Zimybe 10/10

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Ezetimibe 10 mg; Simvastatin 10 mg;  
Available from:
Viatris Limited
INN (International Name):
Ezetimibe 10 mg
Dosage:
10mg/10mg
Pharmaceutical form:
Tablet
Composition:
Active: Ezetimibe 10 mg Simvastatin 10 mg   Excipient: Ascorbic acid Butylated hydroxyanisole Citric acid monohydrate Croscarmellose sodium Hypromellose Lactose monohydrate Magnesium stearate Microcrystalline cellulose Sodium laurilsulfate
Prescription type:
Prescription
Manufactured by:
Mylan Laboratories Limited
Therapeutic indications:
Primary Hypercholesterolaemia Zimybe is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in adult and adolescent (10 to 17 years of age) patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia in patients not adequately treated on a statin alone. Homozygous Familial Hypercholesterolaemia (HoFH) Zimybe is indicated for the reduction of elevated total-C and LDL-C levels in adult and adolescent (10 to 17 years of age) patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/Aclar/Al - 10 tablets - 24 months from date of manufacture stored at or below 25°C - Blister pack, PVC/Aclar/Al - 30 tablets - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-9193
Authorization date:
2013-01-07

Read the complete document

Page 1 of 5

NEW ZEALAND CONSUMER MEDICINE INFORMATION

ZIMYBE

Ezetimibe/Simvastatin Tablets

10mg/10mg, 10mg/20mg, 10mg/40mg & 10mg/80mg

What is in this leaflet

Please read this leaflet carefully

before you start taking ZIMYBE.

This leaflet answers some common

questions about ZIMYBE.

It does not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking ZIMYBE

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the

medicine. You may need to read it

again.

What ZIMYBE is

used for

ZIMYBE helps to lower cholesterol

and triglyceride levels. It is used in

people whose cholesterol levels are

too high and when diet alone cannot

lower these levels adequately.

ZIMYBE contains the active

ingredients ezetimibe and

simvastatin.

It works by reducing elevated total

cholesterol, LDL cholesterol and

triglycerides, and increasing HDL

cholesterol.

ZIMYBE works by decreasing the

absorption of cholesterol in the

small intestine and by reducing the

amount of cholesterol made in the

liver. ZIMYBE does not help you to

lose weight.

Your doctor may have prescribed it

for another reason.

Ask your doctor if you have any

questions about why this

medicine has been prescribed for

you.

This medicine is available only with

a doctor’s prescription.

This medicine is not addictive.

ZIMYBE is not recommended for

use in children under 10 years of

age.

Cholesterol

Cholesterol is one of several fatty

substances found in the

bloodstream. Your total cholesterol

is made up mainly of low-density

lipoprotein (LDL) and high-density

lipoprotein (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 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

Triglycerides are another form of fat

in your blood that may increase

your risk for heart disease.

Before you take

ZIMYBE

When you must not take

it

Do not take ZIMYBE if you have

an allergy to:

any medicine containing

ezetimibe or simvastatin

any of the ingredients listed at

the end of this leaflet.

Some of the symptoms of an

allergic reaction may include:

shortness of breath; wheezing

or difficulty breathing; swelling

of the face, lips, tongue or other

parts of the body; rash, itching

or hives on the skin.

Do not take this medicine if you

are pregnant.

It may affect your developing baby if

you take it during pregnancy.

Do not breast-feed if you are

taking this medicine.

The active ingredients in ZIMYBE

may pass into breast milk and there

is a possibility that your baby may

be affected.

Do not take this medicine if you

have active liver disease or

repeated blood tests indicating

possible liver problems.

Do not take this medicine if you

have had muscle pain,

tenderness or weakness from

other medicines used to treat

high cholesterol or triglycerides.

Do not take this medicine if you

are taking any of the following:

ketoconazole, itraconazole,

posaconazole and

voriconazole used to treat

certain fungal infections

Page 2 of 5

erythromycin,

clarithromycin, telithromycin

and fusidic acid; antibiotics

used to treat infections

HIVprotease inhibitors,

used to treat HIV infection,

including indinavir,

nelfinavir, ritonavir,

saquinavir

boceprevir or telaprevir,

used to treat Hepatitis C

virus infections

medicines containing

cobicistat, used in the

treatment of HIV infection

nefazodone, a medicine

used to treat depression

danazol, a hormone used to

treat gynaecological

problems

cyclosporin, a medicine

used to suppress the

immune system

gemfibrozil, a medicine

used to lower cholesterol

levels

Do not take this medicine after

the expiry date printed on the

pack or if the packaging is torn or

shows signs of tampering.

If it has expired or is damaged,

return it to your pharmacist for

disposal.

If you are not sure whether you

should start taking this medicine,

talk to your doctor.

Before you start to take

it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if you have or

have had any of the following

medical conditions:

an underactive thyroid gland

high blood pressure

high body mass

liver disease or liver problems,

kidney disease or any other

kidney problems

Tell your doctor if you drink

alcohol regularly.

Tell your doctor if you plan to

become pregnant or plan to

breast-feed.

Your doctor can discuss with you

the risks and benefits involved.

If you have not told your doctor

about any of the above, tell them

before you start taking ZIMYBE.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including medicines

that you buy without a

prescription from your pharmacy,

supermarket or health food shop.

You should also tell any health

professional who is prescribing a

new medication for you that you are

taking ZIMYBE.

Some medicines may interfere with

ZIMYBE. These include:

medicines used to lower

cholesterol levels, such as bile

acid sequestrants, e.g.

cholestyramine, other fibrates

or nicotinic acid (also known as

niacin)

elbasvir or grazoprevir used to

treat Hepatitis C virus infections

amiodarone, a medicine used to

treat irregular heartbeat

amlodipine, diltiazem or

verapamil, medicines used to

treat high blood pressure and

angina

colchicine, a medicine used for

gout

lomitapide, a medicine used to

treat a serious and rare genetic

cholesterol condition

warfarin, fluindione or other

medicines used to prevent

blood clots

antacids, medicines which

neutralize stomach acidity and

are used to relieve heartburn,

indigestion or an upset stomach

digoxin, a medicine used to

treat various hearth conditions

ticagrelor, a medicine used in

combination with aspirin to

prevent heart attack.

These medicines may be affected

by ZIMYBE or may affect how well it

works. You may need different

amounts of your medicines, or you

may need to take different

medicines.

Your doctor and pharmacist have

more information on medicines to

be careful with or avoid while taking

this medicine.

How to take ZIMYBE

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the information

contained in this leaflet.

If you do not understand the

instructions on the box, ask your

doctor or pharmacist for help.

How much to take

The recommended dose is one

ZIMYBE 10/10, 10/20, 10/40 or

10/80 tablet once a day, in the

evening.

The 10/80 mg dose of ZIMYBE is

only recommended for patients at

high risk of heart disease problems

who have not yet reached their

cholesterol goal on lower doses and

when the benefits outweigh the risk.

How to take it

Swallow the tablets whole with a

full glass of water.

Grapefruit juice should be

avoided while taking ZIMYBE.

Grapefruit juice contains one or

more components that alter the

metabolism of some medicines,

including ZIMYBE.

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

It does not matter if you take this

medicine before or after food.

If you are taking a bile acid

sequestrant, such as

cholestyramine, take ZIMYBE

either at least two hours before

or four hours after taking the bile

acid sequestrant.

How long to take it

Continue taking your medicine

for as long as your doctor tells

you.

This medicine helps to control your

Page 3 of 5

condition, but does not cure it. It is

important to keep taking your

medicine even if you feel well.

You may have to take cholesterol

lowering medicine for the rest of

your life. If you stop taking ZIMYBE,

your cholesterol levels may rise

again.

If you forget to take it

If it is almost time for your next

dose, skip the dose you missed

and take your next dose when

you are meant to.

Otherwise, take it as soon as you

remember, and then go back to

taking your medicine as you

would normally.

Do not take a double dose to

make up for the dose that you

missed.

This may increase the chance of

you getting an unwanted side effect.

If you are not sure what to do,

ask your doctor or pharmacist.

If you have trouble remembering to

take your medicine, ask your

pharmacist for some hints.

While you are taking

ZIMYBE

Things you must do

If you are about to be started on

any new medicine, remind your

doctor and pharmacist that you

are taking ZIMYBE.

Tell any other doctors, dentists,

and pharmacists who treat you

that you are taking this medicine.

If you are going to have surgery,

tell the surgeon or anaesthetist

that you are taking this medicine.

It may affect other medicines used

during surgery.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

If you are about to have any

blood tests, tell your doctor that

you are taking this medicine.

It may interfere with the results of

some tests.

Keep all of your doctor’s

appointments so that your

progress can be checked.

Your doctor may do some tests

from time to time to make sure the

medicine is working and to prevent

unwanted side effects.

Things you must not do

Do not take ZIMYBE to treat any

other complaints unless your

doctor tells you to.

Do not give your medicine to

anyone else, even if they have

the same condition as you.

Do not stop taking your medicine

or lower the dosage without

checking with your doctor.

Things to be careful of

Avoid drinking large quantities of

alcohol.

Drinking large quantities of alcohol

may increase your chance of

ZIMYBE causing liver problems.

Be careful driving or operating

machinery until you know how

ZIMYBE affects you.

There have been side effects

reported with ZIMYBE that may

affect your ability to drive or operate

machinery.

High cholesterol can

be treated in two

main ways

Lifestyle changes: This includes a

cholesterol-lowering diet, increasing

physical activity, and weight

management. Ask your doctor for

advice before increasing physical

activity.

Medicines: Cholesterol-lowering

medicines are used together with

lifestyle changes to help lower

cholesterol.

In case of overdose

If you take too much

(overdose)

Immediately telephone your

doctor or the National Poisons

Information Centre (telephone

0800 POISON or 0800 764 766), or

go to Accident and Emergency at

your nearest hospital, if you think

that you or anyone else may have

taken too much ZIMYBE. Do this

even if there are no signs of

discomfort or poisoning. You may

need urgent medical attention.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not

feel well while you are taking

ZIMYBE.

This medicine helps most people

with high cholesterol but it may

have unwanted side effects in a few

people.

All medicines can have side

effects. Sometimes they are

serious, most of the time they are

not. You may need medical

treatment if you get some of the

side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor or pharmacist if

you notice any of the following

and they worry you:

dizziness

confusion

poor memory

depression

nausea or vomiting

stomach pain or discomfort

indigestion

excessive gas in the stomach or

bowel

diarrhoea

constipation

tingling or numbness of the

hands or feet

trouble sleeping

erectile dysfunction

hot flush

weight loss

dry mouth

heartburn

coughing

high blood pressure

unusual hair loss.

Page 4 of 5

Tell your doctor as soon as

possible if you notice any of the

following:

unexplained muscle aches,

muscle tenderness or

weakness, not caused by

exercise (in some cases this

may not go away after stopping

ZIMYBE)

muscle cramps or spasms

numbness or weakness of the

arms and legs

tiredness

headache

being short of breath when

exercising, dizziness and

looking pale

fever, generally feeling unwell

bleeding or bruising more easily

than normal

breathing problems including

persistent cough and/or

shortness of breath

steady abdominal pain with

nausea and vomiting

vomiting blood

blood in the bowel motions

pain - back, neck, joint or

muscle pain

skin rash, itchiness or itchy

swellings on the skin

swelling of hands, ankles or

feet.

The above list includes serious side

effects that may require medical

attention.

Muscle problems can be serious

including muscle breakdown

resulting in kidney damage that can

lead to death. You may need urgent

medical attention.

The risk of muscle breakdown is

greater for patients taking higher

doses of ZIMYBE.

The risk of muscle breakdown is

also great for older patients (65

years of age and older), female

patients, patients with abnormal

kidney function and patients with

thyroid problems.

If any of the following happen,

tell your doctor immediately or

go to Accident and Emergency at

your nearest hospital:

swelling of the face, lips, mouth,

throat or tongue which may

cause difficulty in swallowing or

breathing

chest pain

signs of liver problem such as

nausea, vomiting, loss of

appetite, feeling generally

unwell, fever, itching, yellowing

of the skin and eyes, and dark

coloured urine.

The above list includes very serious

side effects. You may need urgent

medical attention or hospitalisation.

Tell your doctor or pharmacist if

you notice anything that is

making you feel unwell.

Other side effects not listed above

may also occur in some people. Tell

your doctor if you notice any other

effects.

Some side effects such as changes

to liver function can only be found

when your doctor does tests from

time to time to check your progress.

Do not be alarmed by this list of

possible side effects. You may

not experience any of them.

After taking ZIMYBE

Storage

Keep your tablets in the pack

until it is time to take them.

If you take the tablets out of the

pack they may not keep well.

Keep your tablets in a cool dry

place where the temperature

stays below 25°C.

Do not store ZIMYBE or any other

medicine in the bathroom or near a

sink. Do not leave it on a window sill

or in the car.

Heat and dampness can destroy

some medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

Product description

What it looks like

ZIMYBE comes in four types of

tablets:

ZIMYBE 10/10 – 10mg

ezetimibe / 10mg simvastatin.

White to off-white, oval,

biconvex tablet marked with M

on one side and ES1 on the

other side

ZIMYBE 10/20 – 10mg

ezetimibe / 20mg simvastatin.

White to off-white, oval,

biconvex tablet marked with M

on one side and ES2 on the

other side

ZIMYBE 10/40 – 10mg

ezetimibe / 40mg simvastatin.

White to off-white, oval,

biconvex tablet marked with M

on one side and ES3 on the

other side

ZIMYBE 10/80 – 10mg

ezetimibe / 80mg simvastatin.

White to off-white, oval,

biconvex tablet marked with M

on one side and ES4 on the

other side.

Ingredients

Active ingredients:

ZIMYBE tablets contain ezetimibe

and simvastatin as the active

ingredients.

Inactive ingredients:

ZIMYBE tablets also contain:

lactose monohydrate

citric acid monohydrate

butylated hydroxyl anisole

ascorbic acid

croscarmellose sodium

hypromellose

sodium lauryl sulphate

microcrystalline cellulose

magnesium stearate.

This medicine does not contain

gluten.

If you want to know

more

Should you have any questions

regarding this product, please

contact your pharmacist or doctor.

Page 5 of 5

Who supplies this

medicine

ZIMYBE is supplied in New Zealand

Mylan New Zealand Ltd,

PO Box 11183,

Ellerslie,

Auckland

NEW ZEALAND

Telephone: (09) 579 2792

Date of Preparation

26 June 2019

(Based on datasheet dated 26 June

2019)

Read the complete document

Page 1 of 43

NEW ZEALAND DATA SHEET

ZIMYBE 10/10; ZIMYBE 10/20; ZIMYBE 10/40

and ZIMYBE 10/80

1. Product Name

ZIMYBE 10/10, ZIMYBE 10/20, ZIMYBE 10/40 or ZIMYBE 10/80, tablets

2. Qualitative and Quantitative Composition

Each tablet contains 10 mg ezetimibe and 10, 20, 40 or 80 mg of simvastatin.

Excipient(s) with known effect:

ZIMYBE tablets contain lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

ZIMYBE 10/10: A white to off-white, oval, biconvex tablet debossed with M on one side of the tablet

and ES1 on the other side, containing 10 mg ezetimibe and 10 mg simvastatin.

ZIMYBE 10/20: A white to off-white, oval, biconvex tablet debossed with M on one side of the tablet

and ES2 on the other side, containing 10 mg ezetimibe and 20 mg simvastatin.

ZIMYBE 10/40: A white to off-white, oval, biconvex tablet debossed with M on one side of the tablet

and ES3 on the other side, containing 10 mg ezetimibe and 40 mg simvastatin.

ZIMYBE 10/80: A white to off-white, oval, biconvex tablet debossed with M on one side of the tablet

and ES4 on the other side, containing 10 mg ezetimibe and 80 mg simvastatin.

4. Clinical Particulars

4.1

Therapeutic indications

Primary hypercholesterolaemia

ZIMYBE is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol

(total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG),

and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein

cholesterol (HDL-C) in adult and adolescent (10 to 17 years of age) patients with primary

(heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia in patients

not adequately treated on a statin alone.

Homozygous familial hypercholesterolaemia (HoFH)

ZIMYBE is indicated for the reduction of elevated total-C and LDL-C levels in adult and adolescent

(10 to 17 years of age) patients with HoFH. Patients may also receive adjunctive treatments (e.g.,

LDL apheresis).

Page 2 of 43

4.2

Dose and method of administration

Dose

The patient should be placed on a standard cholesterol-lowering diet before receiving ZIMYBE and

should continue on this diet during treatment with ZIMYBE. The dosage should be individualised

according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response.

ZIMYBE should be taken as a single daily dose in the evening, with or without food.

The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual starting dose is

10/20 mg/day. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less

aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%)

may be started at 10/40 mg/day. After initiation or titration of ZIMYBE, lipid levels may be analysed

after 2 or more weeks and dosage adjusted, if needed. The 10/80 mg dose of ZIMYBE is only

recommended in patients 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 section 4.4).

Dosage in patients with homozygous familial hypercholesterolaemia

The recommended dosage for patients with homozygous familial hypercholesterolaemia is ZIMYBE

10/40 mg/day or 10/80 mg/day in the evening. The 10/80 mg dose is only recommended when the

benefits are expected to outweigh the potential risks (see sections 4.3 and 4.4)

ZIMYBE 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 ZIMYBE, the dose of ZIMYBE should not exceed

10/40 mg/day (see sections 4.4 and 4.5).

Concomitant therapy

Dosing of ZIMYBE should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile

acid sequestrant.

In patients taking amiodarone, verapamil, diltiazem, amlodipine or ≥ 1 g/day of niacin, or products

containing elbasvir or grazoprevir concomitantly with ZIMYBE, the dose of ZIMYBE should not

exceed 10/20 mg/day (see sections 4.4 and 4.5).

The safety and effectiveness of ezetimibe/simvastatin administered with fibrates have not been

studied. Therefore, the combination of ZIMYBE and fibrates should be avoided (see sections 4.4

and 4.5).

Because the incidence of myopathy when simvastatin is co-administered with lipid-modifying doses

(≥ 1 g/day niacin) of niacin-containing products is higher in Chinese than in non-Chinese patients,

co-administration of

ZIMYBE

with

lipid-modifying doses of

niacin-containing products

recommended in Asian patients (see section 4.4).

Special populations

Renal impairment/chronic kidney disease (CKD)

In patients with mild renal insufficiency (estimated GFR ≥ 60 mL/min/1.73 m

) no dosage adjustment

is necessary. In patients with chronic kidney disease and estimated glomerular filtration

rate < 60 mL/min/1.73 m

, the dose of ZIMYBE is 10/20 mg once a day in the evening. Efficacy and

safety at higher doses have not been evaluated in this CKD population (see sections 5.1 and 5.2).

Elderly

No dosage adjustment is required for elderly patients (see section 5.2).

Page 3 of 43

Paediatric (10 to 17 years of age) patients

Initiation of treatment must be performed under review of a specialist.

The use of ZIMYBE in children and adolescent patients (10 to 17 years) is recommended only for

patients

with

Heterozygous

Familial

Hypercholesterolaemia

(HeFH)

Homozygous

Familia

Hypercholesterolaemia (HoFH).

There are no clinical safety and efficacy data on the use of ezetimibe/simvastatin in children and

adolescent

patients

years)

with

non-familial

hypercholesterolaemia

mixed

hyperlipidaemia.

Adolescents 10 to 17 years old (pubertal status: boys Tanner Stage II and above and girls who are

at least one year post-menarche): The clinical experience in paediatric and adolescent patients

(aged 10 to 17 years old) is limited and mostly includes children and adolescents (10 to 17 years

old) with Heterozygous Familial Hypercholesterolaemia. There are also no long-term (> 1 year)

safety data in this population.

The recommended usual starting dose is 10/10 mg once a day in the evening. The recommended

dosing range is 10/10 to a maximum of 10/40 mg/day (see section 5.2). Doses should be

individualised according to the recommended goal of therapy.

Children < 10 years: ZIMYBE is not recommended for use in children below age 10 due to very

limited data on safety and efficacy (see section 5.2 and section 4.4). Ezetimibe/simvastatin has not

been studied in pre-menarchal girls or in pre-pubertal boys and is not recommended in children < 10

years.

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or

6). Treatment with ZIMYBE is not recommended in patients with moderate (Child-Pugh score 7 to 9)

or severe (Child-Pugh score > 9) liver dysfunction (see section 4.4 and section 5.2).

4.3

Contraindications

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

Active liver disease or unexplained persistent elevations of serum transaminases.

Pregnancy and lactation (see section 4.6).

Myopathy secondary to other lipid lowering agents.

Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole,

posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin,

clarithromycin, telithromycin, nefazodone and medicines containing cobicistat (see section

4.4 and section 4.5).

Concomitant administration of gemfibrozil, cyclosporine or danazol (see section 4.4 and

section 4.5).

Concomitant use with fusidic acid (see section 4.4 and section 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 10 X the upper limit of

normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal

failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is

increased by high levels of HMG-CoA reductase inhibitory activity in plasma (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). Predisposing

factors

myopathy

include

advanced

(≥

years),

female

gender,

uncontrolled

hypothyroidism, and renal impairment.

Page 4 of 43

The risk of myopathy/rhabdomyolysis is dose related for simvastatin. 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. This includes rhabdomyolysis for which the

incidence was 0.1 to 0.2%, all allocated to simvastatin 80 mg/day. There is no universally accepted

definition of rhabdomyolysis. In this trial, rhabdomyolysis was defined as a subset of myopathy with

CK > 40 X ULN plus evidence of end organ damage (e.g. elevated creatinine, dark urine).

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%.

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

therapies with similar LDL-C lowering efficacy. Therefore the 10/80 mg dose of ezetimibe/simvastatin

should only be used in patients 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 ezetimibe/simvastatin 10/80 mg for whom an interacting agent is needed, a

lower dose of ezetimibe/simvastatin or an alternative statin-ezetimibe regimen with less potential for

drug-drug interactions should be used (see section 4.2 and 4.3).

All patients starting therapy with ezetimibe/simvastatin, or whose dose of ezetimibe/simvastatin is

being increased, should be advised of the risk of myopathy and told to report promptly any

unexplained muscle pain, tenderness or weakness. Ezetimibe/simvastatin therapy should be

discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms,

and a CK level > 10 times the upper limit of normal indicates myopathy. In most cases, when patients

were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases

resolved (see section 4.8). Periodic CK determinations may be considered in patients starting

therapy with ezetimibe/simvastatin or whose dose is being increased. Periodic CK determinations

are recommended for patients titrating to the 10/80 mg dose. There is no assurance that such

monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had

complicated medical histories, including renal insufficiency usually as a consequence of long-

standing diabetes mellitus. Such patients taking ezetimibe/simvastatin merit closer monitoring.

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

surgery and when any major medical or surgical condition supervenes.

In a clinical trial, 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40

mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the

incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where

myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN

or two consecutive observations of CK ≥ 5 and < 10 times ULN. The incidence of rhabdomyolysis

was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined

as unexplained muscle weakness, pain or tenderness with a serum CK ≥ 10 times ULN with evidence

of renal injury, ≥ 5 X ULN and < 10 X ULN on two consecutive occasions with evidence of renal injury

or CK ≥ 10,000 IU/L without evidence of renal injury (see section 4.8).

In a clinical trial in which over 9000 patients with chronic kidney disease were randomised to receive

ezetimibe/simvastatin 10/20 mg daily (n=4650) or placebo (n=4620) (median follow-up 4.9 years),

the incidence of myopathy/rhabdomyolysis was 0.2% for ezetimibe/simvastatin and 0.1% for placebo

(see section 4.8).

An increased risk of myopathy in Chinese subjects has been identified. 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=4 of 7367) compared with 0.24% for Chinese patients (n= 13 of 5468). While the only Asian

Page 5 of 43

population assessed in this clinical trial was Chinese, caution should be used when prescribing

ezetimibe/simvastatin to any Asian patients and the lowest dose necessary should be employed.

Drug interactions

Prescribing recommendations for interacting agents are summarised in Table 1 below (see sections

4.2, 4.3 and 4.5).

Because ZIMYBE contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by

concomitant use of ezetimibe/simvastatin with the following medicines:

Contraindicated medicines

Potent inhibitors of CYP3A4: Concomitant use with medicines labelled as having a potent

inhibitory effect on CYP3A4 at therapeutic doses (e.g., itraconazole, ketoconazole, posaconazole,

voriconazole,

erythromycin,

clarithromycin,

telithromycin,

protease

inhibitors,

boceprevir,

telaprevir, nefazodone or medicines containing cobicistat) is contraindicated. If short-term treatment

with potent CYP3A4 inhibitors is unavoidable, therapy with

ezetimibe/simvastatin should be

suspended during the course of treatment (see section 4.3 and 4.5).

Gemfibrozil, cyclosporine or danazol: Concomitant use of these drugs with ezetimibe/simvastatin

is contraindicated (see section 4.3 and 4.5).

Fusidic acid: Patients on fusidic acid treated concomitantly with simvastatin may have an increased

risk of myopathy/rhabdomyolysis (see section 4.5). Fusidic acid must not be co-administered with

statins (see section 4.3). In patients where the use of systemic fusidic acid is considered essential,

ezetimibe/simvastatin should be discontinued throughout the duration of fusidic acid treatment. The

patient should be advised to seek medical advice immediately if they experience any symptoms of

muscle weakness, pain or tenderness. Ezetimibe/simvastatin therapy may be reintroduced seven

days after the last dose of fusidic acid.

Other medicines

Amiodarone: In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg

and amiodarone. A significant interaction at lower simvastatin doses cannot be excluded. Therefore,

dose

ezetimibe/simvastatin

should

exceed

10/20

daily

patients

receiving

concomitant medication with amiodarone (see section 4.2 and 4.5).

Calcium channel blockers:

Verapamil

or

diltiazem:

Co-administration

verapamil

increased

incidence

myopathy to 0.7% (with simvastatin 40 mg) or 1% (with simvastatin 80 mg). Co-administration

of diltiazem and simvastatin 80 mg led to a mean 70% increase in systemic exposure to

simvastatin-derived HMG-CoA reductase inhibitory activity, with individual increases ranging

up to 200%. In patients taking diltiazem with simvastatin 80 mg, the incidence of myopathy

was about 1%. The dose of ezetimibe/simvastatin should not exceed 10/20 mg daily in

patients receiving concomitant medication with verapamil or diltiazem (see section 4.2 and

section 4.5).

Amlodipine: In a clinical trial, patients on amlodipine treated concomitantly with simvastatin

80 mg had a slightly increased risk of myopathy. The dose of ezetimibe/simvastatin should

not exceed 10/20 mg daily in patients receiving concomitant medication with amlodipine (see

section 4.2 and section 4.5).

Lomitapide: The dose of ezetimibe/simvastatin should not exceed 10/40 mg daily in patients with

HoFH receiving concomitant medication with lomitapide (see section 4.5).

Moderate inhibitors of CYP3A4: Patients taking other medicines labelled as having a moderate

inhibitor

effect

CYP3A4

concomitantly

with

ezetimibe/simvastatin,

particularly

higher

ezetimibe/simvastatin doses, may have an increased risk of myopathy. When co-administering

ezetimibe/simvastatin

with

moderate

inhibitor

CYP3A4,

dose

adjustment

ezetimibe/simvastatin may be necessary.

Page 6 of 43

Inhibitors of breast cancer resistant protein (BCRP): Concomitant administration of products that

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

simvastatin

increased

risk

myopathy;

therefore,

dose

adjustment

ezetimibe/simvastatin

be necessary.

Co-administration of elbasvir

grazoprevir

with

simvastatin has not been studied; however, the dose of ezetimibe/simvastatin should not exceed

10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or

grazoprevir (see section 4.5).

Other fibrates: The safety and effectiveness of ezetimibe/simvastatin administered with fibrates

have not been studied. Therefore, the concomitant use of ezetimibe/simvastatin and fibrates should

be avoided. Concomitant use of gemfibrozil is contraindicated (see section 4.3 and 4.5).

Niacin (≥ 1 g/day): The dose of ezetimibe/simvastatin should not exceed 10/20 mg daily in patients

receiving

concomitant

medication

with

niacin

(nicotinic

acid)

g/day.

Cases

myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid modifying

doses (≥ 1 g/day) of niacin. 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. Therefore, the benefit of the combined use of

simvastatin with niacin should be carefully weighed against the potential risks of the combination. In

addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on

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

simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg co-administered with extended release

niacin/laropiprant 2 g/40 mg. In comparison, in European/Non-Chinese patients the incidence of

myopathy was approximately 0.05% for patients on simvastatin 40 mg or ezetimibe/simvastatin

10/40 mg compared with 0.09% for patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40

mg co-administered with extended-release niacin/laropiprant 2 g/ 40 mg. While the only Asian

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

in Chinese than in non-Chinese patients, co-administration of simvastatin with lipid-modifying doses

(≥ 1 g/day) of niacin is not recommended in Asian patients (see section 4.5).

Daptomycin: Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA

reductase inhibitors co-administered with daptomycin. Caution should be used when prescribing

HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or

rhabdomyolysis

when

given

alone.

Consideration

should

given

suspending

ezetimibe/simvastatin temporarily in patients taking daptomycin (see section 4.5).

Anticoagulants: If ezetimibe/simvastatin is added to warfarin, another coumarin anticoagulant, or

fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section

4.5).

Page 7 of 43

Table 1: Drug interactions associated with increased risk of myopathy/rhabdomyolysis

Interacting agents

Prescribing recommendations

Potent CYP3A4 Inhibitors, e.g.

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Cobicistat

Cyclosporine

Danazol

Gemfibrozil

Fusidic acid

Contraindicated with ezetimibe/simvastatin

Other fibrates (except fenofibrate)

Grapefruit juice

Use with ezetimibe/simvastatin should be avoided

Niacin (≥ 1 g/day)

For Asian patients, not recommended with

ezetimibe/simvastatin

Amiodarone

Verapamil

Diltiazem

Niacin (≥ 1 g/day)

Elbasvir

Grazoprevir

Amlodipine

Do not exceed ezetimibe/simvastatin 10/20 mg daily

Lomitapide

For patients with HoFH, do not exceed

ezetimibe/simvastatin 10/40 mg daily

Daptomycin

Is not recommended with ezetimibe/simvastatin

Liver enzymes

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥ 3 X ULN) in

serum transaminases was 1.7% overall for patients treated with ezetimibe/simvastatin and appeared

to be dose-related with an incidence of 2.6% for patients treated with ezetimibe/simvastatin 10/80.

In controlled long-term (48-week) extensions, which included both newly-treated and previously-

treated patients, the incidence of consecutive elevations (≥ 3 X ULN) in serum transaminases was

1.8% overall and 3.6% for patients treated with ezetimibe/simvastatin 10/80. These elevations in

transaminases were generally asymptomatic, not associated with cholestasis, and returned to

baseline after discontinuation of therapy or with continued treatment.

In another trial, 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40

mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the

Page 8 of 43

incidence

consecutive

elevations

transaminases

(≥

ULN)

2.5%

ezetimibe/simvastatin and 2.3% for simvastatin (see section 4.8). In a controlled clinical study in

which

over

9000

patients

with

chronic

kidney

disease

were

randomised

receive

ezetimibe/simvastatin 10/20 mg daily (n=4650), or placebo (n=4620) (median follow-up period of 4.9

years), the incidence of consecutive elevations of transaminases (> 3 X ULN) was 0.7% for

ezetimibe/simvastatin and 0.6% for placebo (see section 4.8).

It is recommended that LFTs be performed before treatment with ezetimibe/simvastatin begins and

periodically thereafter when clinically indicated. Patients titrated to the 10/80 mg dose should receive

an additional test prior to titration, 3 months after titration to the 10/80 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, the medicine should

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

indicate myopathy (see section 4.4).

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 ezetimibe/simvastatin, promptly interrupt therapy. If an

alternate aetiology is not found do not restart ezetimibe/simvastatin.

Ezetimibe/simvastatin should be used with caution in patients who consume substantial quantities

of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent

transaminase elevations are contraindications to the use of ezetimibe/simvastatin.

Immune mediated necrotizing myopathy

There have been rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after

treatment with some statins. IMNM is clinically characterized by persistent proximal muscle

weakness and elevated serum creatinine kinase, which persists despite discontinuation of statin

treatment.

New-onset type 2 diabetes mellitus

There is sufficient evidence to support an association between statin use and new-onset type 2

diabetes mellitus; however the risk appears to be mainly in patients already at increased risk of

developing diabetes. Risk factors for the development of diabetes include raised fasting blood

glucose, history of hypertension, raised triglycerides and raised body mass. Patients at risk should

be monitored both clinically and biochemically according to national guidelines. There is insufficient

evidence to confirm or exclude an increased risk for any individual statin or a dose-response

relationship. The cardiovascular benefits of statin therapy continue to outweigh the risk of diabetes.

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.

Thyroid function

Simvastatin

The concentration of serum thyroxin has been measured at baseline and at the end of simvastatin

treatment in 785 patients enrolled in multicentre studies. The results of this analysis indicate that

simvastatin has little if any effect upon thyroxin activity. In one study involving 183 patients treated

with simvastatin, four patients had TSH levels within the normal range before commencing

simvastatin, but had an elevated TSH after two years of simvastatin therapy.

Page 9 of 43

Transient hypotension

Simvastatin

Three cases of symptomatic hypotension in the first few days following the start of simvastatin

therapy have been reported. Two of the patients were on antihypertensive medication. The

hypotension resolved with continued therapy with simvastatin.

Neurological effects

Simvastatin

The neurological adverse effects reported to date include cases of peripheral neuropathy and

paraesthesia possibly due to simvastatin.

Effects on laboratory tests

See section 4.8.

Special populations

Hepatic impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or

severe hepatic insufficiency, ezetimibe/simvastatin is not recommended in these patients (see

section 5.2).

Renal impairment

see section 4.2.

Paediatric use

The use of ezetimibe/simvastatin in children and adolescent patients (10 to 17 years old) is

recommended only for patients with Heterozygous Familial Hypercholesterolaemia (HeFH) or

Homozygous Familial Hypercholesterolaemia (HoFH).

However, clinical efficacy/safety study experience in paediatric and adolescent patients (aged 10 to

17 years) has been mostly limited to patients with Heterozygous Familial Hypercholesterolaemia

(see section 5.1). There are also no long term (> 1 year) safety data in this population.

The clinical safety and efficacy of ezetimibe/simvastatin in children and adolescents (10 to 17 years

old) with hypercholesterolaemia other than Heterozygous Familial Hypercholesterolaemia have not

been studied.

Safety and effectiveness of ezetimibe/simvastatin in patients 10 to 17 years of age with heterozygous

familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys

and in girls who were at least one year post-menarche. Doses greater than 10/40 mg/day have

not been studied in this population and are not recommended. 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. However, the effects of ezetimibe/simvastatin for a treatment

period > 33 weeks on growth, sexual maturation, intellectual and psychosocial development have

not been studied (see sections 4.2, 4.8 and 5.1). Adolescent females should be counselled on

appropriate contraceptive methods while on ezetimibe/simvastatin therapy (see sections 4.3 and

4.6).

The safety and efficacy of ezetimibe/simvastatin doses above 10/40 mg daily have not been studied

in children and adolescents (10 to 17 years old) and are not recommended. The long-term efficacy

of therapy with ezetimibe/simvastatin in children and adolescents (10 to 17 years old) to reduce

morbidity and mortality in adulthood has not been studied.

Page 10 of 43

Ezetimibe/simvastatin has not been studied in in pre-menarchal girls or in pre-pubertal boys and is

not recommended in children < 10 years of age.

Use in the elderly

No dosage adjustment is required for elderly patients (see section 5.2). Because advanced age (≥

65 years) is a predisposing factor for myopathy, ezetimibe/simvastatin should be prescribed with

caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥ 65

years of age had an increased risk of myopathy compared to patients < 65 years of age.

4.5

Interaction with other medicines and other forms of interaction

No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered

with simvastatin. Specific pharmacokinetic drug interaction studies with ezetimibe/simvastatin have

not been performed.

Ezetimibe/simvastatin is bioequivalent to co-administered ezetimibe and simvastatin.

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.

Contraindicated medicines

Concomitant use of the following medicines is contraindicated:

Potent inhibitors of CYP3A4

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 medicine

metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed

between ezetimibe and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8,

2C9, and 3A4, or N-acetyltransferase.

Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity; therefore, it is not

expected to affect the plasma concentrations of other medicines metabolised by CYP3A4.

Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of the

simvastatin component of ezetimibe/simvastatin.

Concomitant use with medicines labelled as having a potent inhibitory effect on CYP3A4 (e.g.

itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin,

HIV protease inhibitors, boceprevir, telaprevir, nefazodone or medicines containing cobicistat) is

contraindicated (see sections 4.3 and 4.4).

Gemfibrozil, cyclosporine or danazol

See sections 4.3 and 4.4.

Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total

ezetimibe concentrations approximately 1.7-fold; this increase is not considered clinically significant.

No clinical data are available.

Cyclosporine: In a study of eight post-renal transplant patients with creatinine clearance of > 50

mL/min on a stable dose of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold

(range 2.3 to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control

population from another study (n=17).

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