Novistoric Film Coated Tablets
Usage and indications:
Treatment of hypercholesterolaemia
Adults, adolescents and children aged 10 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, as an adjunct to correction of other risk factors.
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 individualised according to the goal of therapy and patient response, using current consensus guidelines.
May be given at any time of day, with or without food.
Treatment of hypercholesterolaemia
The recommended start dose is 5 mg or 10 mg orally once daily in both statin naive and 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. In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses, 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 20mg, and in whom routine follow-up will be performed. Specialist supervision is recommended when the 40mg dose is initiated.
Prevention of cardiovascular events
In the cardiovascular events risk reduction study, the dose used was 20mg daily.
Paediatric use should only be carried out by specialists.
Experience in children younger than 10 years is limited to a small number of children (aged between 8 and 10 years) with homozygous familial hypercholesterolaemia.
Therefore, Novistoric 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 40 mg dose is contraindicated in patients with moderate renal impairment. The use of Novistoric 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 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. In these patients an assessment of renal function should be considered. There is no experience in subjects with Child-Pugh scores above 9. Rosuvastatin is contraindicated in patients with active liver disease.
Increased systemic exposure has been seen in Asian subjects. The recommended start dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.
Dosage in patients with pre-disposing factors to myopathy
The recommended start dose is 5 mg in patients with predisposing factors to myopathy.
The 40mg dose is contraindicated in some of these patients.
Immune system disorders:
Rare: Hypersensitivity reactions including angioedema.
Common: Diabetes mellitus.
Nervous system disorders:
Common: Headache, dizziness.
Common: Constipation, nausea, abdominal pain.
Skin and subcutaneous tissue disorders:
Uncommon: Pruritus, rash and urticaria.
Musculoskeletal, connective tissue and bone disorders:
Rare: Myopathy (including myositis) and rhabdomyolysis.
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
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.
Not known: Diarrhoea.
Very rare: Jaundice, hepatitis; rare: increased transaminases.
Skin and subcutaneous tissue disorders:
Not known: Stevens-Johnson syndrome.
Very rare: Arthralgia.
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:
Sleep disturbances, including insomnia and nightmares.
Exceptional cases of interstitial lung disease, especially with long term therapy.
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 40mg dose.
Warnings and precautions:
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 40mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease. The reporting rate for serious renal events in post-marketing use is higher at the 40mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40mg.
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 > 20mg. 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.
As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with Rosuvastatin in post-marketing use is higher at the 40mg 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.
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
• Personal or family history of hereditary muscular disorders
• Previous history of muscular toxicity with another HMG-CoA reductase inhibitor
• Alcohol abuse
• Age >70 years
• Situations where an increase in plasma levels may occur
• 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.
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).
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 40mg 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.
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: 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.
Paediatric population: The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 10 to 17 years of age taking rosuvastatin is limited to a one-year period.
After 52 weeks of study treatment, no effect on growth, weight, BMI or sexual maturation was detected.
Pack: Carton box containing (AL-AL) blisters each of 7 tablets.