Treatment of hypercholesterolemia

CREVAST is indicated in adults, adolescents and children aged 10 years or older with primary hypercholesterolemia (type IIa including heterozygous familial hypercholesterolemia) 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. CREVAST is indicated in homozygous familial hypercholesterolemia 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 CREVAST is indicated in 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.

Treatment of hypercholesterolemia

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).  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 hypercholesterolemia at high cardiovascular risk (in particular those with familial hypercholesterolemia), 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 10 to 17 years of age (boys Tanner Stage II and above, and girls who are at least 1 year post-menarche) In children and adolescents with heterozygous familial hypercholesterolemia the usual start dose is 5 mg daily. The usual dose range is 5-20 mg orally once daily. 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. Safety and efficacy of doses greater than 20 mg have not been studied in this population. The 40 mg tablet is not suitable for use in paediatric patients. Children younger than 10 years Experience in children younger than 10 years is limited to a small number of children (aged between 8 and 10 years) with homozygous familial hypercholesterolemia. Therefore, CREVAST is not recommended for use in children younger than 10 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 CREVAST in patients with severe renal impairment is contraindicated for all doses (see section 4.3 and section 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. CREVAST is contraindicated in patients with active liver disease (see section 4.3).

Race

Increased systemic exposure has been seen in Asian subjects (see sections4.3, 4.4 and 5.2). The recommended start dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.

Dosage in patients with predisposing factors to myopathy

The recommended start dose is 5 mg in patients with predisposing factors to myopathy (see section 4.4). The 40 mg dose is contraindicated in some of these patients (see section 4.3). Method of administration CREVAST may be given at any time of day, with or without food.

CREVAST 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 x 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 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 postmarketing 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 HMG-CoA 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 post-marketing 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 pre-disposing 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 section 5.2)

• 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 reintroducing 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. 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 section 4.8).

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, rosuvastatinshould 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 postmarketing use is higher at the 40 mg dose.

In patients with secondary caused by hypothyroidism or nephrotic syndrome, the underlyindisease should be treated prior to initiating therapy with rosuvastatin.

Race

Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see sections 4.2, 4.3 and 5.2).

Protease inhibitors

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

Lactose intolerance

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

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, nonproductive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected that 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 of hyperglycaemia (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/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.

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 10 to 17 years of age taking rosuvastatin is limited to a one-year period. After 52 weeks of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see section 5.1). The clinical trial experience in children and adolescent patients is limited and the long-term effects of rosuvastatin (>1 year) on puberty are unknown. 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 (seesection 4.8).

Ciclosporin: During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin

AUC values were on average 7 times higher than those observed in healthy volunteers (see

section 4.3).

Concomitant administration did not affect plasma concentrations of ciclosporin.

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.

Ezetimibe: Concomitant use of rosuvastatin and ezetimibe resulted in no change to AUC or Cmaxfor either drug. However, a pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out (see section 4.4).

Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax 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 1g/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 section 4.3 and section 4.4). These patients should also start with the 5 mg dose.

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).

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(0-t) and a 30% decrease in Cmaxof rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of rosuvastatin and an oral contraceptive resulted in an increase in ethinyl estradiol 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 and 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: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.

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. 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). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.

Rosuvastatin is pregnancy category X.

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 1.Adverse reactions based on data from clinical studies and post-marketing

experience

System organ class	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders			Thrombocytopenia
Immune system disorders			Hypersensitivity reactions including angioedema
Endocrine disorders	Diabetes mellitus
Psychiatric disorders					Depression
Nervous system disorders	Headache Dizziness			Polyneuropathy Memory loss	Sleep disturbances (including insomnia and nightmares)
Respiratory, thoracic and mediastinal disorders					Cough Dyspnoea
Gastrointestinal disorders	Constipation Nausea Abdominal pain		Pancreatitis		Diarrhoea
Hepatobiliary disorders			Increased hepatic transaminases	Jaundice Hepatitis
Skin and subcutaneous tissue disorders		Pruritis Rash Urticaria			Stevens- Johnson syndrome
Musculoskeletal and connective tissue disorders	Myalgia		Myopathy (including myositis) Rhabdomyolysis	Arthralgia
Renal and urinary disorders				Haematuria
Reproductive system and breast disorders				Gynaecomastia
General disorders and administration site conditions	Asthenia				Oedema
1 Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5,6 mmol/L, BMI >30 kg/m2, raised triglycerides, history of hypertension)

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends

to be dose dependent.

Renal Effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been

observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++

or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and

in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or

trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or

disappears spontaneously on continued therapy. Review of data from clinical trials and postmarketing

experience to date has not identified a causal association between proteinuria and

acute or progressive renal disease.

Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show

that the occurrence is low.

Skeletal muscle effects: Effects on skeletal muscle e.g.myalgia, myopathy (including

myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported

in rosuvastatin -treated patients with all doses and in particular with doses > 20 mg.

A dose-related increase in CK levels has been observed inpatients taking rosuvastatin; the

majority of cases were mild, asymptomatic and transient. If CK levels are elevated

(>5xULN), treatment should be discontinued (see section 4.4).

Liver Effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in

transaminases has been observed in a small number of patients taking rosuvastatin; the

majority of cases were mild, asymptomatic and transient.

The following adverse events have been reported with some statins:

- Sexual dysfunction,

- Exceptional cases of interstitial lung disease, especially with long term therapy (see

section 4.4),

- Tendon disorders, sometimes complicated by rupture.

The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events

(consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

Paediatric population: Creatine kinase elevations >10xULN and muscle symptoms

following exercise or increased physical activity were observed more frequently in a 52-week

clinical trial of children and adolescents compared to adults (see section 4.4). In other

respects, the safety profile of rosuvastatin was similar in children and adolescents compared

to adults.

To report any side effect(s):  The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

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: Lipid modifying agent, plain; 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, nonHDL-C, VLDL-C, VLDL-TG and

increases ApoA-I (see Table 2). 

Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.

Table 2 Dose response in patients with primary (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 , with and without hypertriglyceridaemia, regardless of

race, sex, or age and in special populations such as diabetics, or patients with familial .

From pooled phase III data, rosuvastatin has been shown to be effective at treating the

majority of patients with type IIa and IIb (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 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%. 33% of patients reached EAS guidelines for LDL-C

levels (<3 mmol/l).

In a force-titration, open label trial, 42 patients with homozygous familial 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 40 mg. The 40 mg dose should only be prescribed in patients with severe 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 years) 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 10-17 years of age (Tanner stage II-V, females at

least 1 year post-menarche) with heterozygous familial 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 10-13 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). The clinical trial experience in children and adolescent patients

is limited and the long-term effects of rosuvastatin (>1 year) on puberty are unknown. This

trial (n=176) was not suited for comparison of rare adverse drug events.

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 N-desmethyl 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 non-absorbed 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. The pharmacokinetics of rosuvastatin in children and adolescents with  heterozygous familial was similar to that of adult volunteers (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.

Paediatric population: The pharmacokinetic parameters in paediatric patients with

heterozygous familial aged 10 to 17 years have not been fully characterised. A small

pharmacokinetic study with rosuvastatin (given as tablets) in 18 paediatric patients

demonstrated that exposure in paediatric patients appears comparable to exposure in adult

patients. In addition, the results indicate that a large deviation from dose proportionality is not

expected.

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 repeateddose

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

Microcrystalline cellulose

Crospovidone type A

Calcium hydrogen phosphate dihydrate 

Lactose monohydrate

Magnesium stearate

Tablet coat

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Macrogol 3350

Triacetin

Carmine (E120) (10 mg, 20 mg and 40 mg tablets)

Not applicable.

24 months

This medicinal product does not require any special storage conditions.

Do not store above 30º C.

Blister PVC/PVDC-Al and Al-Al and OPA/AL/PVC Blister : 30 tablets

No special requirements.

Any unused product or waste should be disposed of in accordance with local requirements.