see “Paediatric population” below).
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC and Cmax
in Asian subjects (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared with
Caucasians; Asian-Indians show an approximate 1.3-fold elevation in median AUC and Cmax. A
population pharmacokinetic analysis revealed no clinically relevant differences in
pharmacokinetics between Caucasian and Black groups.
Renal insufficiency: In a study in subjects with varying degrees of renal impairment, mild to
moderate renal disease had no influence on plasma concentration of rosuvastatin or the Ndesmethyl
metabolite. Subjects with severe impairment (CrCl <30 ml/min) had a 3-fold increase
in plasma concentration and a 9-fold increase in the N-desmethyl metabolite concentration
compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in subjects
undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.
Hepatic insufficiency: In a study with subjects with varying degrees of hepatic impairment there
was no evidence of increased exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or
below. However, two subjects with Child- Pugh scores of 8 and 9 showed an increase in systemic
exposure of at least 2-fold compared to subjects with lower Child-Pugh scores. There is no
experience in subjects with Child-Pugh scores above 9.
Genetic polymorphisms: Disposition of HMG-CoA reductase inhibitors, including rosuvastatin,
involves OATP1B1 and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1)
and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure.
Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with a
higher rosuvastatin exposure (AUC) compared to the SLCO1B1 c.521TT or ABCG2 c.421CC
genotypes. This specific genotyping is not established in clinical practice, but for patients who are
known to have these types of polymorphisms, a lower daily dose of rosuvastatin is recommended.

Paediatric population
Two pharmacokinetic studies with rosuvastatin (given as tablets) in paediatric patients with
heterozygous familial hypercholesterolaemia 10 to 17 or 6 to17 years of age (total of 214 patients)
demonstrated that exposure in paediatric patients appears comparable to or lower than that in adult
patients. Rosuvastatin exposure was predictable with respect to dose and time over a 2-year
period.

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.

Tablet Core
Lactose monohydrate
Calcium Hydrogen Phosphate Anhydrous
Microcrystalline cellulose
Crospovidone (type B)
Magnesium stearate
Film-coating
Hypromellose (15cP) (E464)
Lactose monohydrate
Titanium dioxide (E171)
Allura red AC aluminium lake (E129)
Sunset Yellow FCF (E110)
Indigo carmine aluminium lake (E132)
Triacetin.

Not applicable.

24 months

Store below 30°C.

Rosgan tablets are supplied in blister pack of 30’s (10’s Blister x 3).

No special requirements.