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.
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.
 

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).
Pediatric population
Pediatric use should only be carried out by specialists.
Children and adolescents 6 to 17 years of age (Tanner Stage <II-V)
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 pediatric
patients, as recommended by the pediatric 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.
Experience in children with homozygous familial hypercholesterolaemia is limited to a small
number of children aged between 8 and 17 years.
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 of <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 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 ChildPugh 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, Section 4.4 and
Section 5.2). The recommended start dose is 5 mg for patients of Asian ancestry. The 40 mg
dose is contraindicated in these patients.
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).
The 40 mg dose is contraindicated in some of these patients (see Section 4.3).
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 co-administration 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 rosuvastatin or to any of the excipients. - 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)

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Rozavi should be discontined in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

Renal Effects
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in
patients treated with higher doses of Rosuvastatin 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 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 Sections 4.2, 4.5 and 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 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
Section 4.8).
Combination with rosuvastatin and fusidic acid is not recommended. There have been reports
of rhabdomyolysis (including some fatalities) in patients receiving this combination (see Section
4.5).
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, Section 4.3 and Section 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).
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 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.
Pediatric population
The evaluation of linear growth (height), weight, BMI (body mass index), and secondary
characteristics of sexual maturation by Tanner staging in pediatric 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).

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 Film-coated tablets 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 Film-coated tablets, treatment with Rosuvastatin Filmcoated tablets must not be restarted in this patient at any time.

Effect of co-administered 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 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 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 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. In addition, rosuvastatin is
a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome
P450-mediated metabolism are not expected. 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 ritonavir/atazanavir (3.1-fold
increase).

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 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:
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. As
with other statins, muscle related events, including rhabdomyolysis, have been reported in
post-marketing experience with rosuvastatin and fusidic acid given concurrently.
Therefore, the combination rosuvastatin and fusidic acid is not recommended. If possible,
temporary suspension of rosuvastatin treatment is recommended. If unavoidable, patients
should be closely monitored.
Pediatric population: Interaction studies have only been performed in adults. The extent of
interactions in the pediatric population is not known.
 

Pregnancy Category: X

Rozavi Film-coated tablets are 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 fetus, the potential risk from inhibition of HMGCoA reductase outweighs the advantage of treatment during pregnancy.

 If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Breast-feeding

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.

Fertility

No data is available on the effects of rosuvastatin on human fertility. Animal studies provide limited evidence of reproductive toxicity.

 

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.
 

Summary of safety:

 

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

 

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 mellitus1
Psychiatric disorders					Depression
Nervous system	Headache			Polyneuropathy	Peripheral
disorders	Dizziness			Memory loss	neuropathy
					Sleep
					disturbances
					(including
					insomnia and
					nightmares)
					Myasthenia gravis

 

Respiratory, thoracic and mediastinal disorders					Cough Dyspnea
Eyes Disorders					Ocular myasthenia
Gastro-intestinal disorders	Constipation Nausea Abdominal pain		Pancreatitis		Diarrhea
Hepatobiliary disorders			Increased hepatic transaminases	Jaundice Hepatitis
Skin and subcutaneous tissue disorders		Pruritis Rash Urticaria			Stevens- Johnson syndrome
Musculo-skeletal and connective tissue disorders	Myalgia		Myopathy (including myositis) Rhabdomyolysis	Arthralgia	Tendon disorders, sometimes complicated by rupture Immune- mediated necrotising myopathy
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.

 

Description of selected AE:

 

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 post-marketing 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 in patients 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).

 

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.

 

Pediatric 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.

 

Other special population:

 

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

-To report any side effect (s)

·        

Saudi Arabia :      

-  SFDA Call Center: 19999 -  E-mail: npc.drug@sfda.gov.sa -Website: https://ade.sfda.gov.sa

United Arab Emirates

 

 

·         Other GCC states /other countries

 

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, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see
Table 3). Rosuvastatin also lowers the LDL-C/HDL-C, 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)

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%. 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
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, Ruso 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 (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 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 highrisk 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).
Pediatric 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 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 10-13 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). 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, 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-HDL-C, LDLC/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).
The European Medicines Agency has waived the obligation to submit the results of studies with
rosuvastatin in all subsets of the pediatric population in the treatment of homozygous familial
hypercholesterolaemia, primary combined (mixed) dyslipidaemia and in the prevention of
cardiovascular events (see Section 4.2 for information on pediatric 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.
Metabolism: 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.
Excretion: 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 in adults. The pharmacokinetics of rosuvastatin in children and adolescents with
heterozygous familial hypercholesterolaemia was similar to that of adult volunteers (see
“Pediatric 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.
Pediatric population: Two pharmacokinetic studies with rosuvastatin (given as tablets) in
pediatric patients with heterozygous familial hypercholesterolaemia 10-17 or 6-17 years of age
(total of 214 patients) demonstrated that exposure in pediatric 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.
 

Crospovidone
Tribasic calcium phosphate
Lactose Fast Flow
Avicel PH 102
Magnesium stearate
Opadry Pink
 

Not applicable.
 

4 years

Store below 30°C.
 

Aluminium / Aluminium foil blister
Packs of 28 film coated tablets.
 

No special requirements.