Simvastatin 40mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Simvastatin
Available from:
Genesis Pharmaceuticals Ltd
ATC code:
C10AA01
INN (International Name):
Simvastatin
Dosage:
40mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 02120000; GTIN: 5060014442048
Authorization number:
PL 33414/0104

Read the complete document

Product:

MA Holder:

Chelonia

PL No.:

33414/0101-0104

Pack Size:

-

Livery:

Genesis

Manufacturer:

-

Market:

UK

Component:

Leaflet

Dimensions:

148 x 297 mm

Created By:

DTawde

Artwork Code:

CL0101-0102-0103-0104/O/PIL/G6

Bar Code:

-

Font Type:

Arial Narrow

Font Size:

7.25 pt

Printing Colours:

Non-Printing Colours:

Black

Profile

Final Preparation Date For Submission:

06/12/2019

Packing Site Technical Approval:

00/00/0000

Authority Approval Date:

09/01/2020

Latest Implementation Deadline:

09/07/2020

Print Proof Approval:

00/00/0000

Simvastatin 5, 10, 20

& 40 mg Tablets

Simvastatin has not been studied in children under the age of 10

years. For more information, talk to your doctor.

Driving and using machines

Simvastatin is not expected to interfere with your ability to drive or to

use machinery. Simvastatin may cause dizziness in rare cases. If

you feel dizzy, then do not drive or operate any machines.

Simvastatin tablets contain lactose

This medicine contains lactose. If you have been told by your doctor

that you have an intolerance to lactose or other sugars, contact your

doctor before taking this medicine.

Your doctor will determine the appropriate tablet strength for you,

depending

your

condition,

your

current

treatment

your

personal risk status. Always take Simvastatin exactly as your doctor

has told you. You should check with your doctor or pharmacist if you

are not sure.

Swallow the tablets with water. Simvastatin tablets may be taken with

or without food. Remember to keep to a low-fat diet and exercise

while taking Simvastatin.

Dosage:

The recommended dose is Simvastatin 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 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.

Taking another medicine for lowering your cholesterol at the

same time as Simvastatin

Your doctor may ask you to take a bile acid sequestrant (another

type of medicine for lowering cholesterol, such as cholestyramine) at

the same time as taking Simvastatin. This type of medicine can

change the way Simvastatin works. You should take Simvastatin at

least two hours before or at least four hours after taking the bile acid

sequestrant.

Patients with severe kidney problems:

Your doctor may prescribe a lower dose, which will usually not be

more than 10 mg per day.

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 you take more Simvastatin than you should

If you (or someone else) take too many tablets, contact your doctor

nearest

hospital

casualty

department

immediately. Take

this leaflet and the package with you so they know what has been

taken.

If you forget to take Simvastatin

If you forget to take a dose, take it as soon as you remember.

However, if it is nearly time for the next dose, skip the missed dose

and take the next dose when it is due. Do not take a double dose

(two doses at the same time) to make up for a forgotten dose.

If you stop taking Simvastatin

If you suddenly stop taking Simvastatin, your blood cholesterol levels

may rise again. Do not stop taking this medicine without consulting

your doctor beforehand. Your doctor will advise you on how best to

do this.

If you have any further questions on the use of this medicine, ask

your doctor or pharmacist.

Like all medicines, Simvastatin can cause side effects, although not

everybody gets them.

The following rare serious side effects were reported.

If you get any of the following serious side effects, STOP

TAKING Simvastatin and tell your doctor immediately or go to

the nearest hospital emergency department:

a hypersensitivity (allergic) reaction to Simvastatin

You experience some of the following symptoms;

Swelling of the face, tongue or throat which may cause

difficulty in breathing (angioedema)

Lupus-like syndrome (an inflammatory disease which causes

joint pain, skin rashes and fever)

severe muscle pain and stiffness usually in the shoulders and

hips

rash with weakness of the limbs and neck muscles

inflammation of the blood vessels

increased incidents of bleeding or bruising

stiffness, pain or inflammation of the joints

skin eruptions and swelling (dermatomyositis), red, raised

lumps (hives), skin sensitivity to the sun, fever, flushing,

unusal bruising

shortness of breath, feeling unwell

Muscle pain, tenderness, weakness or cramps. On rare

occasions, these muscle problems can be serious, including

muscle breakdown resulting in kidney damage.

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. Do not pass

it on to others. It may harm them, even if their symptoms

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.

PACKAGE LEAFLET: INFORMATION FOR THE USER

SIMVASTATIN 5 mg, 10 mg,

20 mg & 40 mg TABLETS

1. W

hat 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

Simvastatin belongs to a group of medicines called HMG-CoA

reductase inhibitors, also known as ‘statins’, which work by lowering

the levels of total cholesterol, bad cholesterol (LDL cholesterol) and

fatty substances (triglycerides) in your blood. In addition, Simvastatin

raises levels of good cholesterol (HDL cholesterol).

Cholesterol is one of several fatty substances found in the blood

stream. 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 while

taking this medicine to:

treat raised levels of cholesterol (primary hypercholesterolaemia)

or triglycerides (mixed hyperlipidaemia) in your blood.

treat hereditary illness that increased levels of cholesterol in your

blood (homozygous familial hypercholesterolaemia), together

with dieting and other treatments (e.g. LDL-apheresis), or when

such treatments are not appropriate. You may also receive other

treatments.

prevent 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.

most

people,

there

immediate

symptoms

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.

Do not take Simvastatin and tell your doctor if you:

are allergic (hypersensitive) to Simvastatin or any of the other

ingredients in these tablets (listed in section 6)

have liver problems

are pregnant or breast-feeding (see the section ‘Pregnancy and

Breast-feeding’ below)

are taking medicines, with one or more than one of the following

active ingredients (also see the section ‘Taking other medicines’

below)

- itraconazole, ketoconazole, voriconazole or posaconazole

(used to treat fungal infections)

HIV-protease inhibitors such as ritonavir, indinavir, saquinavir

or nelfinavir (used to treat HIV infections)

boceprevir, telaprevir, elbasvir or grazoprevir (used to treat

hepatitis C virus infection)

cobicistat

gemfibrozil (used to lower cholesterol)

ciclosporin (used in organ transplant patients)

danazol (used to treat endometriosis, a condition in which the

lining of the uterus grows outside the uterus)

erythromycin, clarithromycin or telithromycin (used to treat

infections)

nefazodone (used to treat depression)

taking lomitapide (used to treat a serious and rare genetic

cholesterol condition).

If you are not sure, talk to your doctor or pharmacist before taking

Simvastatin.

What is in the leaflet

1. What Simvastatin is and what it is

used for

2. What you need to know before you

take Simvastatin

Warnings and Precautions

Tell your doctor:

if you are taking or have taken, in the last 7 days, a medicine

called fusidic acid.

about all your medical conditions including allergies.

if you consume large amounts of alcohol.

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

for you.

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

you.

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.

Tell your doctor if you have severe lung disease.

Contact your doctor immediately if you experience unexplained

muscle

pain,

tenderness

or

muscle

weakness

while

being

treated with Simvastatin. This is because on rare occasions,

muscle problems can be serious, including muscle breakdown

resulting in kidney damage; and very rare deaths have occurred.

Simvastatin may cause muscle breakdown (see section 4). The risk

of muscle breakdown is greater at higher doses, particularly the

80 mg dose. This risk of muscle breakdown is also greater in certain

patients. Talk with your doctor if you:

regularly consume large amounts of alcohol

have kidney problems

are female

have ever had problems with your muscles while using statins or

fibrates (medicines to reduce fat levels in the blood)

or a close family members suffer from hereditary muscle

disorders

are 65 years or older

have thyroid problems which are not being treated

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.

Operations and tests

If you are going to have an operation, tell the doctor, dentist or nurse

that you are taking Simvastatin. You may need to stop taking

Simvastatin tablets for a short time.

Taking Simvastatin may affect the results of some clinical tests. If you

are going to have a test, it is important to tell your doctor or nurse that

you are taking Simvastatin.

Your doctor may want you to have some simple blood tests to check

your liver both before you start taking Simvastatin and during your

treatment. This is to check how well your liver is working.

Other medicines and Simvastatin

Tell your doctor or pharmacist if you are taking, have recently taken

or might take any other medicines, including medicines bought

without a prescription.

In particular, tell your doctor or pharmacist if you are taking any of the

following medicines:

medicines to treat irregular heart beat, such as amiodarone

medicines to treat bacterial infections such as clarithromycin,

erythromycin, telithromycin or fusidic acid. Do not take fusidic

acid while using this medicine. Taking simvastatin with fusidic

acid may rarely lead to muscle weakness, tenderness or pain

(rhabdomyolysis). Simvastatin may cause muscle breakdown

(see section 4).

medicines to treat fungal infections such as fluconazole,

itraconazole, ketoconazole, voriconazole or posaconazole

HIV protease inhibitors used to treat AIDS, such as indinavir,

nelfinavir, ritonavir or saquinavir

medicines to treat hepatitis C infections such as boceprevir or

telaprevir

medicines with the active ingredient cobicistat.

medicines to treat high blood pressure or chest pain associated

with heart disease or other heart conditions, such as diltiazem,

verapamil or amlodipine

medicines used to thin the blood and stop blood clots from

forming, such as warfarin, phenprocoumon or acenocoumarol

other cholesterol-lowering medicines known as fibrates, such as

bezafibrate and gemfibrozil

niacin or nicotinic acid also to lower cholesterol (in doses greater

than 1 gram a day)

ciclosporin, often used in organ transplant patients.

colchicine to treat gout

danazol to treat endometriosis and breast cysts in women

nefazodone to treat depression

rifampicin, an antibiotic used to treat tuberculosis

fenofibrate, used to lower cholesterol

lomitapide, used to treat a serious and rare genetic cholesterol

condition

Taking Simvastatin with food and drink

You should not drink grapefruit juice whilst you are being treated with

Simvastatin. It may increase the amount of Simvastatin in your blood

and could increase the risk of muscle problems.

Pregnancy and breast-feeding

Do not take Simvastatin if you are pregnant or trying to become

pregnant or think you may be pregnant.

You should stop taking Simvastatin before trying to get pregnant. If

you become pregnant while taking Simvastatin, stop taking it and

see your doctor straight away.

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.

Children and adolescents

Safety and effectiveness 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 4’ below).

inflammation of the liver, (hepatitis), which may cause yellowing

of the skin or whites of the eyes (jaundice), darker urine or paler

stools, feeling tired or weak, loss of appetite; liver failure (very

rare)

inflammation of the pancreas (pancreatitis), which causes severe

pain in the abdomen and back

The following very rare serious side effect was reported:

a serious allergic reaction which causes difficulty in breathing or

dizziness (anaphylaxis)

Tell your doctor or pharmacist if you get any of these side

effects:

Rare side effects (may affect up to 1 in 1000 people):

low levels of red blood cells, (anaemia), which can make your

skin pale and cause tiredness and breathlessness

constipation, stomach pain, wind (flatulence), indigestion,

diarrhoea, feeling sick or being sick (nausea or vomiting)

weakness

headache, tingling or ‘pins and needles’, dizziness, a disorder of

the nerves which can cause weakness or numbness of the arms

and legs

rash, itching, hair loss

Very rare side effects (may affect up to 1 in 10,000 people):

liver failure

trouble sleeping, nighmares

poor memory, memory loss, confusion

Not Known (frequency cannot be estimated from the available

data):

Muscle weakness that is constant, sometimes complicated by

rupture of tendon.

depression

breathing problems including a persistent cough and/or

shortness of breath

impotence

Additional possible side-effects reported with some statins:

sleep disturbances, including sleeplessness and nightmares

sexual difficulties

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

Yellow

card

Scheme

www.mhra.gov.uk/yellowcard. By reporting side effects you can help

provide more information on the safety of this medicine.

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

Do not use the tablets after the expiry date stated on the label [EXP].

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

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

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.

What Simvastatin tablets contain

The active substance is Simvastatin. Each tablet contains 5 mg or 10

mg or 20 mg or 40 mg of the active substance.

other

ingredients

are:

lactose

anhydrous,

microcrystalline

cellulose (E460), pregelatinised maize starch, butylhydroxyanisole

(E320),

talc

(E553b),

magnesium

stearate

(E572),

hydroxypropylcellulose (E463), hypromellose (E464) and titanium

dioxide (E171).

The 5 mg tablets also contain yellow iron oxide (E172).

What Simvastatin tablets look like and contents of the pack

Simvastatin 5 mg Tablets are yellow, oblong, scored film-coated

tablets, with ‘SVT’ on one side and ‘5’ on the other.

Simvastatin 10 mg Tablets are white, oblong, biconvex film-coated

tablets, scored on one side, embossed with ‘10’ on the scored side

and with “SVT” and logo on the other side.

Simvastatin 20 mg Tablets are white, oblong, biconvex film-coated

tablets, scored on one side, embossed with “20” on the scored side

and with “SVT” and logo on the other side.

Simvastatin 40 mg Tablets are white, oblong, biconvex film-coated

tablets, scored on one side, embossed with “40” on the scored side

and with “SVT” and logo on the other side.

Simvastatin tablets are available in blister packs of 28 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Chelonia Healthcare Limited

Boumpoulinas 11, 3rd Floor, Nicosia, P.C. 1060, Cyprus

Manufacturer

DDSA Pharmaceuticals Limited

84 Pembroke Road, London, W8 6NX, UK

more

information

about

this

product,

please

contact

Marketing Authorisation Holder.

This leaflet was last approved in 12/2019

CL0101-0102-0103-0104/O/PIL/G6

Simvastatin has not been studied in children under the age of 10

years. For more information, talk to your doctor.

Driving and using machines

Simvastatin is not expected to interfere with your ability to drive or to

use machinery. Simvastatin may cause dizziness in rare cases. If

you feel dizzy, then do not drive or operate any machines.

Simvastatin tablets contain lactose

This medicine contains lactose. If you have been told by your doctor

that you have an intolerance to lactose or other sugars, contact your

doctor before taking this medicine.

Your doctor will determine the appropriate tablet strength for you,

depending

your

condition,

your

current

treatment

your

personal risk status. Always take Simvastatin exactly as your doctor

has told you. You should check with your doctor or pharmacist if you

are not sure.

Swallow the tablets with water. Simvastatin tablets may be taken with

or without food. Remember to keep to a low-fat diet and exercise

while taking Simvastatin.

Dosage:

The recommended dose is Simvastatin 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 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.

Taking another medicine for lowering your cholesterol at the

same time as Simvastatin

Your doctor may ask you to take a bile acid sequestrant (another

type of medicine for lowering cholesterol, such as cholestyramine) at

the same time as taking Simvastatin. This type of medicine can

change the way Simvastatin works. You should take Simvastatin at

least two hours before or at least four hours after taking the bile acid

sequestrant.

Patients with severe kidney problems:

Your doctor may prescribe a lower dose, which will usually not be

more than 10 mg per day.

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 you take more Simvastatin than you should

If you (or someone else) take too many tablets, contact your doctor

nearest

hospital

casualty

department

immediately. Take

this leaflet and the package with you so they know what has been

taken.

If you forget to take Simvastatin

If you forget to take a dose, take it as soon as you remember.

However, if it is nearly time for the next dose, skip the missed dose

and take the next dose when it is due. Do not take a double dose

(two doses at the same time) to make up for a forgotten dose.

If you stop taking Simvastatin

If you suddenly stop taking Simvastatin, your blood cholesterol levels

may rise again. Do not stop taking this medicine without consulting

your doctor beforehand. Your doctor will advise you on how best to

do this.

If you have any further questions on the use of this medicine, ask

your doctor or pharmacist.

Like all medicines, Simvastatin can cause side effects, although not

everybody gets them.

The following rare serious side effects were reported.

If you get any of the following serious side effects, STOP

TAKING Simvastatin and tell your doctor immediately or go to

the nearest hospital emergency department:

a hypersensitivity (allergic) reaction to Simvastatin

You experience some of the following symptoms;

Swelling of the face, tongue or throat which may cause

difficulty in breathing (angioedema)

Lupus-like syndrome (an inflammatory disease which causes

joint pain, skin rashes and fever)

severe muscle pain and stiffness usually in the shoulders and

hips

rash with weakness of the limbs and neck muscles

inflammation of the blood vessels

increased incidents of bleeding or bruising

stiffness, pain or inflammation of the joints

skin eruptions and swelling (dermatomyositis), red, raised

lumps (hives), skin sensitivity to the sun, fever, flushing,

unusal bruising

shortness of breath, feeling unwell

Muscle pain, tenderness, weakness or cramps. On rare

occasions, these muscle problems can be serious, including

muscle breakdown resulting in kidney damage.

PACKAGE LEAFLET: INFORMATION FOR THE USER

SIMVASTATIN 5 mg, 10 mg,

20 mg & 40 mg TABLETS

1. W

hat 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

Simvastatin belongs to a group of medicines called HMG-CoA

reductase inhibitors, also known as ‘statins’, which work by lowering

the levels of total cholesterol, bad cholesterol (LDL cholesterol) and

fatty substances (triglycerides) in your blood. In addition, Simvastatin

raises levels of good cholesterol (HDL cholesterol).

Cholesterol is one of several fatty substances found in the blood

stream. 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 while

taking this medicine to:

treat raised levels of cholesterol (primary hypercholesterolaemia)

or triglycerides (mixed hyperlipidaemia) in your blood.

treat hereditary illness that increased levels of cholesterol in your

blood (homozygous familial hypercholesterolaemia), together

with dieting and other treatments (e.g. LDL-apheresis), or when

such treatments are not appropriate. You may also receive other

treatments.

prevent 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.

most

people,

there

immediate

symptoms

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.

Do not take Simvastatin and tell your doctor if you:

are allergic (hypersensitive) to Simvastatin or any of the other

ingredients in these tablets (listed in section 6)

have liver problems

are pregnant or breast-feeding (see the section ‘Pregnancy and

Breast-feeding’ below)

are taking medicines, with one or more than one of the following

active ingredients (also see the section ‘Taking other medicines’

below)

- itraconazole, ketoconazole, voriconazole or posaconazole

(used to treat fungal infections)

HIV-protease inhibitors such as ritonavir, indinavir, saquinavir

or nelfinavir (used to treat HIV infections)

boceprevir, telaprevir, elbasvir or grazoprevir (used to treat

hepatitis C virus infection)

cobicistat

gemfibrozil (used to lower cholesterol)

ciclosporin (used in organ transplant patients)

danazol (used to treat endometriosis, a condition in which the

lining of the uterus grows outside the uterus)

erythromycin, clarithromycin or telithromycin (used to treat

infections)

nefazodone (used to treat depression)

taking lomitapide (used to treat a serious and rare genetic

cholesterol condition).

If you are not sure, talk to your doctor or pharmacist before taking

Simvastatin.

6. Contents of the pack and other

information

4. Possible side effects

5. How to store Simvastatin

3. How to take Simvastatin

Warnings and Precautions

Tell your doctor:

if you are taking or have taken, in the last 7 days, a medicine

called fusidic acid.

about all your medical conditions including allergies.

if you consume large amounts of alcohol.

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

for you.

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

you.

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.

Tell your doctor if you have severe lung disease.

Contact your doctor immediately if you experience unexplained

muscle

pain,

tenderness

or

muscle

weakness

while

being

treated with Simvastatin. This is because on rare occasions,

muscle problems can be serious, including muscle breakdown

resulting in kidney damage; and very rare deaths have occurred.

Simvastatin may cause muscle breakdown (see section 4). The risk

of muscle breakdown is greater at higher doses, particularly the

80 mg dose. This risk of muscle breakdown is also greater in certain

patients. Talk with your doctor if you:

regularly consume large amounts of alcohol

have kidney problems

are female

have ever had problems with your muscles while using statins or

fibrates (medicines to reduce fat levels in the blood)

or a close family members suffer from hereditary muscle

disorders

are 65 years or older

have thyroid problems which are not being treated

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.

Operations and tests

If you are going to have an operation, tell the doctor, dentist or nurse

that you are taking Simvastatin. You may need to stop taking

Simvastatin tablets for a short time.

Taking Simvastatin may affect the results of some clinical tests. If you

are going to have a test, it is important to tell your doctor or nurse that

you are taking Simvastatin.

Your doctor may want you to have some simple blood tests to check

your liver both before you start taking Simvastatin and during your

treatment. This is to check how well your liver is working.

Other medicines and Simvastatin

Tell your doctor or pharmacist if you are taking, have recently taken

or might take any other medicines, including medicines bought

without a prescription.

In particular, tell your doctor or pharmacist if you are taking any of the

following medicines:

medicines to treat irregular heart beat, such as amiodarone

medicines to treat bacterial infections such as clarithromycin,

erythromycin, telithromycin or fusidic acid. Do not take fusidic

acid while using this medicine. Taking simvastatin with fusidic

acid may rarely lead to muscle weakness, tenderness or pain

(rhabdomyolysis). Simvastatin may cause muscle breakdown

(see section 4).

medicines to treat fungal infections such as fluconazole,

itraconazole, ketoconazole, voriconazole or posaconazole

HIV protease inhibitors used to treat AIDS, such as indinavir,

nelfinavir, ritonavir or saquinavir

medicines to treat hepatitis C infections such as boceprevir or

telaprevir

medicines with the active ingredient cobicistat.

medicines to treat high blood pressure or chest pain associated

with heart disease or other heart conditions, such as diltiazem,

verapamil or amlodipine

medicines used to thin the blood and stop blood clots from

forming, such as warfarin, phenprocoumon or acenocoumarol

other cholesterol-lowering medicines known as fibrates, such as

bezafibrate and gemfibrozil

niacin or nicotinic acid also to lower cholesterol (in doses greater

than 1 gram a day)

ciclosporin, often used in organ transplant patients.

colchicine to treat gout

danazol to treat endometriosis and breast cysts in women

nefazodone to treat depression

rifampicin, an antibiotic used to treat tuberculosis

fenofibrate, used to lower cholesterol

lomitapide, used to treat a serious and rare genetic cholesterol

condition

Taking Simvastatin with food and drink

You should not drink grapefruit juice whilst you are being treated with

Simvastatin. It may increase the amount of Simvastatin in your blood

and could increase the risk of muscle problems.

Pregnancy and breast-feeding

Do not take Simvastatin if you are pregnant or trying to become

pregnant or think you may be pregnant.

You should stop taking Simvastatin before trying to get pregnant. If

you become pregnant while taking Simvastatin, stop taking it and

see your doctor straight away.

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.

Children and adolescents

Safety and effectiveness 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 4’ below).

inflammation of the liver, (hepatitis), which may cause yellowing

of the skin or whites of the eyes (jaundice), darker urine or paler

stools, feeling tired or weak, loss of appetite; liver failure (very

rare)

inflammation of the pancreas (pancreatitis), which causes severe

pain in the abdomen and back

The following very rare serious side effect was reported:

a serious allergic reaction which causes difficulty in breathing or

dizziness (anaphylaxis)

Tell your doctor or pharmacist if you get any of these side

effects:

Rare side effects (may affect up to 1 in 1000 people):

low levels of red blood cells, (anaemia), which can make your

skin pale and cause tiredness and breathlessness

constipation, stomach pain, wind (flatulence), indigestion,

diarrhoea, feeling sick or being sick (nausea or vomiting)

weakness

headache, tingling or ‘pins and needles’, dizziness, a disorder of

the nerves which can cause weakness or numbness of the arms

and legs

rash, itching, hair loss

Very rare side effects (may affect up to 1 in 10,000 people):

liver failure

trouble sleeping, nighmares

poor memory, memory loss, confusion

Not Known (frequency cannot be estimated from the available

data):

Muscle weakness that is constant, sometimes complicated by

rupture of tendon.

depression

breathing problems including a persistent cough and/or

shortness of breath

impotence

Additional possible side-effects reported with some statins:

sleep disturbances, including sleeplessness and nightmares

sexual difficulties

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

Yellow

card

Scheme

www.mhra.gov.uk/yellowcard. By reporting side effects you can help

provide more information on the safety of this medicine.

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

Do not use the tablets after the expiry date stated on the label [EXP].

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

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

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.

What Simvastatin tablets contain

The active substance is Simvastatin. Each tablet contains 5 mg or 10

mg or 20 mg or 40 mg of the active substance.

other

ingredients

are:

lactose

anhydrous,

microcrystalline

cellulose (E460), pregelatinised maize starch, butylhydroxyanisole

(E320),

talc

(E553b),

magnesium

stearate

(E572),

hydroxypropylcellulose (E463), hypromellose (E464) and titanium

dioxide (E171).

The 5 mg tablets also contain yellow iron oxide (E172).

What Simvastatin tablets look like and contents of the pack

Simvastatin 5 mg Tablets are yellow, oblong, scored film-coated

tablets, with ‘SVT’ on one side and ‘5’ on the other.

Simvastatin 10 mg Tablets are white, oblong, biconvex film-coated

tablets, scored on one side, embossed with ‘10’ on the scored side

and with “SVT” and logo on the other side.

Simvastatin 20 mg Tablets are white, oblong, biconvex film-coated

tablets, scored on one side, embossed with “20” on the scored side

and with “SVT” and logo on the other side.

Simvastatin 40 mg Tablets are white, oblong, biconvex film-coated

tablets, scored on one side, embossed with “40” on the scored side

and with “SVT” and logo on the other side.

Simvastatin tablets are available in blister packs of 28 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Chelonia Healthcare Limited

Boumpoulinas 11, 3rd Floor, Nicosia, P.C. 1060, Cyprus

Manufacturer

DDSA Pharmaceuticals Limited

84 Pembroke Road, London, W8 6NX, UK

more

information

about

this

product,

please

contact

Marketing Authorisation Holder.

This leaflet was last approved in 12/2019

CL0101-0102-0103-0104/O/PIL/G6

Read the complete document

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Simvastatin 40 mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 40 mg of the active ingredient simvastatin.

Excipient with known effect

Lactose monohydrate (tablet core)

281.72 mg per film-coated tablet

Polydextrose (tablet coat only)

3.84 mg per film-coated tablet (containing NMT 4% glucose and NMT 2% sorbitol

(E420))

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet.

Simvastatin 40 mg film-coated tablets are presented as pink coloured, oval shaped,

film-coated tablets with “G” on one side and “SM40” on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to

diet, when response to diet and other non-pharmacological treatments (e.g. exercise,

weight reduction) is inadequate.

Treatment of homozygous familial hypercholaesterolemia (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

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 strating 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).

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 individualised 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

For oral use. Simvastatin 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 breast-feeding (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 (homozygous familial hypercholesterolaemia),

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)

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 acid 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 acid 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.

There have been very rare reports of an immune- mediated necrotizing myopathy

(IMNM) during or after treatment with some statins. IMNM is clinically characterised

by persistent proximal muscle weakness and elevated serum creatine kinase, which

persist despite discontinuation of statin treatment (see section 4.8).

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

member of the class should only be initiated with caution. If CK levels are

significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with

a statin, their CK levels should be measured. If these levels are found, in the absence

of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be

stopped. If muscular symptoms are severe and cause daily discomfort, even if CK

levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is

suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin

or introduction of an alternative statin may be considered at the lowest dose and with

close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose

(see section 5.1). Periodic CK measurements are recommended as they may be useful

to identify subclinical cases of myopathy. However, there is no assurance that such

monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective

major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions

(see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant

use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole,

ketoconazole, 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, including rhabdomyolysis, may be increased by concomitant

use of amiodarone, amlodipine, verapamil, or diltiazem with certain doses of

simvastatin (see sections 4.2 and 4.5). The risk of myopathy, including

rhabdomyolysis, may be increased by concomitant administration of fusidic acid with

statins (see section 4.5).

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. 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.

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 the 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 (

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 coadminstered 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 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.

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>30kg/m

, raised

triglycerides, hypertension) should be monitored both clinically and biochemically

according to national guidelines.

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.

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

This medicinal product contains lactose. Patients with rare hereditary problems of

galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption

should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

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 (

1g/day) of niacin (see section 4.4).

Pharmacokinetic interactions

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:

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) (

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, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin,

HIV protease inhibitors (e.g. nelfinavir), 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.

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 pharmacodynamics or pharmacokinetic, or both) is yet unknown. There

have been reports of rhabdomyolysis (including some fatalities) in patients receiving

this combination. Co-administration of this combination may cause increased plasma

concentrations of both agents.

If treatment with

systemic

fusidic acid is necessary, simvastatin treatment should be

discontinued throughout the duration of the fusidic acid treatment. (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 section 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).

Interaction with glecaprevir/pibrentasvir:

Glecaprevir/pibrentasvir are potent inhibitors of OATP1B1, OATP1B3 and MDR1, and weak

inhibitors of BCRP. The co-administration of simvastatin or simvastatin acid with the

mentioned antiviral agents has been shown to lead to an increased plasma concentration of the

statin, which in turn may increase the risk of dose-dependent adverse reactions such as

myopathy.

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 C

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 renalimpairment. 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.

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 20-40mg/day modestly potentiated the

effect of coumarin anticoagulants: the prothrombin time, reported as International

Normalised Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in

the volunteer and patient studies, respectively. 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.

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).

Breast-feeding

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 categorised based on an assessment of

their incidence rates in large, long-term, placebo-controlled, clinical trials including

HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS,

only serious adverse events were recorded as well as myalgia, 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 categorised 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 to < 1/10), Uncommon (

1/1000 to< 1/100),

Rare (

1/10,000 to< 1/1,000), Very Rare (< 1/10,000), Not known (cannot be

estimated from the available data).

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

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 and connective tissue 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, immune-mediated

necrotizing myopathy (IMNM)**.

** There have been very rare reports of immune-mediated necrotizing myopathy

(IMNM), an autoimmune myopathy, during or after treatment with some statins.

IMNM is clinically characterised by: persistent proximal muscle weakness and

elevated serum creatine kinase, which persist despite discontinuation of statin

treatment; muscle biopsy showing necrotizing myopathy without significant

inflammation; improvement with immunosuppressive agents (see section 4.4)

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,

-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 additional 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).

Paediatric population

In a 48-week study involving children and adolescents (boys Tanner Stage II and

above and girls who were at least one year post-menarche) 10-17 years of age with

heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability

profile of the group treated with simvastatin was generally similar to that of the group

treated with placebo. The long-term effects on physical, intellectual, and sexual

maturation are unknown. No sufficient data are currently available after one year of

treatment. (see sections 4.2, 4.4, and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions

via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA

Yellow Card in the Google Play or Apple App Store.

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

Mechanism of action

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolysed in the

liver to the corresponding active beta-hydroxyacid form which has a potent activity in

inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This

enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-

limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C

concentrations. LDL is formed from very-low-density protein (VLDL) and is

catabolised predominantly by the high affinity LDL receptor. The mechanism of the

LDL-lowering effect of simvastatin may involve both reduction of VLDL-cholesterol

(VLDL-C) concentration and induction of the LDL receptor, leading to reduced

production and increased catabolism of LDL-C. Apolipoprotein B also falls

substantially during treatment with simvastatin. In addition, simvastatin moderately

increases HDL-C and reduces plasma TG. As a result of these changes the ratios of

total- to HDL-C and LDL- to HDL-C are reduced.

Clinical efficacy and safety

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with simvastatin were

assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and

with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In

this study, 10,269 patients were treated with simvastatin 40 mg/day and 10,267

patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793

patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels

between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than

135 mg/dL.

Treatment with simvastatin 40 mg/day compared with placebo significantly reduced

the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus

1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in

coronary death rate 587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk

reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical

significance. Simvastatin also decreased the risk of major coronary events (a

composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001).

Simvastatin reduced the need for undergoing coronary revascularisation procedures

(including coronary artery bypass grafting or percutaneous transluminal coronary

angioplasty) and peripheral and other non-coronary revascularisation procedures by

30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin reduced the risk of

stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p <

0.0001). In addition, within the subgroup of patients with diabetes, Simvastatin

reduced the risk of developing macrovascular complications, including peripheral

revascularisation procedures (surgery or angioplasty), lower limb amputations, or leg

ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in

each subgroup of patients studied, including those without coronary disease but who

had cerebrovascular or peripheral artery disease, men and women, those aged either

under or over 70 years at entry into the study, presence or absence of hypertension,

and notably those with LDL cholesterol below 3.0 mmol/1 at inclusion.

In the Scandinavian simvastatin Survival Study (4S), the effect of therapy with

Simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline

total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicentre, randomised,

double-blind, placebo-controlled study, patients with angina or a previous myocardial

infarction (MI) were treated with diet, standard care, and either simvastatin 20-40

mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years.

Simvastatin reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The

risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %).

Simvastatin also decreased the risk of having major coronary events (CHD death plus

hospital-verified and silent nonfatal MI) by 34 %. Furthermore, simvastatin

significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and

transient ischemic attacks) by 28 %. There was no statistically significant difference

between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and

Homocysteine (SEARCH) evaluated the effect of treatment with simvastatin 80 mg

versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as

fatal CHD, non-fatal MI, coronary revascularization procedure, nonfatal or fatal

stroke, or peripheral revascularization procedure) in 12,064 patients with a history of

myocardial infarction. There was no significant difference in the incidence of MVEs

between the 2 groups; simvastatin 20 mg (n = 1553; 25.7 %) vs. Simvastatin 80 mg (n

= 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C

between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The

safety profiles were similar between the two treatment groups except that the

incidence of myopathy was approximately 1.0 % for patients on simvastatin 80 mg

compared with 0.02 % for patients on 20 mg. 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%.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily

in patients with hypercholesterolaemia, the mean reductions of LDL-C were 30, 38,

41 and 47 %, respectively. In studies of patients with combined (mixed)

hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in

triglycerides were 28 and 33 % (placebo: 2 %) respectively, and mean increases in

HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Paediatric population

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and

above and 76 girls who were at least one year post-menarche) 10-17 years of age

(mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were

randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the

study required a baseline LDL-C level between 160 and 400 mg/dL and at least one

parent with an LDL-C level > 189 mg/dL. The dosage of simvastatin (once daily in

the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40

mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and

received simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results

from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL

(range: 64.0- 289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL

(range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up

to 40 mg daily at 8- week intervals), simvastatin decreased the mean LDL-C by 36.8

% (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and

median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3

% (placebo: 3.6 %). The long-term benefits of simvastatin on cardiovascular events in

children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children

with heterozygous familial hypercholesterolaemia. The long-term efficacy of

simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has

not been established.

5.2

Pharmacokinetic properties

Simvastatin

inactive

lactone

which

readily

hydrolysed

vivo

corresponding

beta-hydroxyacid,

potent

inhibitor

HMG-CoA

reductase.

Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is

very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data

in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass

extraction. The extraction in the liver is dependent on the hepatic blood flow. The

liver is the primary site of action of the active form. The availability of the beta-

hydroxyacid to the systemic circulation following an oral dose of simvastatin was

found to be less than 5 % of the dose. Maximum plasma concentration of active

inhibitors is reached approximately 1-2 hours after administration of simvastatin.

Concomitant food intake does not affect the absorption.

The pharmacokinetics of single and multiple doses of simvastatin showed that no

accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of simvastatin and its active metabolite is > 95%.

Biotransformation and Elimination

Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major

metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four

additional active metabolites. Following an oral dose of radioactive simvastatin to

man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within

96 hours. The amount recovered in the faeces represents absorbed medicinal product

equivalents excreted in bile as well as unabsorbed medicinal product. Following an

intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9

hours. An average of only 0.3 % of the IV dose was excreted in urine as metabolites.

Simvastatin acid is taken up actively into the hepatocytes by the transporter

OATP1B1.

Simvastatin is a substrate of the efflux transporter BCRP.

Special populations

SLOC1B1 polymorphism

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 acid, 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.

6.1

List of Excipients

Tablet Core

ascorbic acid

butylhydroxyanisole (E320)

citric acid monohydrate

lactose monohydrate

magnesium stearate

cellulose, microcrystalline

maize starch, pregelatinised

talc

Tablet Coat

hypromellose

titanium dioxide (E171)

triacetin

iron oxide yellow (E172)

iron oxide red (E172)

polydextrose (containing small amounts of glucose and sorbitol (E420)

macrogol 8000

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

Do not store above 25

6.5

Nature and contents of container

PP containers with PE caps (with optional PE ullage fillers)

HDPE bottles with PP Caps

Al/PVC/PVdC Blisters

Al/PVC/PVAC Blisters

Pack sizes for all pack types: 10, 20, 28, 30, 49, 50, 56, 60, 84, 90, 98, 100,

250 and 1000.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with

local requirements.

7

MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)

PL 04569/0518

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

19/09/2007

10

DATE OF REVISION OF THE TEXT

02/08/2019

Read the complete document

Public Assessment Report

UKPAR

Simvastatin 10mg tablets

Simvastatin 20mg tablets

Simvastatin 40mg tablets

(Simvastatin)

UK Licence No: PL 36722/0060-62

Special Concept Development (UK) Limited (trading as Rx

Farma).

PAR Simvastatin 10mg, 20mg and 40mg tablets

PL 36722/0060-62

2

LAY SUMMARY

Simvastatin 10mg tablets

Simvastatin 20mg tablets

Simvastatin 40mg tablets

(simvastatin, tablet, 10mg, 20mg or 40mg)

This is a summary of the Public Assessment Report (PAR) for Simvastatin 10mg tablets

(PL 36722/0060), Simvastatin 20mg tablets (PL 36722/0061) and Simvastatin 40mg tablets (PL

36722/0062). It explains how Simvastatin 10mg, 20mg and 40mg tablets were assessed and their

authorisation recommended, as well as their conditions of use. It is not intended to provide practical

advice on how to use Simvastatin 10mg, 20mg and 40mg tablets.

The products will be collectively referred to as Simvastatin throughout the remainder of this public

assessment report.

For practical information about using Simvastatin patients should read the package leaflet or contact

their doctor or pharmacist.

What is Simvastatin and what is it used for?

Simvastatin is used to:

- lower levels of cholestrerol and fatty substances (triglycerides) in the blood, thereby reducing the risk

of heart disease.

- slow or reduce the progression of:

atherosclerosis (clogging of blood vessels by cholesterol) which can lead to angina (chest pain)

and heart attack

coronary heart disease (CHD)- this medicine can help to lessen the risk of a heart attack.

These applications are the same as Simvastatin 10mg, 20mg and 40mg tablets (PL 43870/0015-0017)

which are already authorised.

The company (Medley Pharma Limited) that makes Simvastatin (PL 43870/0015-0017) has agreed that

its scientific data can be used as a basis for the grant of identical licences for Simvastatin (informed

consent).

How does Simvastatin work?

This medicine contains the active ingredient simvastatin, which belongs to a group of medicines known

as HMG-CoA reductase inhibitors.

If levels of cholesterol are too high in the bloodstream, it can be deposited on the walls of the arteries

and build up to form plaques. These plaques will eventually block the blood vessels. This medicine

works by reducing the amount of cholesterol and fatty substances (triglycerides) in the blood.

How is Simvastatin used?

The pharmaceutical form of this medicine is a tablet and the route of administration is oral (by mouth).

The patient should always take this medicine exactly as their doctor or pharmacist has told them. The

patient should check with their doctor or pharmacist if they are not sure. It is important the patient stays

on a low-fat diet as well as taking this medicine.

Your doctor may prescribe a dose of 5mg, 10mg, 20mg, 40mg or 80mg once a day by mouth

PAR Simvastatin 10mg, 20mg and 40mg tablets

PL 36722/0060-62

3

For children aged 10-17 years of age, the recommended usual starting dose is 10mg a day in the evening.

The maximum recommended dose is 40mg a day.

For high cholesterol levels, the usual starting dose in 10-20mg per day.

For coronary heart disease, the usual starting dose is 20-40mg per day, given as a single dose in the

evening.

The doctor may adjust the patient’s dose to a maximum dose of 80mg to have the best effect. The 80mg

dose is only recommended for adult patients with very high cholesterol levels and at high risk of heart

disease problems.

This medicine should be taken for as long as the patient’s doctor has recommended.

Please refer to section 3 of the package leaflet for information on how to use this medicine.

This medicine can only be obtained with a prescription.

For further information on how Simvastatin is used, refer to the package leaflet and Summary of Product

Characteristics available on the Medicines and Healthcare products Regulatory Agency (MHRA)

website.

What benefits of Simvastatin have been shown in studies?

Simvastatin is considered identical to previously authorised Simvastatin 10mg, 20mg and 40mg tablets

(PL 43870/0015-0017), with the same benefits and risks. Therefore no new studies have been provided

for Simvastatin but reference is made to the studies for Simvastatin 10mg, 20mg and 40mg tablets (PL

43870/0015-0017).

What are the possible side effects from Simvastatin?

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

Simvastatin is considered identical to previously authorised Simvastatin 10mg, 20mg and 40mg tablets

(PL 43870/0015-0017)

with the same benefits and risks.

For a full list of all the side effects reported with Simvastatin

see section 4 of the package leaflet,

available on the Medicines and Healthcare products Regulatory Agency (MHRA) website.

For the full list of restrictions, see the package leaflet.

Why is Simvastatin approved?

The MHRA decided that the benefits of Simvastatin are greater than the risks and recommended that it is

approved for use.

What measures are being taken to ensure the safe and effective use of Simvastatin?

A Risk Management Plan has been developed to ensure that Simvastatin

is used as safely as possible.

Based on this plan, safety information has been included in the Summary of Product Characteristics and

the package leaflet for Simvastatin

including the appropriate precautions to be followed by healthcare

professionals and patients.

Known side effects are continuously monitored. Furthermore new safety signals reported by

patients/healthcare professionals will be monitored/reviewed continuously.

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Other information about Simvastatin

Marketing Authorisations were granted in the UK on 25 July 2017.

The full PAR for Simvastatin

follows this summary.

For more information about treatment with Simvastatin

read the package leaflet, or contact your doctor

or pharmacist.

This summary was last updated in August 2017.

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TABLE OF CONTENTS

Introduction

Page 6

Quality aspects

Page 7

Non-clinical aspects

Page 9

Clinical aspects

Page 9

User consultation

Page 11

Overall conclusion, benefit/risk assessment and

recommendation

Page 11

Table of content of the PAR update

Page 21

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I

INTRODUCTION

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Special Concept

Development (UK) Limited Marketing Authorisations for the medicinal product Simvastatin (PL

36722/0060-62) on 25 July 2017. The product is a prescription only medicine (POM) indicated for the

treatment of:

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when

response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is

inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid lowering

treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic

cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an

adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1 of the

SmPC).

These applications were submitted as simple abridged (informed consent) applications according to

Article 10c of Directive 2001/83/EC, as amended.

The applications cross-refer to the reference products Simvastatin 10 mg, 20 mg and 40 mg tablets (PL

43870/0015-0017) authorised to the marketing authorisation holder (MAH) Medley Pharma Limited.

These licences were originally granted under Article 4.8 a) (iii) of 65/65/EEC (as amended) to the MAH

Milpharm Limited (PL 16363/0166-8) on 18 August 2004 cross-referring to the reference products

Zocor 10mg, 20mg & 40 mg Tablets (Merck Sharp & Dohme BV, Netherlands; PL 00025/0241-0243).

This is acceptable for a national 10(c) application.

Simvastatin is a HMG-CoA reductase inhibitor.

After oral ingestion simvastatin, which is an inactive lactone, is hydrolysed in the liver to the

corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA

reductase (3 hydroxy-3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-

CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed

from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL

receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of

VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced

production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during

treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma

TG. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these

changes the ratio of total- to HDL-C and LDL- to HDL-C are reduced.

No new data were submitted nor were necessary to be submitted for the applications, as the data are

identical to the data for the previously granted cross-referenced products.

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II

QUALITY ASPECTS

II.1

Introduction

These are abridged applications for Simvastatin (PL 36722/0060-62) submitted under Article 10c of

Directive 2001/83/EC, as amended.

The applications cross-refer to the reference products Simvastatin 10mg, 20mg and 40mg tablets (PL

43870/0015-0017) authorised to the MAH Medley Pharma Limited. These licences were originally

granted under Article 4.8 a) (iii) of 65/65/EEC (as amended) to the MAH Milpharm Limited (PL

16363/0166-8) on 18 August 2004 cross-referring to the reference products Zocor 10mg, 20mg & 40 mg

Tablets (Merck Sharp & Dohme BV, Netherlands; PL 00025/0241-0243). This is acceptable for a

national 10(c) application. The applications are considered valid.

II.2.

Drug Substance

Drug substance specifications

The proposed drug substance specifications are consistent with the details registered for the cross-

reference products.

II.3.

Medicinal Product Name

The proposed product names for these applications are Simvastatin 10mg, 20mg and 40mg tablets. The

product has been named in line with current requirements.

Strength, pharmaceutical form, route of administration, container and pack sizes

Each tablet contains 10mg, 20mg and 40mg of the active substance simvastatin. All strengths of the

finished product are packed in to polyvinyl chloride (PVC)/polyethylene (PE) and polyvinylidene

chloride (PVDc) or polyvinyl chloride (PVC)/aluminium and orientated polyamide foil blisters in

cartons of 28 tablets.

The proposed shelf life of the unopened product is 24 months with no special storage conditions.

The proposed packaging, shelf-life and storage conditions are consistent with the details registered for

the cross-reference product.

Legal status

Prescription only medicine (POM).

Marketing Authorisation Holder/Contact Persons/Company

Special Concept Development (UK) Limited T/A Rx Farma, Units 1-7, Colonial Way, Watford,

Hertfordshire, WD24 4YR, UK.

The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory CV has been

provided.

Manufacturers

The proposed manufacturing sites are consistent with those registered for the cross-reference products

and evidence of Good Manufacturing Practice (GMP) compliance has been provided.

Qualitative and quantitative compositions

The proposed compositions are consistent with the details registered for the cross-reference products.

PAR Simvastatin 10mg, 20mg and 40mg tablets

PL 36722/0060-62

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Manufacturing process

The proposed manufacturing processes are consistent with the details registered for the cross-reference

products and the maximum batch size is stated.

Finished product/shelf-life specifications

The proposed finished product specifications are in line with the details registered for the cross-reference

products.

TSE Compliance

None of the excipients used contain material of animal or human origin.

No genetically modified organisms (GMO) have been used in the preparation of these products.

Bioequivalence

No bioequivalence data are required to support these simple abridged applications because the proposed

products are manufactured to the same formulae utilising the same processes as the cross-reference

products, Simvastatin is considered identical to previously authorised Simvastatin 10mg, 20mg and

40mg tablets (PL 43870/0015-0017).

Expert Report

The applicant cross-refers to the data for Simvastatin is considered identical to previously authorised

Simvastatin 10mg, 20mg and 40mg tablets (PL 43870/0015-0017)

to which these applications are

claimed to be identical. This is acceptable.

Product Name and Appearance

See Section II.3 ‘Medicinal Product; Name’ for details of the proposed product names. The appearance

of the products is identical to that of the cross-reference products.

II.4

Discussion on chemical, pharmaceutical and biological aspects

The data submitted with the applications is acceptable. The grant of Marketing Authorisations is

recommended.

PAR Simvastatin 10mg, 20mg and 40mg tablets

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III

NON-CLINICAL ASPECTS

Introduction

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no

new non-clinical data have been supplied and none are required.

Ecotoxicity/environmental risk assessment (ERA)

Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As

the applications are identical versions of already authorised products, it is not expected that

environmental exposure will increase following approval of the Marketing Authorisations for the

proposed products.

Discussion on the non-clinical aspects

The grant of Marketing Authorisations is recommended.

IV

CLINICAL ASPECTS

Introduction

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no

new clinical data have been supplied and none are required.

Risk Management Plan (RMP)

The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), in accordance

with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities

and interventions designed to identify, characterise, prevent or minimise risks relating to Simvastatin.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are

listed below:

Summary table of safety concerns:

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10

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.

Discussion on the clinical aspects

The grant of Marketing Authorisations is recommended.

V

User consultation

The applicant has committed to submit a user testing report in accordance with the requirements of

Articles 59(3) and 61(1) of Directive 2001/83/EC prior to marketing these products. The text version of

the leaflet (PIL) has been approved for these applications. This is acceptable.

VI

Overall conclusion, benefit/risk assessment and recommendation

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been

identified. The applicant’s product is identical to the cross-reference product. Extensive clinical

experience with simvastatin is considered to have demonstrated the therapeutic value of the compound.

The benefit/risk balance is, therefore, considered to be positive.

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Summaries of Product Characteristics (SmPC), Patient Information Leaflets (PIL) and Labels

The SmPC and PIL are consistent with the details registered for the cross-reference product.

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for this medicine is presented below:

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Annex 1

Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Scope

Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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