Paediatric use should only be carried out by specialists.
Children and adolescents 10 to 17 years of age (boys Tanner Stage II and above, and girls who are at least 1 year post-menarche)
In children and adolescents with heterozygous familial hypercholesterolaemia the usual start dose is 5 mg daily. The usual dose range is 5-20 mg orally once daily. Titration should be conducted according to the individual response and tolerability in paediatric patients, as recommended by the paediatric treatment recommendations (see Section 4.4). Children and adolescents should be placed on standard cholesterol-lowering diet before rosuvastatin treatment initiation; this diet should be continued during rosuvastatin treatment. Safety and efficacy of doses greater than 20 mg have not been studied in this population.
The 40 mg tablet is not suitable for use in paediatric patients.
Children younger than 10 years
Experience in children younger than 10 years is limited to a small number of children (aged between 8 and 10 years) with homozygous familial hypercholesterolaemia. Therefore, Crestor is not recommended for use in children younger than 10 years.
Use in the elderly
A start dose of 5 mg is recommended in patients >70 years (see Section 4.4). No other dose adjustment is necessary in relation to age.
Dosage in patients with renal insufficiency
No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance of <60 ml/min). The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of Crestor in patients with severe renal impairment is contraindicated for all doses (See Section 4.3 and Section 5.2).
Dosage in patients with hepatic impairment
There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9 (see Section 5.2). In these patients an assessment of renal function should be considered (see Section 4.4 ). There is no experience in subjects with Child-Pugh scores above 9. Crestor 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. 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 (see Section 4.4).
The 40 mg dose is contraindicated in some of these patients (see Section 4.3).”
Section 4.4
New text after ‘Lactose intolerance’ paragraph,
”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
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 (see Section 4.8).
Paediatric population
The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 10 to 17 years of age taking rosuvastatin is limited to a one-year period. After 52 weeks of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see Section 5.1). The clinical trial experience in children and adolescent patients is limited and the long-term effects of rosuvastatin (>1 year) on puberty are unknown.
In a clinical trial of children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to observations in clinical trials in adults (see Section 4.8).”
Section 4.8
New text after ’Immune system disorders’ paragraph,
” Endocrine disorders
Common: diabetes mellitus1”
New text after ’General disorders’ paragraph,
” 1 Observed in the JUPITER study (reported overall frequency 2.8% in rosuvastatin and 2.3% in placebo) mostly in patients with fasting glucose 5.6 to 6.9 mmol/L.”
New text after ’Post Marketing Experience’
” 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.
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).
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.”
Section 5.1
Deletion of text and additional text at end of section,
” 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). The clinical trial experience in children and adolescent patients is limited and the long-term effects of rosuvastatin (>1 year) on puberty are unknown. This trial (n=176) was not suited for comparison of rare adverse drug events.”
Section 5.2
Additional text, 6th paragraph, ‘Age and Sex’,
“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: The pharmacokinetic parameters in paediatric patients with heterozygous familial hypercholesterolaemia aged 10 to 17 years have not been fully characterised. A small pharmacokinetic study with rosuvastatin (given as tablets) in 18 paediatric patients demonstrated that exposure in paediatric patients appears comparable to exposure in adult patients. In addition, the results indicate that a large deviation from dose proportionality is not expected.”
Section 10
29th April 2010
