Rosuvastatin 10 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Rosuvastatin 10 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 10 mg of Rosuvastatin (as rosuvastatin calcium).
Excipient with known effect: Each 10 mg tablet contains 45.878 mg lactose monohydrate, 0.015 mg allura red AC and 0.013 mg Sunset yellow FCF.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Pink coloured, round shaped [diameter 5.8 mm], biconvex film-coated tablets, debossed with ‘J’ on one side and ‘54’ on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of hypercholesterolaemia
Adults, adolescents and children aged 6 years or older with primary hypercholesterolaemia (type Ila including heterozygous familial hypercholesterolaemia) or mixed dyslipidaemia (type Ilb) 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.
4.2 Posology and method of administration
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 naive 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.
Paediatric population
Paediatric 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 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.
Experience in children with homozygous familial hypercholesterolaemia is limited to a small number of children aged between 8 and 17 years.
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 of <60 ml/min).
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 4.4 and Section 5.2). The recommended start dose is 5 mg for patients of Asian ancestry.
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).
4.3 Contraindications
Rosuvastatin is contraindicated:
- in patients with hypersensitivity to rosuvastatin 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)
4.4 Special warnings and precautions for use
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 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 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.
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).
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). The patient 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 coadministration of rosuvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.
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 postmarketing 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 and Section 5.2)
Protease inhibitors
The concomitant use with protease inhibitors is not recommended (see Section 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>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 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Azo colouring agents: This product also contains azo colouring agents, allura red AC (E129) and sunset yellow FCF (E110) which may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
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 Cmax for 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 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 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 Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
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
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.
4.6 Fertility, pregnancy and lactation
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).
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
The adverse events seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse events.
The frequencies of adverse events are ranked according to the following: Common (>1/100, <1/10); Uncommon (>1/1,000, <1/100); Rare (>1/10,000, <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Immune system disorders
Rare: hypersensitivity reactions including angioedema
Endocrine disorders
Common: diabetes mellitus1
Nervous system disorders
Common: headache, dizziness
Gastrointestinal disorders
Common: constipation, nausea, abdominal pain
Rare: pancreatitis
Skin and subcutaneous tissue disorders Uncommon: pruritus, rash and urticaria
Musculoskeletal, connective tissue and bone disorders Common: myalgia
Rare: myopathy (including myositis) and rhabdomyolysis
General disorders Common: asthenia
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 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.
Post marketing experience: In addition to the above, the following adverse events have been reported during post marketing experience for rosuvastatin:
Nervous system disorders:
Very rare: polyneuropathy, memory loss.
Respiratory, thoracic and mediastinal disorders:
Not known: cough, dyspnoea.
Gastrointestinal disorders:
Not known: diarrhoea.
Hepatobiliary disorders:
Very rare: jaundice, hepatitis; rare: increased transaminases.
Skin and subcutaneous tissue disorders:
Not known: Stevens-Johnson syndrome.
Musculoskeletal disorders:
Very rare: arthralgia.
Renal disorders:
Very rare: haematuria.
Reproductive system and breast disorders Very rare: gynaecomastia
General disorders and administration site conditions:
Not known: oedema.
The following adverse events have been reported with some statins: Depression.
Sleep disturbances, including insomnia and nightmares.
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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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 1). Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.
Table 1 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
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, 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 (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 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 10-17 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,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).
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 (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
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 in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolaemia 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 N-desmethyl 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: Two pharmacokinetic studies with rosuvastatin (given as tablets) in paediatric patients with heterozygous familial hypercholesterolaemia 10 17 or 6-17 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.
5.3 Preclinical safety data
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
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
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.
6.5 Nature and contents of container
Rosuvastatin tablets are available in Polyamide /Al/PVC/ Aluminium blisters and HDPE bottle with polypropylene closure.
Pack sizes:
Blister: 10, 15, 20, 28, 30, 50, 56, 60, 90, 98 and 100
HDPE: 30, 100, 250 and 500
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 16363/0507
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
08/08/2016
10 DATE OF REVISION OF THE TEXT
08/08/2016
Frequency will depend on the presence or absence of risk factors (fasting blood glucose > 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).