Crestor

Rosuvastatin calcium.

10 mg: A pink, film-coated, round, biconvex, intagliated tablet; obverse side "ZD4522 10", reverse side none.
20 mg: A pink, film-coated, round, biconvex, intagliated tablet; obverse side "ZD4522 20", reverse side none.
Each tablet contains 10 mg, 20 mg of rosuvastatin (as rosuvastatin calcium).
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, Microcrystalline cellulose, Calcium phosphate, Crospovidone, Magnesium stearate.
Tablet coat: Lactose monohydrate, Hypromellose, Glycerol triacetate, Titanium dioxide (E171), Red ferric oxide (E172).

Pharmacotherapeutic group: HMG-CoA reductase inhibitors.
Pharmacology: Pharmacodynamics: 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: 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 Table 1). CRESTOR also lowers the LDL-C/HDL-C, total C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios. (See Table 1.)

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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: CRESTOR 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, CRESTOR 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 CRESTOR 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 with homozygous familial hypercholesterolaemia were evaluated for their response to CRESTOR 20-40 mg. In the overall population, the mean LDL-C reduction was 22%.
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 clinical studies with a limited number of patients, CRESTOR 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 (see Precautions).
Rosuvastatin has not been proven to prevent the associated complications of lipid abnormalities, such as coronary heart disease as mortality and morbidity studies with CRESTOR have not yet been completed.
In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of 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=8,901) or rosuvastatin 20 mg once daily (n=8,901) 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 endpoint), total cholesterol and ApoB levels. Results are shown in Table 2 as follows. (See Table 2.)

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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: 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 vitro metabolism 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 OATP-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 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 hypercholesterolemia appears to be similar to or lower than that in adult patients with dyslipidemia.
Race: Pharmacokinetic studies showed an approximate 2-fold elevation in median AUC and C_max 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 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 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 hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity potential. In a rat pre- and postnatal study, reproductive toxicity was evident from reduced litter sizes, litter weight and pup survival. These effects were observed at maternotoxic doses at systemic exposures several times above the therapeutic exposure level.

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 high sensitivity C-reactive protein (hsCRP) level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, CRESTOR is indicated to reduce total mortality and the risk of major cardiovascular events (cardiovascular death, stroke, myocardial infarction, unstable angina, or arterial revascularization).
In adult patients with hypercholesterolaemia: 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.
Slow or delay the progression of atherosclerosis.
Children and adolescents 6 to 17 years of age: CRESTOR is indicated to reduce the Total Cholesterol, LDL-C and Apo B in patients with heterozygous familial hypercholesterolaemia (HeFH).

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.
The recommended start dose is 5 or 10 mg once daily in both statin naïve patients or patients switched from another HMG CoA reductase inhibitor. The choice of starting dose should take into account the individual patients cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. A dose adjustment to 20 mg can be made after 2 to 4 weeks, if necessary (see Pharmacology: Pharmacodynamics under Actions). A doubling of the dose to 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 (see Precautions).
CRESTOR may be given at any time of day, with or without food.
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).
Use in the elderly: No dose adjustment is necessary.
Dosage in patients with renal insufficiency: No dose adjustment is necessary in patients with mild to moderate renal impairment. The use of CRESTOR in patients with severe renal impairment is contraindicated (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
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 Pharmacology: Pharmacokinetics under Actions). In these patients an assessment of renal function should be considered (see Precautions). There is no experience in subjects with Child-Pugh scores above 9. CRESTOR is contraindicated in patients with active liver disease (see Contraindications).
Race: A 5 mg starting dose of 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 particularly in those 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 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 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. cyclosporin, ticagrelor 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 CRESTOR. Whenever possible, alternative medications should be considered, and if necessary, consider temporarily discontinuing CRESTOR therapy. In situations where co-administration of these medicinal products with CRESTOR is unavoidable, the benefit and the risk of concurrent treatment and 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. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be of benefit.

CRESTOR is contraindicated: in patients with hypersensitivity to rosuvastatin or to any of the excipients; in patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3x the upper limit of normal (ULN); in patients with severe renal impairment (creatinine clearance <30 ml/min); in patients with myopathy; in patients receiving concomitant cyclosporin.

Renal Effects: In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients, predominantly in patients dosed above the recommended dose range (i.e., 80 mg). However, this finding was more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator statins, though it was generally transient and was not associated with worsening renal function. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.
Skeletal Muscle Effects: 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. 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. CRESTOR should be used with caution in patients with these conditions and should be discontinued if they are induced or aggravated.
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 (>5x Upper Limit of Normal) a confirmatory test should be carried out within 5-7 days. If the repeat test confirms a baseline CK >5x Upper Limit of Normal, treatment should not be started.
Before Treatment: CRESTOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis, such as: renal impairment; hypothyroidism; 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 (see Dosage & Administration, Interactions and Pharmacology: Pharmacokinetics under Actions); 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 (>5x Upper Limit of Normal) 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 (>5x Upper Limit of Normal) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤5x Upper Limit of Normal). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing CRESTOR 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 characterized 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 CRESTOR 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, cyclosporin, 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 CRESTOR and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of CRESTOR with fibrates or niacin should be carefully weighed against the potential risks of such combinations (see Interactions and Adverse Reactions).
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).
CRESTOR 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).
Liver Effects: As with other HMG-CoA reductase inhibitors, CRESTOR 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 performed before and at 3 months following both the initiation of therapy and any elevation of dose, and periodically thereafter. CRESTOR 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 40 mg dose.
In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with CRESTOR.
Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
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).
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 CRESTOR in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating CRESTOR doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of CRESTOR is adjusted (see Dosage & Administration and Interactions).
Effects on ability to drive and use machines: Studies to determine the effect of CRESTOR on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, CRESTOR is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.
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 pediatric patients taking rosuvastatin is limited to a two-year period (see Pharmacology: Pharmacodynamics under Actions).

Pregnancy: CRESTOR is not recommended for use in pregnant women. 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 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 CRESTOR. Limited data from published reports indicate that CRESTOR is present in human milk. Due to 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.

The adverse events seen with CRESTOR are generally mild and transient. In controlled clinical trials, less than 4% of CRESTOR-treated patients were withdrawn due to adverse events. This withdrawal rate was comparable to that reported in patients receiving placebo. (See Table 3.)

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As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.
Renal Effects: Refer to Precautions.
Skeletal muscle effects: As with other HMG-CoA reductase inhibitors, effects on skeletal muscle e.g. myalgia and myopathy (including myositis), have been reported in CRESTOR-treated patients. Rare cases of rhabdomyolysis, which were occasionally associated with impairment of renal function, have been reported with rosuvastatin and with other marketed statins.
A dose-related increase in CK levels has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5x Upper Limit of Normal), treatment should be temporarily discontinued (see Precautions).
Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.
Post Marketing Experience: In addition to the previous text, the following adverse events have been reported during post marketing experience for 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 necrotizing 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 disorder: 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 CRESTOR is similar in children or adolescent patients and adults although creatine kinase (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).

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of 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 Dosage & Administration, Precautions and Table 4 as follows).
Cyclosporin: During concomitant treatment with CRESTOR and cyclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 4). CRESTOR is contraindicated in patients receiving concomitant cyclosporin (see Contraindications). Concomitant administration did not affect plasma concentrations of cyclosporin.
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 4). Dose adjustment is needed depending on the level of effect on rosuvastatin exposure (see Dosage & Administration and Precautions).
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of CRESTOR in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of CRESTOR may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
Gemfibrozil and other lipid lowering products: Concomitant use of CRESTOR and gemfibrozil resulted in a 2-fold increase in rosuvastatin C_max and AUC (see Precautions).
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 lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see Precautions). These patients should also start with the 5 mg dose.
Antacid: The simultaneous dosing of 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 CRESTOR. The clinical relevance of this interaction has not been studied.
Erythromycin: Concomitant use of CRESTOR and erythromycin resulted in a 20% decrease in AUC(0-t) and a 30% decrease in C_max of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of CRESTOR and an oral contraceptive resulted in an increase in ethinyl oestradiol 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 CRESTOR and HRT and therefore a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.
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.
Ticagrelor: Ticagrelor has been shown to increase rosuvastatin concentrations, which may result in increased risk of myopathy. Consideration should be given to the benefits of prevention of major adverse cardiovascular events by use of rosuvastatin and the risks with increased rosuvastatin plasma concentrations.
Other medicinal products: Based on data from specific interaction studies no clinically relevant interactions with digoxin or fenofibrate are expected. Gemfibrozil, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see Precautions).
Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
Interactions requiring rosuvastatin dose adjustments (see also Table 4): When it is necessary to co-administer CRESTOR with other medicinal products known to increase exposure to rosuvastatin, doses of CRESTOR should be adjusted. It is recommended that prescribers consult the relevant product information when considering administration of such products together with CRESTOR. If medicinal product is observed to increase rosuvastatin AUC approximately 2-fold or higher, the starting dose of CRESTOR should not exceed 5 mg once daily. The maximum daily dose of CRESTOR should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of CRESTOR taken without interacting medicinal products, for example a 5 mg dose of CRESTOR with cyclosporin (7.1-fold increase in exposure), a 10 mg dose of CRESTOR with ritonavir/atazanavir combination (3.1-fold increase) and a 20 mg dose of 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 CRESTOR dose above 20 mg. (See Table 4.)

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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.

Incompatibilities: Not applicable.

Do not store above 30°C. Store in the original package.

Dyslipidaemic Agents

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

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