Crestor

Rosuvastatin calcium.

Each 5 mg film-coated tablet contains 5.20 mg of rosuvastatin calcium equivalent to 5 mg of rosuvastatin.
5 mg film-coated tablet: Round, biconvex, 7 mm, yellow coloured, impressed with 'ZD4522' and the tablet strength.
Each 10 mg film-coated tablet contains 10.40 mg of rosuvastatin calcium equivalent to 10 mg of rosuvastatin.
10 mg film-coated tablet: Round, biconvex, 7 mm, pink coloured, impressed with 'ZD4522' and the tablet strength.
Each 20 mg film-coated tablet contains 20.80 mg of rosuvastatin calcium equivalent to 20 mg of rosuvastatin.
20 mg film-coated tablet: Round, biconvex, 9 mm, pink coloured, impressed with 'ZD4522' and the tablet strength.
Each 40 mg film-coated tablet contains 41.60 mg of rosuvastatin calcium equivalent to 40 mg of rosuvastatin.
40 mg film-coated tablet: Oval, biconvex, 11.4 x 6.9 mm, pink coloured, impressed with 'ZD4522' and the tablet strength.

Therapeutic classification: Lipid Modifying Agent (HMG CoA Reductase Inhibitor). ATC code: C10AA07.
Pharmacology: Pharmacodynamics: Mechanism of action: Rosuvastatin is a selective, potent and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated, with apolipoprotein B (ApoB), into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. VLDL particles are TG-rich. Cholesterol-rich low density lipoprotein (LDL) is formed from VLDL and is cleared primarily through the high affinity LDL receptor in the liver.
Rosuvastatin produces its lipid-modifying effects in two ways; it 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.
High density lipoprotein (HDL), which contains ApoA-I is involved, amongst other things, in transport of cholesterol from tissues back to the liver (reverse cholesterol transport).
The involvement of LDL-C in atherogenesis has been well documented. Epidemiological studies have established that high LDL-C, TG, low HDL-C and ApoA-I have been linked to a higher risk of cardiovascular disease. Intervention studies have shown the benefits on mortality and CV event rates of lowering LDL-C and TG or raising HDL-C. More recent data has linked the beneficial effects of HMG-CoA reductase inhibitors to lowering of non-HDL (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ApoA-I ratio.
Clinical efficacy: Rosuvastatin (CRESTOR) 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 Tables 1 and 2).
Rosuvastatin (CRESTOR) also lowers the LDL-C/HDL-C, total C/HDL-C, nonHDL-C/HDL-C and ApoB/ApoA-I ratios.
A therapeutic response to Rosuvastatin (CRESTOR) is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that. (See Tables 1 and 2.)

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The data in Tables 1 and 2 are confirmed by the broader clinical programme of over 5,300 patients given Rosuvastatin (CRESTOR).
In a study of patients with heterozygous familial hypercholesterolaemia, 435 subjects were given Rosuvastatin (CRESTOR) from 20 mg to 80 mg in a force-titration design. All doses of Rosuvastatin (CRESTOR) showed a beneficial effect on lipid parameters and treatment to target goals. Following titration to 40 mg (12 weeks of treatment) LDL-C was reduced by 53%.
In a force-titration open label study, 42 patients with homozygous familial hypercholesterolaemia were evaluated for their response to Rosuvastatin (CRESTOR) 20-40 mg titrated at a 6 week interval. In the overall population, the mean LDL-C reduction was 22%. In the 27 patients with at least a 15% reduction by week 12 (considered to be the responder population), the mean LDL-C reduction was 26% at the 20 mg dose and 30% at the 40 mg dose. Of the 13 patients with an LDL-C of less than 15%, 3 had no response or an increase in LDL-C.
In the METEOR study, the effect of rosuvastatin 40 mg on the progression of atherosclerosis was assessed by B-mode ultrasound of the carotid arteries. In this multi-center, double blind, placebo-controlled clinical trial, 984 subjects at low risk for coronary heart disease (defined as Framingham risk <10% over ten years) and with a mean LDL-C of 154.5 mg/dL but with subclinical atherosclerosis as detected by CIMT (Carotid Intima Media Thickness) were randomized in a 5:2 ratio to treatment with either rosuvastatin 40 mg or placebo for 2 years. Rosuvastatin significantly slowed the progression of carotid atherosclerosis compared to placebo. The difference in the rate of change in the maximum CIMT of all 12 carotid artery sites between rosuvastatin-treated patients and placebo-treated patients was -0.0145 mm/year (95% CI -0.0196, -0.0093; p<0.0001). The change from baseline for the rosuvastatin group was -0.0014 mm/year (95% CI -0.0041, 0.0014), but was not significantly different from zero (p=0.3224). The beneficial effects of rosuvastatin were consistent across all 4 secondary CIMT endpoints. There was significant progression in the placebo group (+0.0131 mm/year; 95% CI 0.0087, 0.0174; p<0.0001). In the rosuvastatin group, 52.1% of patients demonstrated an absence of disease progression (i.e. regressed) compared to 37.7% of patients in the placebo group (p=0.0002). Rosuvastatin 40 mg was well-tolerated and the data were consistent to the established safety profile for rosuvastatin.
In a randomized, multicenter, double-blind crossover study, 32 patients (27 with ε2/ε2 genotype and 4 with apo E mutation [Arg145Cys]) with dysbetalipoproteinaemia (Fredrickson type III) received rosuvastatin 10 or 20 mg daily for 6 weeks. Rosuvastatin reduced non-HDL-C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table as follows. (See Table 3.)

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In the ASTEROID Trial, the effect of very intensive statin therapy using rosuvastatin 40 mg on regression of coronary atherosclerosis was determined by IVUS imaging. In this prospective, open-label, blinded endpoint, multi-centre trial, 507 patients who underwent coronary angiography and with evidence of coronary artery disease (at least 1 obstruction with >20% angiographic luminal diameter narrowing in any coronary vessel) were given rosuvastatin 40 mg. Atheroma burden at baseline and after 24 months of treatment was assessed using IVUS ultrasound. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion.
Analysis of the 349 patients with evaluable IVUS showed that rosuvastatin significantly reduced percent atheroma volume in the entire target vessel by 0.98%, with a median of 0.79% (p<0.001) and 63.6% of patients showed regression while 36.4% showed progression. The mean change in atheroma volume in the most diseased 10-mm subsegment was -6.1 mm³, median change of -5.6 mm³ (p<0.001). This change represents a median reduction of 9.1% in atheroma volume, with 78.1% of patients demonstrated progression and 29.1% showed progression. Change in total atheroma volume showed 6.8% median reduction; with a mean reduction of -14.7 mm³, with a median of 12.5 mm³ (p<0.001). Adverse events were infrequent and similar to other statin trials.
The ASTEROID trial demonstrated that patients given very high intensity statin therapy using rosuvastatin 40 mg had significant regression of atherosclerosis for all three prespecified IVUS measures of disease burden. Patients treated with rosuvastatin 40 mg achieved a 53.2% LDL-C reduction, the lowest ever observed in a statin atherosclerosis progression trial and a 14.7% HDL-C increase, which also exceeded effects reported in previous statin trials. Nonetheless, further studies are needed to determine the effect of the observed changes on clinical outcome.
The Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) was a randomized, double-blind, placebo controlled study in 5011 subjects with chronic symptomatic systolic heart failure treated with rosuvastatin 10 mg (n=2514) or placebo (n=2497) for a mean treatment duration of 2.5 years. When rosuvastatin 10 mg was added to extensive pharmacologic background therapy in these subjects, a non-significant 8% decrease versus placebo in the primary endpoint of cardiovascular death, non-fatal MI or non-fatal stroke was observed (HR 0.92, 95% CI 0.83 to 1.02; p=0.12).
The safety profile of the subjects taking rosuvastatin 10 mg was comparable to that of the subjects taking placebo. From the trial, 1.8% of rosuvastatin-treated subjects versus 1.7% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, pruritus, rash, and dizziness. Adverse reactions reported in ≥2% of patients and at a rate greater than or equal to placebo may be found in Table 4. (See Table 4.)

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Rosuvastatin (CRESTOR) is effective in a wide variety of patient populations with hypercholesterolaemia, with and without hypertriglyceridaemia, regardless of race, sex or age and in special populations such as diabetics or patients with familial hypercholesterolaemia.
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of Rosuvastatin (CRESTOR) (rosuvastatin calcium) on the occurrence of major atherosclerotic cardiovascular (CV) disease events was assessed in 17,802 men (≥50 years) and women (≥60 years) who had no established cardiovascular disease, LDL-C levels <130 mg/dL (3.3 mmol/l) and hs-CRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.3% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%) or a family history of premature CHD (12%). 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.
The primary endpoint was a composite endpoint consisting of the time-to-first occurrence of any of the following CV events: CV death, non-fatal myocardial infarction, non-fatal stroke, unstable angina or an arterial revascularization procedure.
Rosuvastatin significantly reduced the risk of CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% (see figure). The benefit was apparent within the first 6 months of treatment. The risk reduction was consistent across multiple predefined population subsets based on assessments of age, sex, race, smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C or hsCRP levels at the time of entry into the study. There was a statistically significant 48% reduction in the combined endpoint of CV death, stroke and myocardial infarction (HR: 0.52, 95% CI: 0.40-0.68, p<0.001), a 54% reduction in fatal or nonfatal myocardial infarction (HR: 0.46, 95% CI: 0.30-0.70) and a 48% reduction in fatal or nonfatal stroke. Total mortality was reduced 20% in the rosuvastatin group (HR: 0.80, 95% CI: 0.67-0.97, p=0.02). (See figure.)

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The safety profile for subjects taking rosuvastatin 20 mg was generally similar to that of subjects taking placebo. There were 1.6% of rosuvastatin and 1.8% of placebo subjects who withdrew from the trial due to an adverse event, irrespective of treatment causality. The most common adverse reactions that led to treatment discontinuation were: myalgia (0.3% rosuvastatin, 0.2% placebo), abdominal pain (0.03% rosuvastatin, 0.02% placebo) and rash (0.03% rosuvastatin, 0.03% placebo). Adverse reactions reported in ≥2% of patients and at a rate greater than or equal to placebo were myalgia (7.6% rosuvastatin, 6.6% placebo), constipation (3.3% rosuvastatin, 3.0% placebo) and nausea (2.4% rosuvastatin, placebo 2.3%).
In JUPITER, there was a statistically significant increase in the frequency of diabetes mellitus reported by investigators; 2.8% of patients in the rosuvastatin group and 2.3% of patients in the placebo group (HR: 1.27, 95% CI: 1.05-1.53, p=0.015). The difference between treatment groups (rosuvastatin versus placebo) in mean HbA1c change from baseline was approximately 0.1%. A post hoc analysis of this study suggests that the risk of development of diabetes on rosuvastatin therapy is limited to patients already at high risk of developing diabetes. The cardiovascular and mortality benefits of rosuvastatin therapy exceeded the diabetes hazard in the trial population as a whole as well as in participants at increased risk of developing diabetes (see Precautions and Adverse Reactions).
Children and Adolescents with Hypercholesterolaemia: 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, 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.
Rosuvastatin reduced LDL-C (primary end point), total cholesterol and ApoB levels. Results are shown in Table 5 as follows. (See Table 5.)

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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 110 mg/dL (2.8 mmol/L).
After 52 weeks of study treatment, no effect on growth or sexual maturation was detected (see Precautions).
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 treatment, 74 of 197 patients (37.6%) in this study achieved the LDL-C goal of less than 110 mg/dL (2.8 mmol/L). All age groups showed statistically significant reductions in LDL-C from baseline values.
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 or sexual maturation was detected after 24 months of treatment.
Pharmacokinetics: Rosuvastatin (CRESTOR) is administered orally in the active form with peak plasma levels occurring 5 hours after dosing. Exposure increases linearly over the dose range. The half life is 19 hours and does not increase with increasing dose. Absolute bioavailability is 20%. There is minimal accumulation on repeated once daily dosing.
Rosuvastatin undergoes first pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance.
Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin. The parent compound, accounts for greater than 90% of the circulating active HMG CoA reductase inhibitor activity.
Rosuvastatin undergoes limited metabolism (approximately 10%), mainly to the N-desmethyl form, and 90% is eliminated as unchanged drug in the faeces with the remainder being excreted in the urine.
Special populations: Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The exposure in children and adolescents with heterozygous familial hypercholesterolaemia appears to be similar to or lower than that in adult patients with dyslipidemia.
Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC in Asian subjects compared with Caucasians. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups.
Renal insufficiency: In a study in subjects with varying degrees of renal impairment, mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin. However, subjects with severe impairment (CrCl <30 ml/min) had a 3-fold increase in plasma concentration compared to healthy volunteers.
Hepatic insufficiency: In a study in subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rosuvastatin other than in the 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores.
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 an approximate 1.6-fold higher rosuvastatin exposure (AUC) or 2.4-fold higher exposure, respectively, compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

Rosuvastatin (CRESTOR) should be used as an adjunct to diet when the response to diet and exercise is inadequate.
Prevention of Cardiovascular Events: In adult patients with an increased risk of atherosclerotic cardiovascular disease based on the presence of cardiovascular disease risk markers such as an elevated hsCRP level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, Rosuvastatin (CRESTOR) is indicated to reduce total mortality and the risk of major cardiovascular events (cardiovascular death, stroke, MI, unstable angina, or arterial revascularization).
In adult patients with hypercholesterolaemia: Rosuvastatin (CRESTOR) is indicated to: reduce elevated LDL-C, Total Cholesterol, triglycerides and to increase HDL-cholesterol in patients with primary hypercholesterolaemia (heterozygous familial and non familial) and mixed dyslipidaemia (Fredrickson Types IIa and IIb). Rosuvastatin (CRESTOR) also lowers ApoB, nonHDL-C, VLDL-C, VLDL-TG, the LDL-C/HDL-C, total C/HDL-C, nonHDL-C/HDL-C, ApoB/ApoA-I ratios and increases ApoA-I in these populations.
Treat patients with primary dysbetalipoproteinaemia (Fredrickson Type III hyper lipoproteinaemia).
Treat isolated hypertriglyceridaemia (Fredrickson Type IV hyperlipidaemia).
Reduce Total Cholesterol and LDL-C in patients with homozygous familial hypercholesterolaemia (HoFH), as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis) or alone if such treatments are unavailable.
Slow or delay the progression of atherosclerosis.
Children and adolescents 6 to 17 years of age: Rosuvastatin (CRESTOR) is indicated to reduce the Total Cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

The usual dose range is 10-40 mg orally once a day.
The dosage of Rosuvastatin (CRESTOR) should be individualised according to the goal of therapy and patient response. The majority of patients are controlled at the start dose. However, if necessary, dose adjustment can be made at 2 to 4 week intervals. (See Pharmacology: Pharmacodynamics under Actions.)
Rosuvastatin (CRESTOR) may be given at any time of day, with or without food.
Adults: Primary hypercholesterolaemia (including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia, dysbetalipoproteinaemia, isolated hypertriglyceridaemia, treatment of atherosclerosis and prevention of cardiovascular events: The usual start dose is 10 mg once a day. A 5 mg start dose is available for special patient populations if needed.
For patients with severe hypercholesterolaemia (including heterozygous familial hypercholesterolaemia) or those with aggressive lipid targets, a start dose of 20 mg may be considered.
Homozygous familial hypercholesterolaemia: For patients with homozygous familial hypercholesterolaemia a start dose of 20 mg once a day is recommended.
Children and adolescents 6 to 17 years of age: 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.
The dose should be appropriately titrated to achieve treatment goal.
In children and adolescents with homozygous familial hypercholesterolaemia experience is limited to a small number of patients (aged 8 years and above).
Special Populations: Use in the elderly: The usual dose range applies.
Dosage in patients with renal insufficiency: The usual dose range applies in patients with mild to moderate renal impairment.
For patients with severe renal impairment the dose of Rosuvastatin (CRESTOR) should not exceed 10 mg once daily.
(See Pharmacology: Pharmacokinetics under Actions.)
Dosage in patients with hepatic insufficiency: The usual dose range applies in patients with mild to moderate hepatic impairment.
Increased systemic exposure to rosuvastatin has been observed in patients with severe hepatic impairment, therefore the use of doses above Rosuvastatin (CRESTOR) 10 mg should be carefully considered.
(See Pharmacology: Pharmacokinetics under Actions).
Race: A 5 mg starting dose of Rosuvastatin (CRESTOR) should be considered for Asian patients. Increased plasma concentration of rosuvastatin has been seen in Asian subjects (see Precautions and Pharmacology: Pharmacokinetics under Actions). The increased systemic exposure should be taken into consideration when treating Asian patients whose hypercholesterolaemia is not adequately controlled at doses up to 20 mg/day.
Genetic polymorphisms: Genotypes of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown to be associated with an increase in rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT and ABCG2 c.421CC. For patients known to have the c.521CC or c.421AA genotype, a maximum once daily dose of 20 mg of Rosuvastatin (CRESTOR) is recommended (see Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions).
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 (CRESTOR) 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; see Precautions and Interactions). It is recommended that prescribers consult the relevant product information when considering administration of such products together with Rosuvastatin (CRESTOR). Whenever possible, alternative medications should be considered, and if necessary, consider temporarily discontinuing Rosuvastatin (CRESTOR) therapy. In situations where co-administration of these medicinal products with Rosuvastatin (CRESTOR) is unavoidable, the benefit and the risk of concurrent treatment and Rosuvastatin (CRESTOR) dosing adjustments should be carefully considered (see Interactions).

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. Haemodialysis is unlikely to be of benefit.

Rosuvastatin (CRESTOR) is contraindicated in patients with hypersensitivity to any component of this product.
Rosuvastatin (CRESTOR) is contraindicated in patients with active liver disease.

Liver: As with other HMG-CoA reductase inhibitors, Rosuvastatin (CRESTOR) should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.
Skeletal muscle: As with other HMG-CoA reductase inhibitors, effects on skeletal muscle, e.g. myalgia, myopathy and, rarely, rhabdomyolysis, have been reported in patients treated with rosuvastatin. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. Rosuvastatin (CRESTOR) therapy should be discontinued if CK levels are markedly elevated (>10xULN) or if myopathy is diagnosed or suspected. There have been very rare reports of an immune-mediated necrotising myopathy clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase during treatment or following discontinuation of statins, including rosuvastatin. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.
Statins may in rare instances induce or aggravate myasthenia gravis or ocular myasthenia (see Adverse Reactions) including reports of recurrence when the same or a different statin was administered. Rosuvastatin (CRESTOR) should be used with caution in patients with these conditions and should be discontinued if they are induced or aggravated.
In Rosuvastatin (CRESTOR) trials there was no evidence of increased skeletal muscle effects when Rosuvastatin (CRESTOR) was dosed with any 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 ciclosporin, fibric acid derivatives (including gemfibrozil), nicotinic acid, azole antifungals and macrolide antibiotics.
Rosuvastatin (CRESTOR) should be prescribed with caution in patients with pre-disposing factors for myopathy, such as, renal impairment, advanced age and hypothyroidism, or situations where an increase in plasma levels may occur (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Rosuvastatin (CRESTOR) should be temporarily withheld 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).
Diabetes Mellitus: As with other HMG-CoA reductase inhibitors, increases in HbA1c and serum glucose levels have been observed in patients treated with rosuvastatin, and in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus, primarily in patients already at high risk for developing diabetes (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Effects on ability to drive and use machines: Pharmacology testing revealed no evidence of a sedative effect of Rosuvastatin (CRESTOR). From the safety profile, Rosuvastatin (CRESTOR) is not expected to adversely affect the ability to drive or use machines.
Use in Children: Children and adolescents 6 to 17 years of age: The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients taking rosuvastatin is limited to a two year period (see Pharmacology: Pharmacodynamics under Actions).

Pregnancy: Rosuvastatin (CRESTOR) is not recommended for use in pregnant women. Rosuvastatin (CRESTOR) should be discontinued as soon as pregnancy is recognized. However, the ongoing therapeutic need and the individual benefit risk in patients with very high risk of cardiovascular events should be considered.
Published data from use of statins in pregnant women have not identified a drug-associated risk of major congenital malformations. However, due to Rosuvastatin (CRESTOR)'s mechanism of action, there is a potential risk for adverse reactions in the foetus. The data is insufficient to assess the risk of miscarriage.
Lactation: Breastfeeding is not recommended during treatment with Rosuvastatin (CRESTOR). Limited data from published reports indicate that Rosuvastatin (CRESTOR) is present in human milk. Due to Rosuvastatin (CRESTOR)'s mechanism of action, there is a potential risk for adverse reactions in the infant. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

Rosuvastatin (CRESTOR) is generally well tolerated. The adverse events seen with Rosuvastatin (CRESTOR) are generally mild and transient. In controlled clinical trials less than 4% of Rosuvastatin (CRESTOR) treated patients were withdrawn due to adverse events. This withdrawal rate was comparable to that reported in patients receiving placebo. (See Table 6.)

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As with other HMG CoA reductase inhibitors, the incidence of adverse drug reactions tends to increase with increasing dose.
Skeletal Muscle Effects: Rare cases of rhabdomyolysis, which were occasionally associated with impairment of renal function, have been reported with rosuvastatin and with other marketed statins.
Laboratory Effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in liver transaminases and CK has been observed in a small number of patients taking rosuvastatin. Increases in HbA1c have also been observed in patients treated with rosuvastatin (see Precautions and Pharmacology: Pharmacodynamics under Actions). Abnormal urinalysis testing (dipstick-positive proteinuria) has been seen in a small number of patients taking Rosuvastatin (CRESTOR) and other HMG-CoA reductase inhibitors. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears spontaneously on continued therapy, and is not predictive of acute or progressive renal disease.
Other effects: In a long-term controlled clinical trial Rosuvastatin (CRESTOR) was shown to have no harmful effects on the ocular lens.
In Rosuvastatin (CRESTOR) treated patients, there was no impairment of adrenocortical function.
Post Marketing Experience: In addition to those previously mentioned, the following adverse events have been reported during post marketing experience for Rosuvastatin (CRESTOR): Eye disorders: Frequency unknown: ocular myasthenia.
Haematological disorders: Frequency unknown: thrombocytopenia.
Hepatobiliary disorders: Very rare: jaundice, hepatitis; rare: increased hepatic transaminases.
Musculoskeletal disorders: Frequency unknown: immune-mediated necrotising myopathy; very rare: arthralgia.
As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose.
Nervous system disorders: Very rare: memory loss; frequency unknown: peripheral neuropathy, myasthenia gravis.
Psychiatric disorders: Frequency unknown: depression, sleep disorders (including insomnia and nightmares).
Reproductive system and breast disorders: Frequency unknown: gynaecomastia.
Skin and subcutaneous tissue disorders: Frequency unknown: drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption.
Children and adolescents 6 to 17 years of age: The safety profile of Rosuvastatin (CRESTOR) is similar in children or adolescent patients and adults although CK elevations >10 x ULN and muscle symptoms following exercise or increased physical activity, which resolved with continued treatment, were observed more frequently in a clinical trial of children and adolescents. However, the same special warnings and special precautions for use in adults also apply to children and adolescents [see Precautions].

Effect of co-administered medicinal products on rosuvastatin: In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as a substrate, inhibitor or inducer). Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Rosuvastatin (CRESTOR) with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see Table 7, and Dosage & Administration and Precautions).
Interactions requiring rosuvastatin dose adjustments (see also Table 7): When it is necessary to co-administer rosuvastatin (CRESTOR) with other medicinal products known to increase exposure to rosuvastatin, doses of rosuvastatin (CRESTOR) should be adjusted. It is recommended that prescribers consult the relevant product information when considering administration of such products together with rosuvastatin (CRESTOR).
If medicinal product is observed to increase rosuvastatin AUC approximately 2-fold or higher, the starting dose of rosuvastatin (CRESTOR) should not exceed 5 mg once daily. The maximum daily dose of rosuvastatin (CRESTOR) should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin (CRESTOR) taken without interacting medicinal products, for example a 5 mg dose of rosuvastatin (CRESTOR) with ciclosporin (7.1-fold increase in exposure), a 10 mg dose of rosuvastatin (CRESTOR) with ritonavir/atazanavir combination (3.1-fold increase) and a 20 mg dose of rosuvastatin (CRESTOR) with gemfibrozil (1.9-fold increase).
If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the rosuvastatin (CRESTOR) dose above 20 mg.
Protease Inhibitors: Coadministration of rosuvastatin with certain protease inhibitors or combination of protease inhibitors may increase the rosuvastatin exposure, (AUC) up to 7-fold (see Table 7). Dose adjustment is needed depending on the level of effect on rosuvastatin exposure (see Dosage & Administration and Precautions). (See Table 7.)

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The following medicinal product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration: Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200 mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing.
Other interacting medicinal products: Antacid: The simultaneous dosing of Rosuvastatin (CRESTOR) 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 (CRESTOR). The clinical relevance of this interaction has not been studied.
Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. As with other statins, muscle related events, including rhabdomyolysis, have been reported in post-marketing experience with rosuvastatin and fusidic acid given concurrently. Patients should be closely monitored and temporary suspension of rosuvastatin treatment may be appropriate.
Effect of rosuvastatin on co-administered medicinal products: Warfarin: The pharmacokinetics of warfarin are not significantly affected following co-administration with Rosuvastatin (CRESTOR). However, as with other HMG-CoA reductase inhibitors, co-administration of Rosuvastatin (CRESTOR) and warfarin may result in a rise in INR compared to warfarin alone. In patients taking vitamin K antagonists monitoring of INR is recommended both at initiation or cessation of therapy with Rosuvastatin (CRESTOR) or following dose adjustment.
Fenofibrates/fibric acid derivatives: Although no pharmacokinetic interaction between rosuvastatin and fenofibrate was observed; a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate and other fibric acids, including nicotinic acid, may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors (see Precautions).
Ciclosporin: Co-administration of Rosuvastatin (CRESTOR) with ciclosporin resulted in no significant changes in ciclosporin plasma concentration.
Other medications: There were no clinically significant interactions with an oral contraceptive, digoxin, ezetimibe or fenofibrate.
In clinical studies Rosuvastatin (CRESTOR) was co-administered with antihypertensive agents, antidiabetic agents and hormone replacement therapy. These studies did not produce any evidence of clinically significant adverse interactions.

Instructions for use, handling and disposal: No special instructions.
Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C.

Dyslipidaemic Agents

C10AA07 - rosuvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

Rx