Indications:
Treatment of hypercholesterolaemia
Adults, adolescents and children patients 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.
Adults, adolescents and children patients aged 6 years or older with 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 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.
Administration, dosage:
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.
Dosage:
Treatment of hypercholesterolaemia: The recommended start dose is 5 mg or 10 mg orally once daily in both statin- naïve patients and for patients switched from another HMG-CoA reductase inhibitor to rosuvastatin. The choice of start dose should take into account the individual patient’s cholesterol level, 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 30 mg or 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. Specialist supervision is recommended when the 30 mg or 40 mg dose is initiated.
Prevention of cardiovascular events: In the cardiovascular events risk reduction study, the dose used was 20 mg daily.
Children and adolescents: Use for children should only be carried out by specialists.
Heterozygous familial hypercholesterolaemia in pediatric patients (6 to 17 years of age):
The usual start dose is 5 mg daily.
– In children 6 to 9 years of age: The usual dose range is 5 – 10 mg once daily. Safety and efficacy of doses greater than 10 mg have not been studied.
– In children 10 to 17 years of age: The usual dose range is 5 – 20 mg once daily. Safety and efficacy of doses greater than 20 mg have not been studied.
Homozygous familial hypercholesterolaemia in pediatric patients (6 to 17 years of age):
The recommended maximum dose is 20 mg once daily.
A start dose of 5 – 10 mg once daily depending on age, weight and prior statin use is advised. Titration to the maximum dose should be conducted according to the individual response and tolerability in paediatric patients. Children and adolescent patients should be placed on standard cholesterol-lowering diet and continued during rosuvastatin treatment.
Experience with doses higher than 20 mg is limited.
The 30 mg and 40 mg tablets are not suitable for use in children and adolescents.
Children younger than 6 years:
The safety and efficacy of use in children younger than 6 years have not been studied. Therefore, rosuvastatin is not recommended in these patients.
The elderly: A start dose of 5 mg is recommended in patients > 70 years. No dose adjustment is necessary in these patients.
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) but the 30 mg and 40 mg doses are contraindicated. Rosuvastatin is contraindicated in patients with severe renal impairment.
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 patients with Child-Pugh scores above 9. Rosuvastatin is contraindicated in patients with active liver disease.
Race: Increased systemic exposure has been seen in Asian patients, the recommended start dose is 5 mg once daily. The 30 mg and 40 mg doses are contraindicated in these patients.
Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure, for patients who are known to have such specific types of polymorphisms, a lower daily dose of rosuvastatin is recommended.
Patients with pre-disposing factors to myopathy: The recommended start dose is 5 mg and the 30 mg and 40 mg doses are contraindicated.
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). Whenever possible, alternative medications should be considered or temporarily discontinuing rosuvastatin therapy if necessary. 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.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
Patients with hypersensitivity to rosuvastatin or to any of the excipients.
Patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
Patients with severe renal impairment (creatinine clearance < 30 ml/min).
Patients with myopathy.
Patients receiving concomitant ciclosporin.
Pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.
The 30 mg and 40 mg doses are contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis.
Such factors include:
- Moderate renal impairment (creatinine clearance < 60 ml/min).
- 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.
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. 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 30 mg and 40 mg.
Skeletal muscle effects: Effects on skeletal muscle such as 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 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 with rosuvastatin should not be started.
Before treatment: As with other HMG-CoA reductase inhibitors, rosuvastatin 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 or fibrate.
- 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 with statins should not be started.
While on treatment: Patients should be asked to report inexplicable muscle pain, stiffness, weakness or cramps immediately, particularly if associated with malaise, 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 ≤ 5xULN). 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 30 mg and 40 mg doses are contraindicated with concomitant use of a fibrate.
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. Patients 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 co-administration of rosuvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.
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 (such as 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. A dose of 40 mg increased the risk of elevated hepatic transaminases has been reported.
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: 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.
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 cause hyperglycemia in some patients at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. However, this risk 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 – 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 growth evaluation of height, weight, BMI (body mass index) and secondary characteristics of sexual maturation by Tanner staging in children 6 – 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.
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.
This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation:
Pregnancy: Rosuvastatin is contraindicated in pregnancy. 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.
Lactation: Rosuvastatin is contraindicated in lactation. Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.
Effects on ability to drive, use machines:
There is no evidence of an effect of Agitrin on the ability to drive and use machines. However, when driving or operating machinery, it should be taken into account that dizziness may occur during treatment.
Interactions, incompatibilities of medicine:
Interaction:
Effect of co-administered medicinal products on rosuvastatin:
Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OA TP1B1 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.
– Ciclosporin: During concomitant treatment with 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. Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin.
– Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure. For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir and 100 mg ritonavir) in healthy volunteers was associated with an approximately 3-fold and 7-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.
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 pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and niacin (nicotinic acid) of lipid lowering doses (> or equal to 1 g/day) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 30 mg and 40 mg doses are contraindicated with concomitant use of a fibrate. 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. A pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out.
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 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 (when rosuvastatin taken without interacting medicinal products), e.g. 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).
| Table 1: Effect of co-administered medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) from published clinical trials | ||
| Interacting drug dose regimen | Rosuvastatin dose regimen | Change in rosuvastatin
AUC* |
| Ciclosporin 75 mg BID to 200 mg BID, 6 months | 10 mg, OD, 10 days | 7.1-fold ↑ |
| Regorafenib 160 mg, OD, 14 days | 5 mg, single dose | 3.8-fold ↑ |
| Atazanavir 300 mg/ritonavir 100 mg, OD, 8 days | 10 mg, single dose | 3.1-fold ↑ |
| Velpatasvir 100 mg, OD | 10 mg, single dose | 2.7-fold ↑ |
| Ombitasvir 25 mg/paritaprevir 150 mg/ ritonavir 100 mg, OD /dasabuvir 400 mg, BID, 14 days | 5 mg, single dose | 2.6-fold ↑ |
| Grazoprevir 200 mg/elbasvir 50 mg, OD, 11 days | 10 mg, single dose | 2.3-fold ↑ |
| Glecaprevir 400 mg/pibrentasvir 120 mg, OD, 7 days | 5 mg, OD, 7 days | 2.2-fold ↑ |
| Lopinavir 400 mg/ritonavir 100 mg, BID, 17 days | 20 mg, OD, 7 days | 2.1-fold ↑ |
| Clopidogrel 300 mg loading, followed by 75 mg at 24 hours | 20 mg, single dose | 2-fold ↑ |
| Gemfibrozil 600 mg, BID, 7 days | 80 mg, single dose | 1.9-fold ↑ |
| Eltrombopag 75 mg, OD, 5 days | 10 mg, single dose | 1.6-fold ↑ |
| Darunavir 600 mg/ritonavir 100 mg, BID, 7 days | 10 mg, OD, 7 days | 1.5-fold ↑ |
| Tipranavir 500 mg/ritonavir 200 mg, BID, 11 days | 10 mg, single dose | 1.4-fold ↑ |
| Dronedaron 400 mg, BID | Not available | 1.4-fold ↑ |
| Itraconazole 200 mg, OD, 5 days | 10 mg, single dose | ** 1.4-fold ↑ |
| Ezetimibe 10 mg OD, 14 days | 10 mg, OD, 14 days | ** 1.2-fold ↑ |
| Fosamprenavir 700 mg/ritonavir 100 mg BID, 8 days | 10 mg, single dose | ↔ |
| Aleglitazar 0.3 mg, 7 days | 40 mg, 7 days | ↔ |
| Silymarin 140 mg TID, 5 days | 10 mg, single days | ↔ |
| Fenofibrate 67 mg TID, 7 days | 10 mg, 7 days | ↔ |
| Rifampin 450 mg, OD, 7 days | 20 mg, single dose | ↔ |
| Ketoconazole 200 mg, BID, 7 days | 80 mg, single dose | ↔ |
| Fluconazole 200 mg, OD, 11 days | 80 mg, single dose | ↔ |
| Erythromycin 500 mg, QID, 7 days | 80 mg, single dose | 20% ↓ |
| Baicalin 50 mg, TID, 14 days | 20 mg, single dose | 47% ↓ |
| * Data given as x-fold change represent a simple ratio between co-administration and rosuvastatin alone. Data given as % change represent % difference relative to rosuvastatin alone.
Increase is indicated as “↑”, no change as “↔”, decrease as “↓”. ** Several interaction studies have been performed at different rosuvastatin dosages, the table shows the most significant ratio OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily |
||
Effect of rosuvastatin on co-administered medicinal products:
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 (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, 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. 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.
Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Adverse effects reported with rosuvastatin are usually mild and transient.
Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); can not be estimated from the available data “Not known”.
The frequencies of undesirable effects are as follows:
Table 2. Adverse reactions based on data from clinical studies and post-marketing experience
| Organ | Common | Uncommon | Rare | Very rare | Not known |
| Blood and
lymphatic system disorders |
Thrombocytopenia | ||||
| Immune system
disorders |
Hypersensitivity
reactions including angioedema |
||||
| Endocrine
disorders |
Diabetes
mellitus 1 |
||||
| Psychiatric
disorders |
Depression | ||||
| Nervous system
disorders |
Headache
Dizziness |
Polyneuropathy
Memory loss |
Peripheral
neuropathy Sleep disturbances (including insomnia and nightmares), cognitive impairment |
||
| Respiratory,
thoracic and mediastinal disorders |
Cough
Dyspnoea |
||||
| Gastro-intestinal
disorders |
Constipation
Nausea Abdominal pain |
Pancreatitis | Diarrhoea | ||
| Hepatobiliary
disorders |
Increased hepatic
transaminases |
Jaundice
Hepatitis |
|||
| Skin and
subcutaneous tissue disorders |
Pruritus
Rash Urticaria |
Stevens-Johnson
syndrome |
|||
| Musculo-skeletal
and connective tissue disorders |
Myalgia | Myopathy (including
myositis) Rhabdomyolysis Lupus-like syndrome Muscle rupture |
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.
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 mg and 20 mg, and in approximately 3% of patients treated with 40 mg of rosuvastatin. 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 and is not a precursor of acute or progressive renal disease.
Haematuria has been observed in patients treated with low-dose rosuvastatin.
Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy and rarely, rhabdomyolysis has 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.
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 side effects have been reported with some statins:
Sexual dysfunction.
Exceptional cases of interstitial lung disease, especially with long term therapy.
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. In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.
Inform the doctor about the undesirable effects encountered when using the drug.
Overdose and management:
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.
Pharmacodynamics:
Pharmacodynamic:
Pharmacotherapeutic group: Cardiovascular system – Cholesterol and triglyceride lowering drugs – Rosuvastatin (Oral)
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, non-HDL-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 non-HDL-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 before treatment) | ||||||||
| Dose | N | LDL-C | Total-C | HDL-C | TG | Non HDL-C | ApoB | Apo A-1 |
| 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 |
Rosuvastatin làm giảm LDL-choles 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 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 (including 8 paediatric 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.
Pharmacokinetics:
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 vitrometabolism 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 OA TP-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 were no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The exposure in children and adolescents with heterozygous familial hypercholesterolemia appears to be similar to or lower than that in adult patients with dyslipidaemia.
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.
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.
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.
Preclinical safety data:
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. 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.
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