Cresulip® 10: Each film coated tablet contains Rosuvastatin Calcium equivalent to Rosuvastatin 10mg.
Microcrystalline cellulose, lactose, calcium carbonate, povidone, polysorbate, croscarmellose sodium, magnesium stearate, hydroxy propyl methyl cellulose, polyethylene glycol, talc, titanium dioxide.
Cresulip® 20: Each film coated tablet contains Rosuvastatin Calcium equivalent to Rosuvastatin 20mg.
Microcrystalline cellulose, lactose, calcium carbonate, povidone, polysorbate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, polyethylene glycol, sodium bicarbonate, methacrylic acid and ethyl acrylate copolymer, talc, titanium dioxide, red iron oxide, yellow iron oxide.
- Treatment of hypercholesterolemia:
Adults, adolescents and children aged 10 years or older with primary hypercholesterolemia (type IIa including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (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 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:
Prevention of major cardiovascular events in patients who are estimated to have a high risk for a first cardiovascular event, as an adjunct to correction of other risk factors.
- Skeletal muscle effects: effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Rosuvastatin-treated patients with all doses. 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 and caution should be exercised with their combined use.
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.
- 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. In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Rosuvastatin.
- Protease inhibitors: the concomitant use with protease inhibitors is not recommended.
- 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. 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: in patients with fasting glucose 5.6 to 6.9 mmol/L, treatment with Rosuvastatin has been associated with an increased risk of diabetes mellitus.
- 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 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. The clinical trial experience in children and adolescent patients is limited and the long-term effects of Rosuvastatin (>1 year) on puberty are unknown.
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. 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
- Ciclosporin: during concomitant treatment with Rosuvastatin and Ciclosporin, Rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers. 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.
- Gemfibrozil and other lipid-lowering products: concomitant use of Rosuvastatin and Gemfibrozil resulted in a 2-fold increase in Rosuvastatin Cmax and AUC. Based on data from specific interaction studies, no pharmacokinetic relevant interaction with Fenofibrate is expected, however a or equal to 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. 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.
- 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.
- 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.
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 mellitus.
- 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. 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. Hematuria 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. 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.
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: diarrhea.
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: hematuria.
General disorders and administration site conditions: not known: edema.
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. In other respects, the safety profile of Rosuvastatin was similar in children and adolescents compared to adults.
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.
DOSAGE AND ADMINISTRATION
Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualized according to the goal of therapy and patient response, using current consensus guidelines. Cresulip® may be given at any time of day, with or without food.
- Treatment of hypercholesterolemia:
The recommended start dose is 5 mg 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. A dose adjustment to the next dose level can be made after 4 weeks, if necessary.
- Prevention of cardiovascular events:
In the cardiovascular events risk reduction study, the dose used was 20 mg daily.
- Pediatric population:
Pediatric 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 pediatric patients, as recommended by the pediatric treatment recommendations. Children and adolescents should be placed on standard cholesterol-lowering diet before Cresulip® treatment initiation; this diet should be continued during Cresulip® treatment. Safety and efficacy of doses greater than 20 mg have not been studied in this population.
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, Cresulip® 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. 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 use of Cresulip® in patients with severe renal impairment is contraindicated for all doses.
- Dosage in patients with hepatic impairment:
There was no increase in systemic exposure to Cresulip® 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. In these patients an assessment of renal function should be considered. There is no experience in subjects with Child-Pugh scores above 9. Cresulip® is contraindicated in patients with active liver disease.
- Dosage in patients with pre-disposing factors to myopathy:
The recommended start dose is 5 mg in patients with predisposing factors to myopathy.
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. Hemodialysis is unlikely to be of benefit.
Store below 30°C.
Keep in original pack in intact conditions.