Class: Cardiovascular System
Dosage Form: Tablets
Description: HMG Co-A Reductase Inhibitor
Rouvastatin………….5, 10, and 20 mg
Pharmacotherapeutic group: HMG-CoA reductase inhibitors
Mechanism of Action:
Rouvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl conenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rouvastatin is the liver, the target organ for cholesterol lowering.
Rouvastatin 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.
Crestor induces elevated LDL-cholesterol, total cholesterol and trigylcerides and increases HDL-cholesterol. It also lowers ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see Table). Crestor also lowers the LDL-C/HDL-C, total C/HDL-G and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.
A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum reponse is usually achieved by 4 weeks and is maintained after that.
Crestor is effective in adults with hypercholestrolaemia, with and without hypertriglyceridaemia, regardless of race, sex or age and in special populations such as diabetics, or patients with familial hypercholestrolaemia.
From pooled phase III data, Crestor has been shown to be effective at treating the majority of patients with type IIa and IIb hypercholestrolaemia (mean baselines LDL-C about 4.8 mmol/l) to recognised European Atherosclerosis Soceity (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 hypercholestrolaemia 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 hypercholestrolaemia were evaluated for their response to Crestor 20-40 mg. in the overall production, the mean LDL-C reduction was 22%.
In clinical studies with a limited number of patients, Crestor has been shown to have additive efficacy in lowering trigylcerides when used in combination with fenofibrate and in increasing HDL-C levels when used in combination with niacin (see Special Warnings and Precautions for Use).
Rouvastatin 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.
Maximum rouvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.
Rouvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rouvastatin is approximately 134 L. Approximately 90% of rouvastatin is bound to plasma proteins, mainly to albumin.
Rouvastatin undergoes limited metabolism (apprximately 10%). In vitro metabolism studies using human hepatocytes indicate that rouvastatin 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 rouvastatin whereas the lactone form is considered clinically inactive. Rouvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.
Approximately 90% of the rouvastatin does is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in the urine. Approximately 5% is excreted unchanged in the urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase of higher doses. The geometric mean plasma clearance is approximately 50 liters/hour (coeffecient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rouvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rouvastatin.
Systemic exposure of rouvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.
a) Age and sex: There was no clinically relevant effect of age and sex on the pharmacokinetics of rouvastatin.
b) Race: Pharmacokinetic studies (conducted in subjects of Chinese, Fillipino, Asian, Indian, Korea, Vietnamese, Japanese or Malay origin) show an approximate 2-fold elevation in median AUC and Cmax in Asia compared with Caucasians living in Asia and Europe. The contribution of environmental and genetic factors to these observed differences has not been determined. A popluation pharmacokinetic anaylsis revealed no clincally 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 rouvastatin or the N-desmethyl metabolite. Subjects with severe impairment (CrCl <30ml/min) had a 3-fold increase in plasma concentration and a 9-fold increase in the N-desmethly metabolite concentration compared to healthy volunteers. Steady-state plasma concentrations of rouvastatin in subjects undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.
c) Hepatic insufficiency: In a study with subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rouvastatin 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.
Preclinical Safety Data
Preclinical safety data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, gentotoxicity 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 exposure several times above the therapeutic exposure level.
Primary hypercholestrolaemia (type IIa including heterozygous familial hypercholestrolaemia) or mixed dyslipidaemia (type IIb) as an ajunct to diet when response to diet and other non-pharmacologic treatments (e.g. exercise, weight reduction) is inadequate.
Homozygous familial hypercholestrolaemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.
Crestor is contraindicated in:
- Patients with hypersensitivity to rouvastatin or any of the excipients.
- 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).
- Patients with severe renal impairment (creatinine clearance <30 ml/min).
- Patietns with myopathy.
- Patients receiving concomitant cyclosporin.
- Pregnancy and lactation and women of childbearing potential not using appropriate contraceptive measures.
The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:
- Moderate renal impairment (creatinine clearance <60 ml/min)
- Presonal 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.
(see Special Warnings and Precuations for Use, Interactions and Pharmacokinetic properties)
The following interactions have been reported:
During concomitant treatment with Crestor and cyclosporin, rouvastatin AUC values were on average 7 times higher than those observe in healthy volunteers (see Contraindications).
Concomitant administration did not affect plasma concentrations of cyclosporin.
2. 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) may result in an increase in International Normalized 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 rouvastatin Cmax and AUC (see Special Warnings and Precautions for Use).
Based on data from specific interactions 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. The 40 mg dose is contraindicated with concomitant use of a fibrate (see Contraindications and Special Warnings and Precautions for Use). These patients should also start with the 5 mg dose.
The simultaneous dosing of Crestor with an antacid suspension containing aluminium and magnesium hydroxide resulted in an decrease in rouvastatin 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 Cmax of rouvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
4. Oral Contraceptive/Hormone Replacement Therapy (HRT):
Concomitant use of Crestor 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 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.
5. Other medicinal products:
Based on data from specific interaction studies, no clinically relevant interactions with digoxin is expected.
6. Cytochrome P450 Enzymes:
Results from in vitro and in vivo studies show that rouvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rouvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rouvastatin 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 rouvastatin resulted in a 28% increase in AUC of rouvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
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.
The frequencies of adverse events are ranked according to the following: Common (>1/100,<1/10); Uncommon (>1/1000,<1/100); Rare (>1/10,000,<1/1000); Very rare (<1/10.000).
1. Immune System Disorders:
- Rare: Hypersensitivity reactions including angioedema
2. Nervous System Disorders:
- Common: Headache, dizziness
3. Gastrointestinal Disorders:
- Common: Constipation, nausea, abdominal pain
4. Skin and Subcutaneous Tissue Disorders:
- Uncommon: Pruritus, rash and urticaria
5. Musculoskeletal, Connective Tissue and Bone Disorders:
- Common: Myalgia
- Rare: Myopathy and rhabdomyolysis
6. General Disorders:
- Common: Asthenia
As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose-dependent.
7. Renal Effects:
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with Crestor. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy, and has not been shown to be predictive of acute or progressive renal disease.
8. Skeletal Muscle Effects:
Effects on skeletal muscles, e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Crestor-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 rouvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued (see Special Warnings and Precautions for Use).
9. Liver Effects:
As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a smaller number of patients taking rouvastatin; the majortiy of cases were mild, asymptomatic and transient.
10. Post-marketing Experience:
In addition to the above, the following adverse events have been reported during post-marketing experience for Crestor:
- Hepatobiliary Disorders:
- Very rare: Jaundice, hepatitis. Rare: Increased hepatic transaminases
- Musculoskeletal Disorders:
- Rare: Arthralgia
- Nervous System Disorders:
- Very rare: Polyneuropathy
Dosage and Administration:
1. Posology and Method of Administration:
Before initiation of the treatment, the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualized according to the goal of therapy and patient response, using current consensus guidelines.
The recommended start dose is 5 mg or 10 mg orally once daily in both statin naiive or patients switched from another HMG-CoA reductase inhibitor. The choice of start dose should take into account the individual patient’s cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions (see below). A dose adjustment to the next dose level can be made after 4 weeks, if necessary (see Pharmacodynamic Properties). In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses (see Undesirable Effects), a final titration to the maximum dose of 40 mg should only be considered in patients with severe hypercholestrolaemia at high cardiovascular risk (in particular those with familial hypercholestrolaemia), who do not achieve their treatment goal on 20 mg, and in whom routine follow-up will be performed (see Special Warnings and Precautions for Use). Specialist supervision is recommended when the 40 mg dose is initiated.
Crestor may be given at any time of day, with or without food.
2. Paediatric Use:
Safety and efficacy have not been established in children. Pediatric experience is limited to a small number of children (aged 8 years or above) with homozygous familial hypercholestrolaemia. Therefore, Crestor is not recommended for pediatric use at this time.
3. Use in Elderly:
A start dose of 5 mg is recommended in patients >70 years (see Special Warnings and Precautions for Use). No other dose adjustment is necessary in relation to age.
4. Dosage in Patients with Renal Insufficiency:
No dose adjustment is necessary in patients with mild to moderate renal impairment. the recommended start dose is 5 mg in patients with moderate renal impairment (creatine clearance <60ml/min). The 40 mg dose is contraindicated in patient with moderate renal impairment. The use of Crestor in patients with severe renal impairment is contraindicated for all doses (see Contraindications and Pharmacokinetics).
5. Dosage in Patients with Hepatic Impairment:
There was no increase in systemic exposure to rouvastatin 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 Pharmacokinetics). In these patients an assessment of renal function should be considered (see Special Warnings and Precautions for Use). There is no experience in subjects with Child-Pugh scores above 9. Crestor is contraindicated in patients with active liver disease (see Contraindications).
Increased systemic exposure has been see in Asian subjects (see Special Warnings and Precautions for Use and Pharmacokinetics). The recommended start dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.
7. Dosage in Patients with Pre-disposing Factors to Myopathy:
The recommended start dose is 5 mg in patients with predisposing factors to myopathy (see Special Warnings and Precautions for Use).
The 40 mg dose is contraindicated in some of these patients (see Contraindications).
There is no specific treatment in the even 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 of be of benefit.
Pregnancy and Lactation:
Crestor is contraindicated in pregnancy and lactation.
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 fetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity (see Preclinical Safety Data). If a patient becomes pregnant during use of this product , treatment should be discontinued immediately.
Rouvastatin is excreted in the milk of rats. There are no data with respect to excretio in milk in humans (see Contraindications).
1. Renal Effects:
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of Crestor, 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 (see Undesirable effects). An assessment of renal function should not be considered during routine follow-up of patients treated with a dose of 40 mg.
2. Skeletal Muscle Effects:
Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in Crestor-treated patients with all doses and in particular with doses >20 mg.
3. Creatine Kinase Measurements:
Creatine Kinase (CK) should not be measured following stenuous 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 5-6 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.
a) Before treatment:
Crestor, as with other HMG-CoA reductase inhibitors, should not be prescribed with caution in patients, with pre-disoposing 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 (see Pharmacokinetics properties)
- Concomitant use of fibrates
In such patients the risk of treatment should be considered in relation to possible benefit and clincal monitoring is recommended. If CK levels are significantly elevated at baseline (>5xLUN) treatment should not be started.
b) Whilst on treatment:
Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort.
Routine monitoring of CK levels in asymptomatic patients is not warranted.
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 reducatse 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 reducatse 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 of niacin should be carefully weighed againt the potential risks of such combinations. The 40 mg dose is contraindicated with concomitant use of a fibrate. (See Interactions and Undesirable Effects).
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).
4. 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 carried out prior to, and 3 months following, the initiation of treatment. Crestor should be discontinued or the dose reduced if the level of serum transaminases is greated than 3 times the upper limit of normal.
In patients with secondary hypercholestrolaemia caused by hypothyroidism or nephrotic snydrome, the underyling disease should be treated prior to initiating therapy with Crestor.
Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see Posology and Method of Administrations and Pharmacokinetic properties).
6. 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.
Pack of 1 , 2 or 4 strips of 7 tablets each.
Store at room temperature, below 25°C.