Simvastatin 20mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Simvastatin 20mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 20mg simvastatin
For excipients see 6.1
3 PHARMACEUTICAL FORM
Film-coated tablet
White, oblong, biconvex, film-coated tablets scored on one side and embossed with ‘20’ on scored side and with ‘SVT’ on the opposite side.
Or
White, oblong, biconvex film-coated tablets scored on both sides embossed with ’SVT’ and ‘20’ on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypercholesterolaemia
Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.
Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.
Cardiovascular prevention
Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1)
4.2 Posology and method of administration
The dosage range is 5-80 mg/day given orally as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80mg/day given as a single dose in the evening. The 80mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications.
Hypercholesterolaemia
The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Simvastatin. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45%) may be started at 2040 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.
Homozygous familial hypercholesterolaemia
Based on the results of a controlled clinical study, the recommended dosage is 40mg/day in the evening or 80mg/day in 3 divided doses of 20mg, 20mg and an evening dose of 40mg. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Cardiovascular Prevention
The usual dose of Simvastatin is 20 to 40mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.
Concomitant therapy
Simvastatin is effective alone or in combination with bile acid sequestrants. Dosing should occur either >2 hours before or >4 hours after administration of a bile acid sequestrant. In patients taking ciclosporin, gemfibrozil, other fibrates (except fenofibrate) or lipid-lowering doses (> 1g/day) of niacin concomitantly with Simvastatin, the dose of simvastatin should not exceed 10mg/day. In patients taking amiodarone or verapamil concomitantly with Simvastatin, the dose of simvastatin should not exceed 20 mg/day. (see sections 4.4 and 4.5)
Dosage in renal insufficiency
No modification of dosage should be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30ml/min), dosages above 10mg/day should be carefully considered and, if deemed necessary, implemented cautiously.
Use in elderly
No dosage adjustment is necessary.
Use in children and adolescents (10-17 years of age)
For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.
The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.
The experience of simvastatin in pre-pubertal children is limited.
4.3 Contraindications Contraindications
• Hypersensitivity to simvastatin or to any of the excipients
• Active liver disease or unexplained persistent elevations of serum transaminases.
• Pregnancy and lactation (see section 4.6)
• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5)
4.4 Special warnings and precautions for use
Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. The risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m , raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Myopathy Rhabdomyolysis
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper
limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. The risk of myopathy/rhabdomyolysis is dose related. The incidence in clinical trials, in which patients were carefully monitored and some interacting medicinal products were excluded, has been approximately 0.03% at 20mg, 0.08% at 40mg and 0.4% at 80mg.
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
Creatine Kinase measurement
Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (>5x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.
Before the treatment
All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.
Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:
- Elderly (age >70 years)
- Renal impairment
- Uncontrolled hypothyroidism
- Personal or familial history of hereditary muscle disorders
- Previous history of muscular toxicity with a statin or fibrate
- Alcohol abuse
In such situations, the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or statin, treatment with a different member of the class should only be initiated with caution. IF CK levels are significantly elevated at baseline (>5 x ULN), treatment should not be started.
Whilst on treatment
If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (>5x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are <5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.
If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)
The risk of myopathy and rhabdomyolysis is increased by concomitant use of simvastatin with inhibitors of CYP3A4 (such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, ciclosporin, nefazodone), gemfibrozil, other fibrates or lipid lowering doses (> 1g/day) of niacin.
The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). There is also a slight increase in risk when diltiazem is used with simvastatin 80mg.
Use of simvastatin concomitantly with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment. Caution should be exercised when combining simvastatin with other CYP3A4 inhibitors (see sections 4.3 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.
The dose of simvastatin should not exceed 10mg daily in patients receiving concomitant medication with ciclosporin, gemfibrozil, other fibrates (except fenofibrate) or lipid-lowering doses (> 1g/day) of niacin (see sections 4.2 and 4.5). The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10mg daily with other fibrates (except fenofibrate), niacin or ciclosporin should be carefully weighed against the potential risks of these combinations.
Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.
The combined use of simvastatin at doses higher than 20mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5)
Hepatic Effects
In clinical studies, persistent increases (to more than 3 times the upper limit of normal) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.
It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80 mg dose should receive an additional test prior to titration, 3 months after titration to the 80 mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3X ULN and are persistent, simvastatin should be discontinued.
The product should be used with caution in patients who consume substantial quantities of alcohol.
As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Reduced function of transport proteins
Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.
Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (See section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.
Use in children and adolescents (10-17 years of age)
Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods > 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.
Excipient
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Interactions with lipid-lowering medicinal products that can cause myopathy when given alone
The risk of myopathy is increased during concomitant administration with fibrates (except fenofibrate) and niacin (nicotinic acid) (> 1g/day). There is also a pharmacokinetic interaction with gemfibrozil (see below and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent.
Effects of other medicinal products on simvastatin Interactions involving CYP3A4
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, and ciclosporin. Concomitant administration of itraconazole resulted in a more than-10 fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.
Therefore, combination with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment. Caution should be exercised when combining simvastatin with other CYP3A4 inhibitors (see sections 4.3 and 4.4).
Gemfibrozil
Gemfibrozil increases the AUC of simvastatin acid by 1.9 fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).
Amiodarone and verapamil
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin (see section 4.4). Therefore, the dose of simvastatin should not exceed 20mg daily in patients receiving concomitant medication with amiodarone and verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis. In an on-going clinical trail, myopathy has been reported in 6% of patients receiving simvastatin 80mg and amiodarone.
An analysis of the available clinical trials showed an approximately 1% incidence of myopathy in patients receiving simvastatin 40mg or 80mg and verapamil. In a pharmacokinetic study, concomitant administration with verapamil resulted in 2.3-fold increase in exposure of simvastatin acid.
Diltiazem
An analysis of the available clinical trials showed a 1% incidence of myopathy in patients receiving simvastatin 80mg and diltiazem. The risk of myopathy in patients taking simvastatin 40mg was not increased by concomitant diltiazem
(see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid.
Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7fold increase in exposure to simvastatin acid. Intake of 240 ml grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.
Oral anticoagulants
In two clinical studies, one in normal volunteers and other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Effects of simvastatin on the pharmacokinetics of other medicinal products
Simvastatin does not have inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.
4.6 Fertility, Pregnancy and lactation
Pregnancy
Simvastatin is contraindicated during pregnancy (see section 4.3).
Safety in pregnant women has not been established. No controlled trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies were comparable to that seen in the general population. This number of pregnancies were statistically sufficient to exclude a 2.5 fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, simvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (see section 4.3)
Lactation
It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking simvastatin should not breast-feed their infants. (see section 4.3).
4.7 Effects on ability to drive and use machines
Simvastatin has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.
4.8 Undesirable effects
The frequencies of the following adverse events, which have been reported during clinical studies and/or post marketing use, are categorised based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increase in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably casually related spontaneous report events, these adverse events are categorised as “rare”.
In HPS (see section 5.1) involving 20,536 patients treated with 40mg/day of simvastatin (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with simvastatin 40mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8% in patients treated with simvastatin 40mg compared with 5.1% in patients treated with placebo). The incidence of myopathy was < 0.1% in patients treated with simvastatin 40mg. Elevated transaminases (>3 X ULN confirmed by repeat test) occurred in 0.21% (n=21) of patients treated with simvastatin 40mg compared with 0.09% (n=9) of patients treated with placebo.
The frequencies of adverse events are ranked according to the following: Very common (>1/10), Common (> 1/100, <1/10), Uncommon (> 1/1000, < 1/100), Rare (>1/10,000, <1/1000), Very rare (<1/10,000) including isolated reports.
Blood and lymphatic system disorders:
Rare: anaemia
Gastrointestinal disorders
Rare: Constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis
General disorders and administration site conditions Rare: Asthenia
Hepato-biliary disorders Rare: hepatitis/jaundice
Musculoskeletal, connective tissue and bone disorders:
Rare: myopathy, rhabdomyolysis (see section 4.4), myalgia, muscle cramps. Frequency not known: Immune-mediated necrotizing myopathy (see section 4.4)
Nervous system disorders
Rare: headache, paresthesia, dizziness, peripheral neuropathy
Skin and subcutaneous tissue disorders:
Rare: rash, pruritus, alopecia
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.
Investigations:
Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, y-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CL levels (see section 4.4)
The following adverse events have been reported with some statins:
• Sleep disturbances, including insomnia and nightmares
• Memory loss
• Sexual dysfunction
• Diabeties Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose > 5.6 mmol/L, BMI>30kg/m , raised triglycerides, history of hypertension).
Children and adolescents (10-17 years of age)
In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.
4.9 Overdose
To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacodynamic properties
Pharmacotherapeutic group: HMG-CoA reductase inhibitor.
ATC -Code: C10A A01
After oral ingestion simvastatin, which is an inactive lactone, is hydrolysed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy-3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.
Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratio of total- to HDL-C and LDL- to HDL-C are reduced.
High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease
In the Heart Protection Study (HPS), the effects of therapy with simvastatin were assessed in 20, 536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10, 269 patients were treated with Simvastatin 40mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33%) had LDL-C levels below 116mg/dL; 5,063 patients (25%) had levels between 116mg/dL and 135 mg/dL; and 8,680 patients (42%) had levels greater than 135 mg/dL.
Treatment with simvastatin 40mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9%] for simvastatin treated patients versus 1507 [14.7%] for patients given placebo; p= 0.0003), due to an 18% reduction in coronary death rate (587 [5.7%] versus 707 [6.9%]; p= 0.0005). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events ( a composite endpoint comprised of non-fatal MI or CHD death) by 27% (p<0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30% (p<0.0001) and 16% (p= 0.006), respectively. Simvastatin reduced the risk of stroke by 25% (p< 0.0001), attributable to a 30% reduction in ischaemic stroke (p<0.0001). In addition, within the subgroup of patients with diabetes, simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21% (p=0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.
In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30%. The risk of CHD death was reduced by 42%. Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34%. Furthermore, simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischaemic attacks) by 28%. There was no statistically significant difference between groups in non-cardiovascular mortality.
Clinical Studies in Children and Adolescents (10-17 years of age)
In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 1017 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level > 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.
Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.
After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0- 289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.
After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week intervals), simvastatin decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of simvastatin on cardiovascular events in children with heFH are unknown.
The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
5.2 Pharmacokinetic properties
Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very low.
The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.
Absorption
In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is depending on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose.
Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin. Concomitant food intake does not affect the absorption.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.
Distribution
The protein binding of simvastatin and its active metabolite is >95% Elimination
Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite its half-life averaged 1.9 hours. An average of only 0.3% of the IV dose was excreted in urine as inhibitors.
Simvastatin is taken up actively into the hepatocytes by the transporter OATP1B1.
Special populations
Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The mean exposure (AUC) of the main active metabolite, simvastatin acid is 120% in heterozygote carriers (CT) of the C allele and 221% in homozygote (CC) carriers relative to that of patients who have the most common genotype (TT). The C allele has a frequency of 18% in the European population. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of simvastatin, which may lead to an increased risk of rhabdomyolysis (see section 4.4).
5.3 Preclinical safety data
Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and rabbit, simvastatin produced no foetal malformations, and had no effects on fertility, reproductive function or neonatal development.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Lactose anhydrous Microcrystalline cellulose Pregelatinised maize starch Butylhydroxyanisole (E320)
Magnesium stearate Talc
Coating:
Hydroxypropylcellulose
Hypromellose
Talc
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
24 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
The tablets are packed in blisters constituted from PVC/PE/PVDC or PVC-Al-OPA and aluminium foil.
The tablets are available in a pack of 28 tablets.
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
MEDLEY PHARMA LIMITED
2A OLYMPIC WAY, SEFTON BUSINESS PARK
BOOTLE
L30 1RD
UNITED KINGDOM
8 MARKETING AUTHORISATION NUMBER(S)
PL 43870/0016
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18 August 2004
10 DATE OF REVISION OF THE TEXT
04/03/2016