Simvastatin 40 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Simvastatin
Available from:
Accord Healthcare Ireland Ltd.
ATC code:
C10AA; C10AA01
INN (International Name):
Simvastatin
Dosage:
40 milligram(s)
Pharmaceutical form:
Film-coated tablet
Therapeutic area:
HMG CoA reductase inhibitors; simvastatin
Authorization status:
Marketed
Authorization number:
PA2315/130/003
Authorization date:
2009-06-19

Package leaflet: Information for the patient

Simvastatin 10 mg Film-coated Tablets

Simvastatin 20 mg Film-coated Tablets

Simvastatin 40 mg Film-coated Tablets

simvastatin

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

1 What Simvastatin is and what it is used for

2 What you need to know before you take Simvastatin

3 How to take Simvastatin

4 Possible side effects

5 How to store Simvastatin

6 Contents of the pack and other information

1. What Simvastatin is and what it is used for

Simvastatin contains the active substance simvastatin. Simvastatin is a medicine used to

lower levels of total cholesterol, “bad” cholesterol (LDL cholesterol), and fatty substances

called triglycerides in the blood. In addition, Simvastatin raises levels of “good” cholesterol

(HDL cholesterol). Simvastatin is a member of the class of medicines called statins.

Cholesterol is one of several fatty substances found in the bloodstream. Your total cholesterol

is made up mainly of LDL and HDL cholesterol.

LDL cholesterol is often called “bad” cholesterol because it can build up in the walls of your

arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the

arteries. This narrowing can slow or block blood flow to vital organs such as the heart and

brain. This blocking of blood flow can result in a heart attack or stroke.

HDL cholesterol is often called “good” cholesterol because it helps keep the bad cholesterol

from building up in the arteries and protects against heart disease.

Triglycerides are another form of fat in your blood that may increase your risk for heart

disease.

You should stay on a cholesterol-lowering diet while taking this medicine.

Simvastatin is used in addition to your cholesterol-lowering diet if you have:

a raised cholesterol level in your blood (primary hypercholesterolaemia) or elevated

fat levels in your blood (mixed hyperlipidaemia),

a hereditary illness (homozygous familial hypercholesterolaemia), that increases the

cholesterol level in your blood. You may also receive other treatments,

coronary heart disease (CHD) or are at high risk of CHD (because you have diabetes,

history of stroke, or other blood vessel disease). Simvastatin may prolong your life by

reducing the risk of heart disease problems, regardless of the amount of cholesterol in

your blood.

In most people, there are no immediate symptoms of high cholesterol. Your doctor can

measure your cholesterol with a simple blood test. Visit your doctor regularly, keep track of

your cholesterol, and discuss your goals with your doctor.

2. What you need to know before you take Simvastatin

Do not take Simvastatin:

if you are allergic to simvastatin or any of the other ingredients of this medicine

(listed in section 6)

if you currently have liver problems

if you are pregnant or breast-feeding

if you are taking medicine(s) with one or more than one of the following active

ingredients :

- itraconazole, ketoconazole, posaconazole, or voriconazole ( used to treat fungal

infections)

- erythromycin, clarithromycin, or telithromycin (used to treat infections)

- HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and

saquinavir ( HIV protease inhibitors are used for HIV infections)

- boceprevir or telaprevir ( used to treat hepatitis C virus infection)

- nefazodone (used to treat depression)

- cobicistat

- gemfibrozil ( used to lower cholesterol)

- ciclosporin (used in organ transplant patients)

- danazol (a man-made hormone used to treat endometriosis,

a condition in

which the lining of the uterus grows outside the uterus)

Do not take more than 40 mg Simvastatin if you are taking lomitapide (used to treat a serious

and rare genetic cholesterol condition).

Ask your doctor if you are not sure if your medicine is listed above.

Warnings and precautions

Talk to your doctor or pharmacist before taking Simvastatin

Tell your doctor:

about all your medical conditions including allergies

if you drink large amounts of alcohol

if you have ever had liver disease. Simvastatin may not be right for you

if you are due to have an operation. You may need to stop taking Simvastatin tablets

for a short time

if you have severe respiratory failure

if you are Asian, because a different dose may be applicable to you

if you are taking or have taken in the last 7 days a medicine called fusidic acid (a

medicine for bacterial infection) orally or by injection. The combination of fusidic

acid and Simvastatin can lead to serious muscle problems (rhabdomyolysis).

Your doctor should do a blood test before you start taking Simvastatin and if you have any

symptoms of liver problems while you take Simvastatin. This is to check how well your liver

is working.

Your doctor may also want you to have blood tests to check how well your liver is working

after you start taking Simvastatin.

While you are on this medicine your doctor will monitor you closely if you have diabetes or

are at risk of developing diabetes. You are likely to be at risk of developing diabetes if you

have high levels of sugars and fats in your blood, are overweight and have high blood

pressure.

Contact your doctor immediately if you experience unexplained muscle pain,

tenderness, or weakness. This is because on rare occasions, muscle problems can be

serious, including muscle breakdown resulting in kidney damage; and very rare deaths

have occurred.

The risk of muscle breakdown is greater at higher doses of Simvastatin, particularly the 80

mg dose. The risk of muscle breakdown is also greater in certain patients.

Talk with your doctor if any of the following applies:

you consume large amounts of alcohol,

you have kidney problems,

you have thyroid problems,

you are more than 65 years old,

you are female,

you have ever had muscle problems during treatment with cholesterol-lowering medicines

called “statins” or fibrates,

you or close family members have a hereditary muscle disorder.

Also tell your doctor or pharmacist if you have a muscle weakness that is constant.

Additional tests and medicines may be needed to diagnose and treat this.

Children and adolescents

Safety and effectiveness of Simvastatin have been studied in 10-17 year old boys and in girls

who had started their menstrual period (menstruation) at least one year before (see section 3:

How to take Simvastatin).

Simvastatin has not been studied in children under the age of 10 years. For more information,

talk to your doctor.

Other medicines and Simvastatin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicine(s) with any of the following active ingredients. Taking Simvastatin with any of the

following medicines can increase the risk of muscle problems (some of these have already

been listed in the above section “Do not take Simvastatin”).

If you need to take oral fusidic acid to treat a bacterial infection you will need to

temporarily stop using this medicine. Your doctor will tell you when it is safe to

restart Simvastatin. Taking Simvastatin with fusidic acid may rarely lead to

muscle weakness, tenderness or pain (rhabdomyolysis). See more information

regarding rhabdomyolysis in section 4.

ciclosporin (often used in organ transplant patients),

danazol (a man-made hormone used to treat endometriosis, a condition in which the

lining of the uterus grows outside the uterus)

medicines with an active ingredient like itraconazole, ketoconazole, fluconazole,

posaconazole, or voriconazole (used to treat fungal infections)

fibrates with an active ingredient like gemfibrozil and bezafibrate (used to lower

cholesterol),

erythromycin, clarithromycin or telithromycin ( used to treat bacterial infections),

HIV protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir (used to

treate AIDS),

hepatitis C antiviral agents such as boceprevir, teleprevir, elbasvir or grazoprevir

(used to treat hepatitis C virus infection)

nefazodone ( used to treat depression),

medicines with the active ingredient cobicistat,

amiodarone (used to treat an irregular heartbeat),

verapamil, diltiazem, or amlodipine (used to treat high blood pressure, chest pain

associated with heart disease, or other heart conditions),

lomitapide (used to treat a serious and rare genetic cholesterol condition),

colchicine (used to treat gout).

ticagrelor (used to prevent blood clots)

As well as the medicines listed above, tell your doctor or pharmacist if you are taking or have

recently taken any other medicines, including those obtained without a prescription. In

particular, tell your doctor if you are taking medicine(s) with any of the following active

ingredients:

Medicines with an active ingredient to prevent blood clots such as warfarin,

phenprocoumon or acenocoumarol (anticoagulants),

fenofibrate (also used to lower cholesterol),

niacin (also used to lower cholesterol),

rifampicin (used to treat tuberculosis).

You should also tell any doctor who is prescribing a new medicine for you that you are taking

Simvastatin.

Simvastatin with food and drink

Grapefruit juice contains one or more components that alter how the body uses some

medicinal products, including Simvastatin. Consuming grapefruit juice should be avoided.

Pregnancy and breast-feeding

Do not take Simvastatin if you are pregnant, trying to get pregnant or think you may be

pregnant. If you get pregnant while taking Simvastatin, stop taking it immediately and

contact your doctor. Do not take Simvastatin if you are breast-feeding, because it is not

known if the medicine is passed into breast milk.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Simvastatin is not expected to interfere with your ability to drive or use machinery.

However, it should be taken into account that some people get dizzy after taking Simvastatin.

Simvastatin contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact

your doctor before taking this medicinal product.

3. How to take Simvastatin

Your doctor will determine the appropriate tablet strength for you, depending on your

condition, your current treatment and your personal risk status.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with

your doctor or pharmacist if you are not sure. You should stay on a cholesterol-lowering diet

while taking Simvastatin.

Dosage:

The recommended dose is 5 mg, 10 mg, 20 mg, 40 mg or 80 mg by mouth once a day.

Adults: The usual starting dose is 10, 20 or, in some cases, 40 mg a day. Your doctor may

adjust your dose after at least 4 weeks to a maximum of 80 mg a day. Do not take more than

80 mg a day. Your doctor may prescribe lower doses, particularly if you are taking certain

medicinal products listed above or have certain kidney conditions.

The 80 mg dose is only recommended for adult patients with very high cholesterol levels and

at high risk of heart disease problems who have not reached their cholesterol goal on lower

doses.

Use in children and adolescents

For children (10 -17 years old), the recommended usual starting dose is 10 mg a day in the

evening. The maximum recommended dose is 40 mg a day.

Method of administration:

Take Simvastatin in the evening. You can take it with or without food. Keep taking

Simvastatin unless your doctor tells you to stop.

If your doctor has prescribed Simvastatin along with another medicine for lowering

cholesterol containing any bile acid sequestrant, you should take Simvastatin at least 2 hours

before or 4 hours after taking the bile acid sequestrant.

If you take more Simvastatin than you should

please contact your doctor or pharmacist.

If you forget to take Simvastatin

- do not take a double dose to make up for a forgotten tablet. Just take your normal amount of

Simvastatin at the usual time the next day.

If you stop taking Simvastatin

Talk to your doctor or pharmacist because your cholesterol may rise again.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following terms are used to describe how often side effects have been reported:

Rare (may affect up to 1 of 1000 people).

Very rare (may affect up to 1 of 10,000 people).

Not known (frequency cannot be estimated from the available data).

The following rare serious side effects were reported.

If any of these serious side effects happen, stop taking the medicine and tell your doctor

immediately or go to the emergency room at your nearest hospital:

muscle pain, tenderness, weakness, or cramps. On rare occasions, these muscle

problems can be serious, including muscle breakdown (rhabdomyolysis) resulting in

kidney damage; and very rare deaths have occurred .

hypersensitivity (allergic) reactions including:

- swelling of the face, tongue and throat which may cause difficulty in

breathing (angioedema)

- severe muscle pain usually in the shoulders and hips

- rash with weakness of limbs and neck muscles

- pain or inflammation of the joints (polymyalgia rheumatica)

- inflammation of the blood vessels (vasculitis)

- unusual bruising, skin eruptions and swelling (dermatomyositis), hives, skin

sensitivity to the sun, fever, flushing

- shortness of breath (dyspnoea) and feeling unwell

- lupus-like disease picture (including rash, joint disorders, and effects on

blood cells)

inflammation of the liver with the following symptoms; yellowing of the skin and

eyes, itching, dark-coloured urine or pale-coloured stool, feeling tired or weak, loss of

appetite, liver failure (very rare)

inflammation of the pancreas (often with severe abdominal pain).

The following very rare serious side effect was reported:

a serious allergic reaction which causes difficulty in breathing or dizziness

(anaphylaxis)

The following side effects have also been reported rarely:

low red blood cell count (anaemia)

numbness or weakness of the arms and legs,

headache, dizziness, tingling sensation,

digestive disturbances (abdominal pain, constipation, flatulence, indigestion,

diarrhoea, nausea, vomiting),

rash, itching, hair loss

blurred vision and impaired vision (which each may affect up to 1 in 1,000 people),

rash that may occur on the skin or sores in the mouth (lichenoid drug eruptions) (which each

may affect up to 1 in 10,000 people),

weakness,

trouble sleeping (very rare),

poor memory (very rare), memory loss, confusion.

The following side effects have also been reported but the frequency cannot be estimated

from the available information (frequency not known):

erectile dysfunction,

depression,

muscle pain, tenderness, weakness or cramps; muscle breakdown, muscle rupture (which

may affect up to 1 in 10,000 people);

tendon problems, sometimes complicated by

rupture of the tendon.

gynecomastia (breast enlargement in men) (which may affect up to 1 in 10,000 people)

Possible side effects reported with some statins:

sleep disturbances, including nightmares,

sexual difficulties,

breathing problems including persistent cough and/or shortness of breath or fever

diabetes. This is more likely if you have high levels of sugars and fats in your blood,

are overweight and have high blood pressure. Your doctor will monitor you while you

are taking this medicine,

Laboratory Values

Elevations in some laboratory blood tests of liver function and a muscle enzyme (creatine

kinase) have been observed.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1

6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you

can help provide more information on the safety of this medicine.

5 How to store Simvastatin

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after EXP.

The expiry date refers to the last day of that month.

Do not store above 30°C.

Store the tablets in the original package, in order to protect from light and moisture.

After first opening of the HDPE container: Store below 25°C and use within 6 months.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help protect the

environment.

6. Contents of the pack and other information

What Simvastatin contains

Simvastatin 10 mg: The active substance is Simvastatin, 10 mg

Simvastatin 20 mg: The active substance is Simvastatin, 20 mg

Simvastatin 40 mg: The active substance is Simvastatin, 40 mg

The other ingredients are:

Tablet core: Lactose monohydrate, microcrystalline cellulose (E460), Starch (maize)

pregelatinised 1500, butylhydroxyanisole (E320), ascorbic acid (E300), Citric acid (E330),

silica, colloidal anhydrous (E551), talc (E553b), magnesium stearate (E470b).

Film-coating: Hypromellose (E464), iron oxide, red (E172), iron oxide, yellow (E172),

triethylcitrate (E1505), titanium dioxide (E171), talc (E553b), povidone K-30.

What Simvastatin looks like and contents of the pack

Simvastatin 10 mg is a peach-coloured, oval, biconvex, film-coated tablet, scored on one

side; the tablets can be divided into equal halves along the score line.

Simvastatin 20 mg is a tan-coloured, oval, biconvex, film-coated tablet, scored on one side;

the tablets can be divided into equal halves along the score line.

Simvastatin 40 mg is a brick red-coloured, oval, biconvex, film-coated tablet, scored on one

side; the tablets can be divided into equal halves along the score line.

The tablets are packed in blisters in a carton box or HDPE container.

Pack sizes:

Blisters:

Simvastatin 10 mg, film-coated tablets: 10, 20, 28, 30, 50, 60, 98 and 100 tablets.

Simvastatin 20 mg, film-coated tablets: 10, 20, 28, 30, 50, 60, 98 and 100 tablets.

Simvastatin 40 mg, film-coated tablets: 10, 20, 28, 30, 50, 60, 98 and 100 tablets.

Tablet container:

Simvastatin 10 mg, film-coated tablets: 100, 250 and 500 tablets.

Simvastatin 20 mg, film-coated tablets: 100, 250 and 500 tablets

Simvastatin 40 mg, film-coated tablets: 100, 250 tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

MA Holder:

Accord Healthcare Ireland Ltd, Euro House, Euro Business Park, Little Island, Cork T45 K857,

Ireland

Manufacturer:

Balkanpharma-Dupnitsa AD, 3 Samokovsko Shosse Str., 2600 Dupnitsa, Bulgaria;

Accord UK Ltd, Whiddon Valley, Barnstaple, North Devon EX32 8NS, UK.

This leaflet was last revised in April 2020

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Simvastatin 40 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet Simvastatin Actavis 40 mg contains 40 mg of simvastatin.

Excipient (s) with known effect

Each tablet contains 262.92 mg of lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Brick red-coloured, oval, biconvex, film-coated tablet, scored on one side.

The tablets can be divided into equal doses

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 (HoFH) 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

Posology

The dosage range is 5-80 mg/day of simvastatin 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 80 mg/day given as a single dose in the

evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and at high risk for

cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected

to outweigh the potential risks (see sections 4.4 and 5.1).

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 20-40 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 starting dosage is simvastatin 40 mg/day 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.

In patients taking lomitapide concomitantly with Simvastatin, the dose of Simvastatin must not exceed 40 mg/day (see sections

4.3, 4.4 and 4.5).

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Cardiovascular prevention

The usual dose of simvastatin is 20 to 40 mg/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 simvastatin concomitantly with fibrates other than gemfibrozil (see section 4.3) or fenofibrate, the dose of

simvastatin should not exceed 10 mg/day. In patients taking amiodarone, amlodipine, verapamil, diltiazem, or products

containing elbasvir or grazoprevir concomitantly with simvastatin, the dose of simvastatin should not exceed 20 mg/day (see

sections 4.4 and 4.5).

Renal impairment

No modification of dosage should be necessary in patients with moderate renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully

considered and, if deemed necessary, implemented cautiously.

Elderly

No dosage adjustment is necessary.

Paediatric population

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.

Method of administration

Simvastatin Actavis is for oral administration. Simvastatin Actavis can be administered as a single dose in the evening.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Active liver disease or unexplained persistent elevations of serum transaminases.

Pregnancy and lactation (see section 4.6).

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, and medicinal products containing

cobicistat) (see sections 4.4 and 4.5).

Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5).

In patients with HoFH, concomitant administration of lomitapide with doses >40 mg Simvastatin (see sections 4.2,

4.4 and 4.5)

4.4 Special warnings and precautions for use

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 (i.e., elevated simvastatin and

simvastatin acid plasma levels), which may be due, in part, to interacting drugs that interfere with simvastatin metabolism

and/or transporter pathways (see section 4.5).

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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, 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 %, 0.08 % 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).

The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar

LDL-C-lowering efficacy. Therefore, the 80-mg dose of simvastatin should only be used in patients with severe

hypercholesterolemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower

doses and when the benefits are expected to outweigh the potential risks. In patients taking simvastatin 80 mg for whom an

interacting agent is needed, a lower dose of simvastatin or an alternative statin-based regimen with less potential for

drug-drug interactions should be used (see below Measures to reduce the risk of myopathy caused by medicinal product

interactions and sections 4.2, 4.3, and 4.5).

In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median

follow-up 3.9 years), the incidence of myopathy was approximately 0.05 % for non-Chinese patients (n =7367) compared with

0.24 % for Chinese patients (n = 5468). While the only Asian population assessed in this clinical trial was Chinese, caution

should be used when prescribing simvastatin to Asian patients and the lowest dose necessary should be employed.

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 (e.g. 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.

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 ≥ 65 years).

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

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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.

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 (see section 4.8).

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, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV

protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat), as well as

gemfibrozil, ciclosporin, and danazol. Use of these medicinal products is contraindicated (see section 4.3).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil, or

diltiazem with certain doses of simvastatin (see sections 4.2 and 4.5). For patients with HoFH, this risk may be increased by

concomitant use of lomitapide with simvastatin.

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole,

posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin,

telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated (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 must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover,

caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole,

verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The use of simvastatin with gemfibrozil is contraindicated (see section 4.3). Due to the increased risk of myopathy and

rhabdomyolysis, the dose of simvastatin should not exceed 10 mg daily in patients taking simvastatin with other fibrates,

except fenofibrate. (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.

Simvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid

treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued

throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in

patients receiving fusidic acid and statins in combination (see section 4.5). 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 only be considered on a case by case basis and under close

medical supervision.

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The combined use of simvastatin at doses higher than 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem

should be avoided. In patients with HoFH, the combined use of simvastatin at doses higher than 40 mg daily with lomitapide

must be avoided (see sections 4.2, 4.3 and 4.5).

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin,

particularly higher simvastatin doses, may have an increased risk of myopathy. When co-administering simvastatin with a

moderate inhibitor of CYP3A4 (agents that increase AUC approximately 2-5 fold), a dose adjustment of simvastatin may be

necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20 mg simvastatin is recommended (see

section 4.2).

Simvastatin is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of

products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin

and an increased risk of myopathy; therefore, a dose adjustment of simvastatin should be considered depending on the

prescribed dose. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of

simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with products containing

elbasvir or grazoprevir (see section 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.

In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled

LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular

outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid). Therefore, 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 addition, in this trial, the incidence of myopathy was approximately 0.24 % for Chinese patients on simvastatin 40 mg or

ezetimibe/simvastatin 10/40 mg compared with 1.24 % for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin

10/40 mg co-administered with modified-release nicotinic acid/laropiprant 2000 mg/40 mg.

While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in

Chinese than in non-Chinese patients, co-administration of simvastatin with lipid-modifying doses (≥1 g/day) of niacin

(nicotinic acid) is not recommended in Asian patients.

Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be

similar to niacin.

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. Note that ALT may emanate from muscle, therefore ALT rising with CK may

indicate myopathy (see above Myopathy/Rhabdomyolysis).

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

simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with

simvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart simvastatin.

The product should be used with caution in patients who consume substantial quantities of alcohol.

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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.

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. This 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 > 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and

biochemically according to national guidelines.

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.

Paediatric population

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 (s)

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interactions

Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products

that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin

acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.

Consult the prescribing information of all concomitantly used drugs to obtain further information about their

potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible

adjustments to dose and regimens.

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.

Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below

Pharmacokinetic interactions and sections 4.3 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.

Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of

myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (≥ 1 g/day) of

niacin (see section 4.4).

Pharmacokinetic interactions

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Prescribing recommendations for interacting agents are summarized in the table below (further details are provided in the text;

see also sections 4.2, 4.3, and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ​

Interacting agents

Prescribing recommendations

Potent CYP3A4 inhibitors, e.g.,

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors (e.g., nelfinavir)

Boceprevir

Telaprevir

Nefazodone

Cobicistat

Ciclosporin

Danazol

Gemfibrozil

Contraindicated with simvastatin

Other fibrates (except fenofibrate)

Do not exceed 10 mg simvastatin daily

Fusidic acid

Is not recommended with simvastatin

Niacin (nicotinic acid) (≥ 1 g/day)

For Asian patients, not recommended with simvastatin

Amiodarone

Amlodipine

Verapamil

Diltiazem

Elbasvir

Grazoprevir

Do not exceed 20 mg simvastatin daily

Lomitapide

For patients with HoFH, do not exceed 40 mg simvastatin daily

Grapefruit juice

Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving inhibitors of 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, nefazodone and medicinal products containing

cobicistat. 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.

Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir,

telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and medicinal products containing cobicistat is

contraindicated, as well as gemfibrozil, 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: fluconazole, verapamil, or diltiazem (see sections 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 is presumably due,

in part, to inhibition of CYP3A4 and/or OATP1B1.

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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 and/or

OATP1B1 (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. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown.

There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, simvastatin treatment should be discontinued throughout the duration of

the fusidic acid treatment. Also see section 4.4.

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin (see

section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone.

Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with

amiodarone.

Calcium Channel Blockers

Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or

80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase

in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of simvastatin should not

exceed 20 mg daily in patients receiving concomitant medication with verapamil.

Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see

section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of

simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in

patients receiving concomitant medication with diltiazem.

Amlodipine

Patients on amlodipine treated concomitantly with simvastatin have an increased risk of myopathy. In a pharmacokinetic study,

concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of

simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amlodipine.

Lomitapide

The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with simvastatin (see

sections 4.3 and 4.4). Therefore, in patients with HoFH, the dose of simvastatin must not exceed 40 mg daily in patients

receiving concomitant medication with lomitapide.

Moderate Inhibitors of CYP3A4

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin,

particularly higher simvastatin doses, may have an increased risk of myopathy (see section 4.4).

Inhibitors of the Transport Protein OATP1B1

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are

inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased

risk of myopathy (see sections 4.3 and 4.4).

Inhibitors of Breast Cancer Resistant Protein (BCRP)

Concomitant administration of medicinal products that are inhibitors of BCRP, including products containing elbasvir or

grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy (see sections 4.2

and 4.4).

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Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (≥

1 g/day) of niacin (nicotinic acid). In a pharmacokinetic study, the co-administration of a single dose of nicotinic acid

prolonged-release 2 g with simvastatin 20 mg resulted in a modest increase in the AUC of simvastatin and simvastatin acid and

in the Cmax of simvastatin acid plasma concentrations.

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 impairment. Close clinical monitoring of such patients taking this combination is advised.

Rifampicin

Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term 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.

Ticagrelor

Co-administration of ticagrelor with simvastatin increased simvastatin C

by 81% and AUC by 56% and increased simvastatin

acid C

by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Co-administration of ticagrelor with

doses of simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should be weighed against

potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. The concomitant use of ticagrelor with doses

of simvastatin greater than 40 mg is not recommended.

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 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.

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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

must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with

simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.

(See sections 4.3 and 5.3).

Breastfeeding

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

breast-feed their infants (see section 4.3).

Fertility

No clinical trial data are available on the effects of simvastatin on human fertility. Simvastatin had no effect on the fertility of

male and female rats (see section 5.3).

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 categorized 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, increases 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

causally related spontaneous report events, these adverse events are categorized as "rare".

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of simvastatin (n = 10,269) or placebo (n =10,267),

the safety profiles were comparable between patients treated with simvastatin 40 mg 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 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients

treated with simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of

patients treated with simvastatin 40 mg 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 (³ 1/1000, < 1/100), Rare (> 1/10,000, < 1/1000), Very Rare (< 1/10,000), Not known (cannot be estimated from the

available data).

Eye disorders:

Rare: vision blurred, visual impairment

Blood and lymphatic system disorders:

Rare: anaemia

Immune system disorders:

Very rare: anaphylaxis

Psychiatric disorders:

Very rare: insomnia

Not known: depression

Nervous system disorders:

Rare: headache, paraesthesia, dizziness, peripheral neuropathy

Very rare: memory impairment

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