SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dexcel Cholesterol Lowering 10mg Tablets

Lloydspharmacy Cholesterol Lowering 10mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg simvastatin.

For a full list of excipients, see section 6.1.

Each 10 mg tablet contains 72.21 mg of lactose monohydrate.

3    PHARMACEUTICAL FORM

Film-coated tablets

Peach coloured, film-coated, oval shaped tablets, debossed with ‘SST’ on one side and ‘10’ on the other side with intact coating.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

To reduce the risk of a first major coronary event (non fatal myocardial infarction and coronary heart disease (CHD) deaths) in individuals who are likely to be at moderate risk (approximately 10-15% 10-year risk of a first major event) of CHD, i.e.:

• Men aged 55 years and above.

• Men aged 45-54 years and women aged 55 years and above who have one or more of the following:

o Family history of coronary heart disease in a first-degree relative (parent or sibling); CHD in male first degree relative below 55 years or female first degree relative below 65 years.

o Smoker (is currently a smoker or has been a smoker in the last 5 years). o Overweight (Body Mass Index > 25kg/m2) or truncal obesity (waist: 40 inches or 102cm in men; 35 inches or 88cm in women).

o Of South Asian ethnic origin i.e. from the Indian subcontinent that includes India, Bangladesh, Pakistan or Sri Lanka.

Simvastatin 10mg should be taken as part of a programme of actions designed to reduce the risk of CHD. These include cessation of smoking, eating a healthy diet, weight loss and regular exercise.

4.2. Posology and method of administration

Route of administration is oral.

Simvastatin is given as a single 10mg dose in the evening.

Simvastatin treatment can be initiated simultaneously with diet, exercise and smoking cessation.

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 < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly: No dosage adjustment is necessary.

Children: Dexcel Cholesterol Lowering 10mg Tablets is not indicated for paediatric use.

4.3 Contraindications

Hypersensitivity to simvastatin or to any of the excipients listed in section 6.1; concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, gemfibrozil, ciclosporin or danazol (see sections 4.4 and 4.5); active liver disease or unexplained persistent elevations of serum transaminases; pregnancy and lactation (see section 4.6).

4.4 Special warnings and precautions for use

Simvastatin 10mg treatment is not intended for individuals who are known to have:

•    Existing coronary heart disease

•    Diabetes

•    History of stroke or peripheral vascular disease

•    Diagnosis of the genetic disorder called Familial Hypercholesterolaemia

Individuals with these conditions are at higher risk of cardiovascular disease and should be managed under the supervision of a physician.

Individuals who have been diagnosed as having hypertension are also at increased risk of cardiovascular disease. Therefore, these individuals should consult their doctor before undertaking treatment with Simvastatin 10mg.

If an individual is found to have a fasting LDL-C level of 5.5 mmol/l or greater before or during treatment, they should be advised to consult their doctor, since it is unlikely that simvastatin 10mg will give a satisfactory reduction in cholesterol.

Reducing the risk of myopathy:

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 rarely fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

General measures

All individuals starting therapy with Simvastatin 10mg must be advised of the risk of myopathy and told to immediately stop taking Simvastatin 10mg until they consult with a physician, if they experience unexplained generalised muscle pain, tenderness or weakness (e.g. muscle pain not associated with flu, unaccustomed exercise, or recent strain or injury). A creatine kinase (CK) level should be measured in people with these symptoms.

Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms and/or a CK level >5 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes. Such patients merit closer monitoring (see 4.4, Special warnings and precautions for use). 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.

People aged >65 years or with uncontrolled hypothyroidism, renal impairment, a personal or familial history of hereditary muscle disorders, previous history of muscular toxicity with a statin or fibrate, alcohol abuse or female gender should not take Simvastatin 10 mg except on medical advice.

Measures to reduce the risk of myopathy caused by drug interactions (see above)

Use of simvastatin concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole erythromycin, telithromycin, clarithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, as well as gemfibrozil, ciclosporin and danazol is contraindicated and should be avoided. (see sections 4.3 and 4.5)

If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) is unavoidable, therapy with simvastatin should be suspended (and use of an alternative statin condsidered) during the course of treatment. 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. (See 4.5 Interactions with other medicinal products and other forms of interaction).

The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of amiodarone, amlodipine, verapamil, diltiazem and fusidic acid with statins (section 4.5).

Simvastatin must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see section 4.5). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of simvastatin and fusidic acid should be only considered on a case by case basis and under close medical supervision.

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.

Diabetes Mellitus

Some evidence suggests that statin 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 outweighted 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/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Hepatic effects

In clinical studies with higher doses of simvastatin, persistent increases (to more than 3X ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. These changes appear to be less common with lower doses.

When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

As with other lipid lowering agents, moderate (less than 3X ULN) elevations of serum transaminase 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.

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a known past history of liver disease. Individuals consuming more than the nationally recommended upper limit for weekly units of alcohol (28 for men and 21 for women) should not take Simvastatin 10mg without medical supervision.

Active liver diseases or unexplained persistent transaminase elevations are contra-indications to the use of simvastatin.

There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin.

If an individual develops symptoms or signs of liver disease (e.g.

hyperbilirubinaemia or jaundice) while taking Simvastatin 10mg the drug should be discontinued immediately and medical advice should be sought.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including simvastatin 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.

Excipient

This product contains lactose. Individuals 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

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates and niacin (nicotinic acid) (> 1 g/day). Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and section 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. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates.

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting agents	Prescribing recommendations
Potent CYP3A4 inhibitors eg.:
Itraconazole	Contraindicated with simvastatin
Ketoconazole
Posaconazole

Vorizonazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors (e.g. nelfinavir)
Boceprivir
Telaprevir
Nefazodone
Gemfibrozil
Ciclosporin
Danazol
Other fibrates (except fenofibrate)	Do not exceed 10 mg simvastatin daily
Fusidic acid	Is not recommended with simvastatin
Grapefruit juice	Avoid grapefruit juice when taking simvastatin

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, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir and nefazodone. 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, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated, as well as ciclosporin and danazol (see section

4.3) . If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) is unavoidable, therapy with simvastatin must be suspended (and use of an alternative statin considered) during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin (see section 4.2 and

4.4) .

Fluconazole

Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported (see section 4.4)

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with simvastatin; therefore, use with ciclosporin is contraindicated (see sections 4.3 and 4.4). Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with simvastatin; therefore, use with danazol is contraindicated (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 4.3 and 4.4). Concomitant administration with gemfibrozil is contraindicated.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Coadministration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, simvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. (See section 4.4.)

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of 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.

Colchicine

There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.

Rifampicin

Because rifampicin is a potent CYP3A4 inducer, patients undertaking longterm rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.

Effects of simvastatin on the pharmacokinetics of other medicinal products. Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

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 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. Very rare cases of elevated INR have been reported. 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Simvastatin 10mg is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical 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 was comparable to that seen in the general population. This number of pregnancies was 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 10mg or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Simvastatin 10mg 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 10mg must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Simvastatin 10mg must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3.and 5.3)

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 must not breastfeed their infants (see section 4.3).

4.7 Effects on ability to drive and use machines

Simvastatin Tablets have 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 postmarketing experiences.

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, the most commonly reported side effects were abdominal pain, constipation, flatulence, asthenia and headache.

The following adverse effects have been reported:

Blood and lymphatic system disorders:

Rare: anaemia Psychiatric disorders:

Very rare: insomnia Not known: depression Nervous system disorders:

Rare: headache, paresthesia, dizziness, peripheral neuropathy

Very rare: memory impairment

Respiratory, thoracic and mediastinal disorders:

Not known: interstitial lung disease (see section 4.4)

Gastrointestinal disorders:

Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis Hepatobiliary disorders:

Rare: hepatitis/jaundice

Very rare: fatal and non-fatal hepatic failure

Skin and subcutaneous tissue disorders:

Rare: rash, pruritus, alopecia

Musculoskeletal, connective tissue and bone disorders:

Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps

•    In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively) (see sections 4.4 and 4.5).

Not known: tendinopathy, sometimes complicated by rupture, bursitis Reproductive system and breast disorders:

Not known: erectile dysfunction

General disorders and administration site conditions:

Rare: asthenia

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 CK levels (see section 4.4). Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including simvastatin. The reports are generally non serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). The following adverse events have been reported with some statins:

•    Sleep disturbances, including nightmares* Sexual dysfunction

•    Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose > 5.6 mmol/L, BMI > 30kg/m², raised triglycerides, history of hypertension).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. 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

Pharmacotherapeutic group: HMG-CoA reductase inhibitor ATC-Code: C10A A01

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 10 mg/day reduces Low Density Lipoprotein Cholesterol (LDL-C) by around 27%. This degree of reduction has been shown to reduce the risk of a first major coronary event by about one third after 3 years of treatment.

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed 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 10mg 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 10mg 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 10mg . In addition, Simvastatin 10mg moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

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, 100 mg (20 uCi) of drug was administered as capsules (5 * 20 mg), and blood, urine, and faeces collected. Thirteen percent 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.

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 the rabbit, simvastatin produced no foetal malformations, and had no effects on fertility, reproductive function or neonatal development.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core tablet:

Lactose monohydrate Pregelatinised maize starch Ascorbic acid Citric acid monohydrate Microcrystalline cellulose Butylhydroxyanisole (E320) Croscarmellose sodium Magnesium stearate

Film-coat:

Hydroxypropylcellulose (E463) Hypromellose 15cP (E464) Titanium dioxide (E171)

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

Blister strips comprising of PVdC coated PVC clear transparent film with a backing of hard tempered heat sealable aluminium foil coated with heat seal lacquer containing 14 or 28 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Dexcel-Pharma Laboratories Limited

Ashacres House, Ashacres Industrial Part, Draycott in the Clay, Ashbourne, Derbyshire, DE6 5GX UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 31623/0098

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20^th May 2005

10    DATE OF REVISION OF THE TEXT

07/10/2014