Simvastatin 40mg Film-Coated Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 40mg of Simvastatin

For excipients see 6.1 3. PHARMACEUTICAL FORM

Film coated tablet

Brick red-coloured, oval-shaped biconvex tablets of 14mm length.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Coronary heart disease

In patients with coronary heart disease with a plasma cholesterol level of 5.5 mmol/l or greater, simvastatin is indicated to:

• reduce the risk of mortality

• reduce the risk of coronary death and non-fatal myocardial infarction

• reduce the risk for undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty)

• slow the progression of coronary atherosclerosis, including reducing the development of new lesions and new total occlusions.

Hyperlipidaemia

Simvastatin is indicated as an adjunct to diet for reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolaemia, heterozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia when response to diet and other non-pharmacological measures is inadequate. Simvastatin also raises HDL-cholesterol and therefore lowers the LDL/HDL and total cholesterol/HDL ratios.

As with any cholesterol-lowering therapy other modifiable risk factors should also be considered when treatment is started.

Homozygous familial hypercholesterolaemia

Simvastatin is indicated as an adjunct to diet and other non-dietary measures in reducing elevated total cholesterol, LDL-cholesterol and apolipoprotein B in patients with homozygous familial hypercholesterolaemia when response to these measures is inadequate.

4.2 Posology and method of administration

Route of administration is oral.

The patient should be placed on a standard cholesterol-lowering diet before receiving simvastatin and should continue on this diet during treatment with simvastatin.

Coronary heart disease

Patients with coronary heart disease can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Adjustment of dosage, if required, should be made at intervals of not less than four weeks, to a maximum of 80 mg/day given as a single dose in the evening, depending on the patient's individual response.

If LDL-cholesterol levels fall below 1.94 mmol/l or total serum cholesterol levels fall below 3.6 mmol/l, consideration should be given to reducing the dose of simvastatin.

Hyperlipidaemia

The recommended dose is 10 mg once daily taken in the evening. The dose range is 10 to 80 mg a day in single doses taken in the evening. A marked response to simvastatin is seen within two weeks and the maximum therapeutic response occurs within four to six weeks. The response is maintained during continuation of therapy. When therapy with simvastatin is stopped, total cholesterol has been shown to return to pretreatment levels. Adjustment of dosage, if required, should be made as specified above (see 4.2 'Posology and method of administration', Coronary heart disease).

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage for patients with homozygous familial hypercholesterolaemia is simvastatin 40 mg/day taken as a single dose in the evening, or 80 mg/day in three divided doses of 20 mg, 20 mg and a 40 mg dose taken in the evening. 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.

Concomitant therapy: Simvastatin is effective alone or in combination with bile-acid sequestrants. In patients taking ciclosporin, fibrates or nicotinic acid concomitantly with simvastatin, the maximum recommended dosage is 10 mg/day (see 4.4 'Special warning and precautions for use', Muscle effects and 4.5 'Interaction with other medicinal products and other forms of interaction').

Dosage in renal insufficiency: Simvastatin does not undergo significant renal excretion, therefore modification of dosage should not be necessary in patients with moderate renal insufficiency.

In patients with severe renal insufficiency (creatinine clearance <30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly: Although experience in elderly patients is limited, efficacy using standard doses appears similar to that seen in the population as a whole. There is no apparent increase in the frequency of clinical or laboratory adverse findings.

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

Hypersensitivity to this product; active liver disease or unexplained persistent elevations of serum transaminases; porphyria; pregnancy and breastfeeding (see also 4.6 'Pregnancy and lactation'); women of childbearing potential unless adequately protected by non-hormonal methods.

4.4 Special warning and precautions for use

Muscle Effects: Simvastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy, which is manifested as muscle pain or weakness associated with grossly elevated creatine phosphokinase (CPK) (>10X the upper limit of normal [ULN]). Rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria, has been reported rarely. In the Scandinavian Simvastatin Survival Study, there was one case of myopathy among 1,399 patients taking simvastatin 20 mg and no cases among 822 patients taking 40 mg daily for a median duration of 5.4 years. In two 6-month controlled clinical studies, there was one case of myopathy among 436 patients taking 40 mg and five cases among 669 patients taking 80 mg. The risk of myopathy is increased by concomitant therapy with certain drugs, some of which were excluded by the designs of these studies.

Myopathy caused by drug interactions: The incidence and severity of myopathy are increased by concomitant administration of HMG-CoA reductase inhibitors with drugs that can cause myopathy when given alone, such as gemfibrozil and other fibrates, and lipid-lowering doses (p1 g/day) of nicotinic acid.

In addition, the risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Simvastatin and other HMG-CoA reductase inhibitors are metabolised by the cytochrome P450 isoform 3A4 (CYP3A4). Certain drugs that have a significant inhibitory effect at therapeutic doses on this metabolic pathway can substantially raise the plasma levels of HMG-CoA reductase inhibitors and thus increase the risk of myopathy. These include ciclosporin, the azole antifungals itraconazole and ketoconazole, the macrolide antibiotics, erythromycin and clarithromycin,

HIV protease inhibitors and the antidepressant nefazodone.

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.

Reducing the risk of myopathy:

1. General measures

Patients starting therapy with simvastatin should be advised of the risk of myopathy and told to report promptly unexplained muscle pain, tenderness or weakness. A CPK level above 10x ULN in a patient with unexplained muscle symptoms indicates myopathy. Simvastatin therapy should be discontinued if myopathy is diagnosed or suspected. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CPK increases resolved.

Of the patients with rhabdomyolysis, many had complicated medical histories. Some had pre-existing renal insufficiency, usually as a consequence of longstanding diabetes. In such patients, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with simvastatin should be stopped a few days before elective major surgery and when any major acute medical or surgical condition supervenes.

2. Measures to reduce the risk of myopathy caused by drug interactions (see

above)

Physicians contemplating combined therapy with simvastatin and any of the interacting drugs should weigh the potential benefits and risks, and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy.

The combined use of simvastatin with fibrates or nicotinic acid should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. Combinations of fibrates or nicotinic acid with low doses of simvastatin have been used without myopathy in small, short-term clinical trials with careful monitoring. Addition of these drugs to HMG-CoA reductase inhibitors typically provides little additional reduction in LDL-cholesterol, but further reductions of triglycerides and further increases in HDL cholesterol may be obtained. If one of these drugs must be used with simvastatin, clinical experience suggests that the risk of myopathy is less with nicotinic acid than with the fibrates.

In patients taking concomitant ciclosporin, fibrates or nicotinic acid, the dose of simvastatin should generally not exceed 10 mg/day (see 4.2 'Posology and method of administration', Concomitant therapy), as the risk of myopathy increases substantially at higher doses. Concomitant use of simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, or nefazodone is not recommended. If no alternative to a short course of treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is available, a brief suspension of simvastatin therapy can be considered as there are no known adverse consequences to brief interruption of long-term cholesterol-lowering therapy. Concomitant use with other medicines labelled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.

Hypertriglyceridaemia: Although simvastatin has a triglyceride lowering effect, it is not indicated where hypertriglyceridaemia is the abnormality of most concern (i.e. hyperlipidaemia types I, IV, and V).

Hepatic effects: Minor asymptomatic transient rises in serum transaminase may occur soon after initiation of therapy with simvastatin which do not require the drug to be discontinued. There is no evidence that these changes are due to hypersensitivity to simvastatin.

In the Scandinavian Simvastatin Survival Study (see 5.1 'Pharmacodynamic properties') the number of patients with one or more transaminase elevation to >3 times the upper limit of normal, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs 12 [0.6%]), the number of patients with single elevations of SGPT (ALT) to 3 times the upper limit of normal was significantly higher in the simvastatin group in the first year of the study (20 vs 8, p=0.023), but not thereafter.

Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to >3 times the upper limit of normal and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

In two controlled clinical studies in 1,105 patients, the six month incidence of persistent hepatic transaminase elevations considered drug-related was 0.7% and 1.8% at the 40 and 80 mg dose respectively.

It is recommended that liver-function tests be performed before treatment begins, and periodically thereafter, (e.g. twice a year) for the first year of treatment or until one year after the last elevation in dose in all patients. Patients titrated to the 80 mg dose should receive an additional test at three months. 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 three times the upper limit of normal and are persistent, the drug should be discontinued.

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.

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.

Ophthalmic examination: In the absence of any drug therapy, an increase in the prevalence of lens opacities with time is expected as a result of ageing. Current long-term data from clinical trials do not indicate an adverse effect of simvastatin on the human lens.

Use in children and adolescents (10-17 years of age)

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.

4.5 Interaction with other medicinal products and other forms of interaction

Gemfibrozil and other fibrates, lipid-lowering doses (pt1 g/day) of nicotinic acid: These drugs increase the risk of myopathy when given concomitantly with simvastatin, probably because they can produce myopathy when given alone (see 4.4 'Special warnings and special precautions for use' Muscle effects). There is no evidence to suggest that these agents affect the pharmacokinetics of simvastatin.

CYP3A4 interactions: Simvastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect plasma levels of other drugs metabolised by CYP3A4. However, simvastatin itself is a substrate for CYP3A4. Potent inhibitors of CYP3A4 may increase the risk of myopathy by increasing the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy. These include ciclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone (see 4.4 'Special warning and precautions for use' Muscle effects).

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolised by CYP3A4. The effect of typical consumption (one 240 ml glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, very large quantities (over 1 litre daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided (see 4.4 'Special warning and precautions for use' Muscle effects). Amounts of grapefruit juice between 240 ml and 1 litre have not been studied.

Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of simvastatin and propranolol.

Digoxin: Concomitant administration of simvastatin and digoxin resulted in a slight elevation (less than 0.3 ng/ml) in drug concentrations (as measured by a digoxin radio-immuno-assay) in plasma compared to concomitant administration of placebo and digoxin.

Coumarin derivatives: In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalised 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, 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.

Other concomitant therapy: In clinical studies, simvastatin was used concomitantly with ACE inhibitors, beta-blockers, calcium antagonists, diuretics, and non-steroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions. There is, however, an increased risk of muscular disorders (myopathy, rhabdomyolysis) with concomitant amiodarone administration.

4.6 Pregnancy and lactation

Pregnancy: Simvastatin is contraindicated in pregnancy.

Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidaemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for foetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as simvastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, simvastatin is contraindicated for use in pregnancy and women of child bearing potential unless such patients are highly unlikely to conceive or such patients are adequately protected by nonhormonal methods. An interval of one month should elapse between the end of therapy with simvastatin and planned conception. If the patient becomes pregnant while taking this drug simvastatin should be discontinued immediately and the patient apprised of the potential hazard to the foetus.

The active metabolite of simvastatin was shown to produce foetal malformations in the offspring of pregnant rats. A few reports have been received of congenital anomalies in infants whose mothers were treated during pregnancy with HMG-CoA reductase inhibitors.

In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and foetal death/stillbirths did not exceed what would be expected in the general population. As safety in pregnant women has not been established and there is no apparent benefit to therapy with simvastatin during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognised.

Breast-feeding mothers: It is not known whether simvastatin or its metabolites are excreted in human milk. Simvastatin should be avoided during lactation.

4.7 Effects on ability to drive and use machines

Simvastatin is not known to affect ability to drive or use machines.

4.8 Undesirable effects

Simvastatin is generally well tolerated; for the most part, side effects have been usually mild and transient in nature. Less than 2% of patients on simvastatin were discontinued from controlled clinical studies due to side effects attributable to simvastatin.

In the pre-marketing controlled clinical studies, adverse effects occurring with a frequency of 1% or more and considered by the investigator as possibly, probably or definitely drug-related were: abdominal pain, constipation, and flatulence. Other side effects occurring in 0.5-0.9% of patients were asthenia and headache. Myopathy has been reported rarely.

In the Scandinavian Simvastatin Survival Study (4S) involving 4,444 patients treated with simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study.

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea, and malaise.

Laboratory test findings: Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and y-glutamyl transpeptidase have been reported.

Liver-function test abnormalities have generally been mild and transient. Increases in serum creatine phosphokinase (CPK) levels derived from skeletal muscle have been reported (see 4.4 'Special warning and precautions for use').

The following additional side effects were reported either in long-term extension studies or in marketed use: nausea, diarrhoea, rash, dyspepsia, pruritus, alopecia, dizziness, muscle cramps, myalgia, pancreatitis, paraesthesia, peripheral neuropathy, vomiting, and anaemia. Rarely, rhabdomyolysis and hepatitis/jaundice occurred.

Side effects - causal relationship unknown: The following side effects have been reported; however, a causal relationship to therapy with simvastatin has not been established: depression, erythema multiforme including Stevens-Johnson syndrome, leucopenia, and purpura.

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.).

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Memory loss

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4).

Immune-mediated necrotizing myopathy (see section 4.4) has been reported with an unknown frequency of occurrence.

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 at www.mhra.gov.uk/yellowcard.

4.9 Overdose

A few cases of overdosage have been reported; no patient had any specific symptoms, and all patients recovered without sequelae. The maximum dosage taken was 450 mg. General measures should be adopted.

The maximum plasma concentration of inhibitors occurred within 1.3 to 2.4 hours of administration

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The involvement of LDL cholesterol in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have established that high LDL cholesterol and low HDL (high-density lipoprotein) cholesterol are both risk factors for coronary heart disease.

Simvastatin has been shown to reduce both normal and elevated LDL-cholesterol concentrations. LDL is formed from 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 concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL cholesterol. Apolipoprotein B also falls substantially during treatment with simvastatin. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that simvastatin does not merely cause cholesterol to be lost from LDL but also reduces the concentration of circulating LDL particles. In addition, simvastatin increases HDL cholesterol and reduces plasma triglycerides. As a result of these changes the ratios of total to HDL cholesterol and LDL to HDL cholesterol are reduced.

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily the mean reductions of LDL-C were 30, 38, 41 and 47%, respectively. The percent reduction in LDL-C was essentially independent of baseline.

In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in three divided doses, or 80 mg/day in three divided doses. The mean LDL-cholesterol reductions for the 40 mg and 80 mg doses were 14% and 25%, respectively. One patient with absent LDL-cholesterol receptor function had an LDL-cholesterol reduction of 41% with the 80 mg dose.

In the Scandinavian Simvastatin Survival Study (4S), the effect on total mortality of therapy with simvastatin for a median of 5.4 years was assessed in 4,444 patients with coronary heart disease (CHD) and baseline total cholesterol 5.5 to 8.0 mmol/l. In this multicentre, randomised, double-blind, placebo-controlled study, simvastatin reduced the risk of death by 30%, of CHD death by 42%, and of having a hospital-verified non-fatal myocardial infarction by 37%. Furthermore simvastatin reduced the risk for undergoing myocardial revascularisation procedures (coronary artery by-pass grafting or percutaneous transluminal coronary angioplasty) by 37%.

In a post hoc analysis performed on fatal plus non-fatal cerebrovascular events (stroke and transient ischaemic attacks), there were 75 patients with such events in the simvastatin group and 102 in the placebo group (risk reduction 28%, p=0.033).

In a multicentre, placebo-controlled clinical trial in 404 patients using quantitative coronary angiography, simvastatin slowed the progression of coronary atherosclerosis and reduced the development of both new lesions and new total occlusions, whereas coronary atherosclerosis lesions steadily worsened over four years in patients receiving standard care.

Simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyses the conversion of HMG-CoA to mevalonate. However, at therapeutic doses, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with simvastatin would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolised readily back to acetyl CoA, which participates in many biosynthetic processes in the body.

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) 10-17 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: 128.0-334.0mg/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

5.2 Pharmacokinetic properties

Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding B-hydroxyacid, L-654,969, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the B-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors). Both are measured in plasma following administration of simvastatin. In a disposition study with ¹⁴C-labelled simvastatin, 100mg (20 uCi) of drug was administered as capsules (5 x 20mg), and blood, urine, and faeces collected. Thirteen per cent of the radioactivity was recovered in the urine and 60% in faeces. The latter represents absorbed drug equivalents excreted in bile as well as any unabsorbed drug. Less than 0.5% of the dose was recovered in urine as HMG-CoA reductase inhibitors. In plasma, the inhibitors account for 14% and 28% (active and total

inhibitors) of the AUC of total radioactivity, indicating that the majority of chemical species present were inactive or weak inhibitors.

The major metabolites of simvastatin present in human plasma are L-654,969 and four additional active metabolites. Both simvastatin and L-654,969 are highly bound to human plasma proteins >94%). The availability of L-654,969 to the systemic circulation following an oral dose of simvastatin was estimated using an i.v. reference dose of L-654,969; the value was found to be less than 5% of the dose. By analogy to the dog model, simvastatin is well absorbed and undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the general circulation is low.

In dose-proportionality studies, utilising doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.

The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the above pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours post-dose.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Elimination

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

The oral LD₅₀ of simvastatin in mice is approximately 3.8 g/kg and in rats approximately 5 g/kg.

Administration of high dosage levels of simvastatin and related analogues to a variety of animal species has revealed a spectrum of changes in several tissues. These changes were not unexpected in view of the large doses used, the potency of these drugs in inhibiting mevalonate synthesis, and the essential role of the target enzyme in maintenance of cellular homeostasis. Extensive data generated on several of these changes indicate that they represent an exaggeration of the biochemical effect of these drugs at the high end of the dose-response curve. Thus, morphological changes in the livers of rats, squamous epithelial hyperplasia of the forestomach of rats and mice, and hepatotoxicity in rabbits have all been shown to be directly related to inhibition of HMG-CoA reductase.

Cataracts have been detected at high dosage levels in dog studies with simvastatin, although at a very low incidence. While there is no clear correlation between the magnitude of serum lipid-lowering and the development of cataracts, a consistent relationship has been observed between high serum levels of drug and cataract development with simvastatin and related HMG-CoA reductase inhibitors.

Serum levels (expressed as total inhibitors) in dogs receiving the minimally cataractogenic dose of simvastatin of 50 mg/kg/day are six times higher than those in man receiving the maximally anticipated therapeutic dose of 1.6 mg/kg (based on a 50 kg man).

Elevated serum transaminases have been observed in dogs receiving simvastatin. These occur either as chronic low-level elevations or as transient enzyme spikes in approximately 10-40% of the dogs receiving this drug. None of the dogs experiencing these transaminase elevations demonstrated any symptoms of illness; and none of the transaminase elevations have progressed to levels associated with frank hepatic necrosis, despite continued drug administration. No histopathological changes have been identified in the liver of any dogs receiving simvastatin.

Testicular degeneration has been seen in two dog safety studies with simvastatin. Special studies designed to further define the nature of these changes have not met with success, since the effects are poorly reproducible and unrelated to dose, serum cholesterol levels, or duration of treatment. Simvastatin has been administered for up to 2 years to dogs at a dose of 50 mg/kg/day without any testicular effects.

Skeletal muscle necrosis was seen in one study in rats given 90 mg/kg b.d., but this was a lethal dosage in rats.

Genetic toxicology and carcinogenicity : An extensive battery of in vitro and in vivo genetic toxicity tests have been conducted on both simvastatin and the corresponding open acid L-654,969. These include assays for microbial mutagenesis, mammalian cell mutagenesis, single stranded DNA breakage, and tests for chromosome aberrations. The results of these studies provided no evidence of an interaction between simvastatin or L654,969 with genetic material at the highest soluble non-cytotoxic concentration tests in in vitro assay systems or at maximally tolerated doses tested in vivo.

Initial carcinogenicity studies conducted in rats and mice with simvastatin employed doses ranging from 1 mg/kg/day to 25 mg/kg/day. No evidence of a treatment-related incidence of tumour types was found in mice in any tissue. A statistically significant (p < 0.05) increase in the incidence of thyroid follicular cell adenomas was observed in female rats receiving 25 mg/kg of simvastatin per day (15.5 times the maximum recommended human dose). This benign tumour type was limited to female rats; no similar changes were seen in male rats or in female rats at lower dosages (up to 5 mg/kg/day). These tumours are a secondary effect reflective of a simvastatin-mediated enhancement of thyroid hormone clearance in the female rat. No other statistically significant increased incidence of tumour types was identified in any tissues in rats receiving simvastatin.

Data from both of these studies indicated that squamous epithelial hyperplasia of the forestomach occurred at all dosage levels. These gastric changes are confined to an anatomical structure which is not found in man. Moreover, identical cells found in other locations (e.g. oesophagus and anorectal junction of the rat, mouse and dog) are unaffected.

Results of a 73-week carcinogenicity study in mice receiving simvastatin doses up to 400 mg/kg/day (250 times the maximum recommended human dose, based on a 50 kg person) exhibited increased incidences of hepatocellular adenomas and carcinomas, pulmonary adenomas and Harderian gland adenomas. A no-effect dose of 25 mg/kg/day (15.5 times the maximum recommended human dose) was established in this study and from the results of the initial 92-week carcinogenicity study in mice. In an additional 106-week rat carcinogenicity study, treatment-related increases in the incidences of lens opacities (after 103 weeks) and hepatocellular neoplasms were observed at doses 31 to 62.5 times the maximum recommended human dose and at exposures (based on 24-hour plasma AUC of total inhibitors) more than 3.5 times that achieved in male volunteers administered a maximum daily dose of 80 mg simvastatin. The no-effect dose remains at 25 mg/kg/day (15.5 times the maximum recommended human dose) as established in the initial carcinogenicity study. An increase in the incidence of thyroid hyperplastic lesions was also observed; however, this is consistent with the previous finding that this is a species-specific response and has no implications for man.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core

Lactose monohydrate Microcrystalline cellulose (E460)

Pregelatinised starch Butylated hydroxyanisole (E320)

Ascorbic acid (E300)

Anhydrous citric acid (E330)

Colloidal anhydrous silica Talc (E553b)

Magnesium stearate (E572)

Tablet Coat

Hypromellose (E464)

Talc (E553b)

Triethyl Citrate (E1505)

Titanium Dioxide (E171)

Povidone K30 (E1201)

Iron Oxide Red (E172)

Iron oxide Yellow (E172)

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, 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 very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin with > 24,747 (approximately 60 %) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03 %o, 0.08 %o and 0.61 % at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0 % compared with 0.02 % for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %. (See sections 4.8 and 5.1.)

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 (> 5 x 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 > 65years)

• Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular 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 a 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 a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x 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.

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

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 significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, fluconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (eg nelfinavir), nefazodone), as well as gemfibrozil, ciclosporin, and danazol (see section 4.2)

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlodipine is used with simvastatin 80 mg (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, fluconazole, posaconazole, HIV protease inhibitors (eg nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, fluconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol or gemfibrozil.. 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 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

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 20 mg 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).

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

Physicians contemplating combined therapy with simvastatin and lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co-administered with lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of simvastatin 80 mg with lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin coadministered with lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid) or products containing niacin.

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastatin treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to > 3 x ULN) 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 3 x 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 (< 3 x 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.

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

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

6.5 Nature and contents of container

Blister packs of PVC-PVDC film / aluminium foil. Packed in cartons of 28 tablets.

6.6 Special precautions for disposal

Not applicable.

7. MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK.

8. MARKETING AUTHORISATION NUMBER

PL 29831/0187

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/07/2010

10 DATE OF REVISION OF THE TEXT

07/10/2015