Consumer medicine information

APO-Ezetimibe/Simvastatin

Ezetimibe; Simvastatin

BRAND INFORMATION

Brand name

APO-Ezetimibe/Simvastatin

Active ingredient

Ezetimibe; Simvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Ezetimibe/Simvastatin.

SUMMARY CMI

APO-EZETIMIBE/SIMVASTATIN

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using APO-EZETIMIBE/SIMVASTATIN?

APO-EZETIMIBE/SIMVASTATIN contains the active ingredients Ezetimibe and Simvastatin. APO-EZETIMIBE/SIMVASTATIN is used to 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.

For more information, see Section 1. Why am I using APO-EZETIMIBE/SIMVASTATIN? in the full CMI.

2. What should I know before I use APO-EZETIMIBE/SIMVASTATIN?

Do not use if you have ever had an allergic reaction to Ezetimibe and Simvastatin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use APO-EZETIMIBE/SIMVASTATIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-EZETIMIBE/SIMVASTATIN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use APO-EZETIMIBE/SIMVASTATIN?

The recommended dose in adults (18 years and over) is one tablet of the prescribed strength once a day, in the evening. The recommended dose in adolescents (10 to 17 years of age) with familial hypercholesterolaemia is one tablet of the prescribed strength once a day, in the evening. The maximum recommended dose in adolescents is 10/40 mg.

More instructions can be found in Section 4. How do I use APO-EZETIMIBE/SIMVASTATIN? in the full CMI.

5. What should I know while using APO-EZETIMIBE/SIMVASTATIN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-EZETIMIBE/SIMVASTATIN.
  • Have your blood fats checked when your doctor says, to make sure APO-EZETIMIBE/SIMVASTATIN is working. If you are about to have elective surgery, tell your doctor that you are taking APO-EZETIMIBE/SIMVASTATIN
  • If you become pregnant while taking APO-EZETIMIBE/SIMVASTATIN, stop taking it and tell your doctor immediately.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Grapefruit juice should be avoided while taking APO-EZETIMIBE/SIMVASTATIN.
  • Do not give APO-EZETIMIBE/SIMVASTATIN to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how APO-EZETIMIBE/SIMVASTATIN affects you.
Drinking alcohol
  • Avoid drinking large quantities of alcohol.
  • Drinking large quantities of alcohol may increase your chance of APO-EZETIMIBE/SIMVASTATIN causing liver problems.
Looking after your medicine
  • Store below 25°C.
  • Keep your tablets in the blister pack until it is time to take them.

For more information, see Section 5. What should I know while using APO-EZETIMIBE/SIMVASTATIN? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). The most common side effects are headache nausea, muscle aches, dizziness, feeling tired, cough, stomach irritation, diarrhoea, decreased appetite, hot flush, hypertension, pain.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APO-EZETIMIBE/SIMVASTATIN

Active ingredient(s): ezetimibe and simvastatin

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-EZETIMIBE/SIMVASTATIN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APO-EZETIMIBE/SIMVASTATIN.

Where to find information in this leaflet:

1. Why am I using APO-EZETIMIBE/SIMVASTATIN?
2. What should I know before I use APO-EZETIMIBE/SIMVASTATIN?
3. What if I am taking other medicines?
4. How do I use APO-EZETIMIBE/SIMVASTATIN?
5. What should I know while using APO-EZETIMIBE/SIMVASTATIN?
6. Are there any side effects?
7. Product details

1. Why am I using APO-EZETIMIBE/SIMVASTATIN?

APO-EZETIMIBE/SIMVASTATIN contains the active ingredients Ezetimibe and Simvastatin. APO-EZETIMIBE/SIMVASTATIN is lipid modifying agent.

APO-EZETIMIBE/SIMVASTATIN is used to help 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.

APO-EZETIMIBE/SIMVASTATIN reduces elevated total-cholesterol, LDL (bad) cholesterol and triglycerides and increases HDL (good) cholesterol.

APO-EZETIMIBE/SIMVASTATIN works by decreasing the absorption of cholesterol in the small intestine and by reducing the amount of cholesterol made in the liver.

APO-EZETIMIBE/SIMVASTATIN does not help you lose weight. If you have heart disease and a history of heart attack or hospitalisation for unstable angina (chest pain), APO-EZETIMIBE/SIMVASTATIN reduces the risk of heart attack, stroke, surgery to increase heart blood flow, or hospitalisation for chest pain.

Your doctor may have prescribed APO-EZETIMIBE/SIMVASTATIN for another reason. Ask your doctor if you have any questions about why APO-EZETIMIBE/SIMVASTATIN has been prescribed for you.

APO-EZETIMIBE/SIMVASTATIN is not addictive.

Cholesterol

Cholesterol is one of several fatty substances found in the bloodstream. Your total cholesterol is made up mainly of LDL and HDL cholesterol. LDL cholesterol is often called 'bad' cholesterol because it can build up in the walls of your arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the arteries.

This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blocking of blood flow can result in a heart attack or stroke.

HDL cholesterol is often called 'good' cholesterol because it helps keep the bad cholesterol from building up in the arteries and protects against heart disease.

Triglycerides

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

2. What should I know before I use APO-EZETIMIBE/SIMVASTATIN?

Warnings

Do not use APO-EZETIMIBE/SIMVASTATIN if:

  • you are allergic to Ezetimibe and Simvastatin, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you have active liver disease or repeated blood tests indicating possible liver problems.
  • you have unexplained muscle pain, tenderness or weakness not caused by exercise. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage that can lead to death.
  • You are taking certain medicines such as gemfibrozil, ciclosporin, danazol, fusidic acid or strong CYP3A4 inhibitors like itraconazole and ketoconazole. Please see the Section 3. What if I am Taking other medicines in this CMI for more information.
  • the packaging is torn or shows signs of tampering.
  • the expiry date on the pack has passed.
  • If you take this medicine after the expiry date has passed, it may not work.

Check with your doctor if you:

  • have unexplained muscle pain, tenderness or weakness not caused by exercise. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage that can lead to death.
  • your doctor may do a blood test to check for certain muscle problems.
  • are Asian.
  • are taking niacin or a niacin-containing product.
  • have, or have had, any medical conditions, including liver disease or liver problems.
  • your doctor will do a blood test to make sure you have no problems with your liver.
  • have kidney disease, diabetes or any other medical problems.
  • drink alcohol regularly.
  • have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Use in Children and Adolescents

APO-EZETIMIBE/SIMVASTATIN is used in children and adolescents (10 to 17 years of age) to treat familial hypercholesterolaemia, a type of high cholesterol that is hereditary (i.e. passed on through families). APO-EZETIMIBE/SIMVASTATIN is not recommended for use in children under 10 years of age, as there have been no studies of its effects in this age group.

Your doctor will assess whether APO-EZETIMIBE/SIMVASTATIN is suitable for your child. Depending on the pubertal development of your child, APO-EZETIMIBE/SIMVASTATIN may not be suitable for them.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

APO-EZETIMIBE/SIMVASTATIN is contraindicated (i.e. should not be used) during pregnancy and breastfeeding. If you take this medicine during pregnancy and breastfeeding, your baby may absorb this medicine and it may affect your baby's normal development causing foetal malformations (birth defects) or irreversible damage.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with APO-EZETIMIBE/SIMVASTATIN and affect how it works. Some medicines should not be taken with APO-EZETIMIBE/SIMVASTATIN. These include:

  • nefazodone, used to treat depression
  • medicines containing cobicistat, a drug used in the treatment of HIV infection.
  • protease inhibitors, including indinavir, nelfinavir, ritonavir, saquinavir, used to treat HIV infection
  • certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir)
  • gemfibrozil, used to treat high cholesterol levels
  • ciclosporin, used to suppress the immune system
  • danazol
  • antibiotics used to treat infections, such as erythromycin, clarithromycin, telithromycin and fusidic acid
  • medicines used to treat certain fungal infections, such as ketoconazole, itraconazole, posaconazole and voriconazole

If you are taking any of the above, your doctor may suggest stopping APO-EZETIMIBE/SIMVASTATIN temporarily or permanently.

Some medicines and APO-EZETIMIBE/SIMVASTATIN may interfere with each other. These include:

  • certain hepatitis c antiviral agents, such as elbasvir, or grazoprevir
  • bile acid sequestrants, such as cholestyramine, used to lower cholesterol levels.
  • other medicines to lower cholesterol levels, for example, other fibrates, nicotinic acid (also known as niacin).
  • warfarin, fluindione, or other drugs used to prevent blood clots
  • colchicine, used for gout
  • verapamil, used to treat high blood pressure and angina
  • diltiazem, used to treat angina
  • amiodarone, used to treat irregular heart beat
  • amlodipine, used to treat high blood pressure and angina
  • digoxin, used to treat heart failure
  • lomitapide (a drug used to treat a serious and rare genetic cholesterol condition)
  • daptomycin, a drug used to treat complicated skin and skin structure infections and bacteraemia

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-EZETIMIBE/SIMVASTATIN.

4. How do I use APO-EZETIMIBE/SIMVASTATIN?

How much to take

  • The recommended dose in adults (18 years and over) is one of the prescribed strength of tablet once a day, in the evening. Your doctor will adjust your APO-EZETIMIBE/SIMVASTATIN dose depending on your response.
  • The recommended dose in adolescents (10 to 17 years of age) with familial hypercholesterolaemia is one of the prescribed strength of tablet once a day, in the evening. The maximum recommended dose in adolescents is 10/40 mg.
  • Because of the increased risk of muscle problems, the APO-EZETIMIBE/SIMVASTATIN 10/80 tablet is only for patients at high risk of heart disease problems who have not yet reached their cholesterol goal on lower doses.
  • Follow the instructions provided and use APO-EZETIMIBE/SIMVASTATIN until your doctor tells you to stop

When to take APO-EZETIMIBE/SIMVASTATIN

  • APO-EZETIMIBE/SIMVASTATIN should be taken once a day, in the evening.
  • The liver produces its greatest amount of cholesterol when the body is at rest and when there is no dietary intake. For most people this is at night when asleep. Therefore, APO-EZETIMIBE/SIMVASTATIN is more effective when taken in the evening. A good time would be after your evening meal. However, it does not matter whether you take it before or after food.
  • take APO-EZETIMIBE/SIMVASTATIN about the same time each day.
  • Taking APO-EZETIMIBE/SIMVASTATIN at the same time each day will have the best effect. It will also help you remember when to take your dose.
  • Your doctor may ask you to take APO-EZETIMIBE/SIMVASTATIN with other cholesterol lowering agents such as bile acid sequestrants.
  • If you are taking a bile acid sequestrant, such as cholestyramine, take your APO-EZETIMIBE/SIMVASTATIN either at least two hours before or four hours after taking the bile acid sequestrant.

How to take APO-EZETIMIBE/SIMVASTATIN

Swallow APO-EZETIMIBE/SIMVASTATIN with a glass of water.

How long to take APO-EZETIMIBE/SIMVASTATIN

APO-EZETIMIBE/SIMVASTATIN helps lower your cholesterol. It does not cure your condition.

Therefore, you must continue to take it as directed by your doctor if you expect to lower your cholesterol and keep it down.

You may have to take cholesterol lowering medicine for the rest of your life. If you stop taking APO-EZETIMIBE/SIMVASTATIN, your cholesterol levels may rise again.

If you forget to use APO-EZETIMIBE/SIMVASTATIN

APO-EZETIMIBE/SIMVASTATIN should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your tablet as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much APO-EZETIMIBE/SIMVASTATIN

If you think that you have used too much APO-EZETIMIBE/SIMVASTATIN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using APO-EZETIMIBE/SIMVASTATIN?

Things you should do

If you become pregnant while taking APO-EZETIMIBE/SIMVASTATIN, stop taking it and tell your doctor immediately.

Have your blood fats checked when your doctor says, to make sure APO-EZETIMIBE/SIMVASTATIN is working.

Even if you are taking medicines to treat high cholesterol, it is important to have your cholesterol measured regularly. You should also know your cholesterol levels and goals.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking APO-EZETIMIBE/SIMVASTATIN.

If you are about to have elective surgery, tell your doctor that you are taking APO-EZETIMIBE/SIMVASTATIN.

Your doctor may suggest stopping the tablets a few days before surgery.

Remind any doctor, dentist or pharmacist you visit that you are using APO-EZETIMIBE/SIMVASTATIN.

Things you should not do

  • Do not give APO-EZETIMIBE/SIMVASTATIN to anyone else, even if they have the same condition as you.
  • Avoid grapefruit juice while taking APO-EZETIMIBE/SIMVASTATIN.

Grapefruit juice contains one or more components that alter the metabolism of some medicines, including APO-EZETIMIBE/SIMVASTATIN.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-EZETIMIBE/SIMVASTATIN affects you.

There have been side effects reported with APO-EZETIMIBE/SIMVASTATIN that may affect your ability to drive or operate machinery. Individual responses to APO-EZETIMIBE/SIMVASTATIN may vary.

Drinking alcohol

Avoid drinking large quantities of alcohol.

Drinking large quantities of alcohol may increase your chance of APO-EZETIMIBE/SIMVASTATIN causing liver problems.

Looking after your medicine

  • Keep APO-EZETIMIBE/SIMVASTATIN in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Headache
  • Nausea
  • Muscle aches
  • Dizziness
  • Feeling tired
  • Cough
  • Stomach irritation
  • Diarrhoea
  • Decreased appetite
  • Hot flush
  • Hypertension
  • Pain
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in swallowing or breathing
  • skin rash and hives
  • raised red rash, sometimes with target-shaped lesions
  • dark coloured urine
  • light coloured bowel motions
  • joint pain
  • bleeding or bruising more easily than normal
  • steady abdominal pain with nausea and vomiting.
  • symptoms of liver problems:
    - feel tired or weak
    - loss of appetite
    - upper belly pain
    - yellowing of the skin or the white of your eyes.
  • unexplained muscle aches, tenderness or weakness, not caused by exercise (in very rare cases this may not go away after stopping APO-EZETIMIBE/SIMVASTATIN).
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Rare side effects

Rare side effectsWhat to do
  • Depression.
  • Tingling or numbness of the hands or feet.
  • Trouble sleeping.
  • Poor memory.
  • Confusion.
  • Blurred or impaired vision
  • Erectile dysfunction.
  • Breathing problems including persistent cough and/or shortness of breath, that may also occur with fatigue.
  • Unexplained weight loss or fever.
  • Gynaecomastia (breast enlargement in men).
  • Muscle rupture.
  • Rash that occurs on the skin or sores in the mouth (lichenoid drug eruptions).
Call your doctor straight away if you notice any of these. These are rare side effects of ezetimibe or simvastatin.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What APO-EZETIMIBE/SIMVASTATIN contains

Active ingredient
(main ingredient)		Ezetimibe
Simvastatin
Other ingredients
(inactive ingredients)		Butylated hydroxyanisole
Citric acid monohydrate
Croscarmellose sodium
Hypromellose
Lactose monohydrate
Magnesium stearate
Microcrystalline cellulose
Propyl gallate
Ascorbic acid
Ferric oxide red
Potential allergensLactose monohydrate

Do not take this medicine if you are allergic to any of these ingredients.

What APO-EZETIMIBE/SIMVASTATIN looks like

  • APO-EZETIMIBE/SIMVASTATIN 10/10 -:
    Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets ‘335’ on one side and plain on other side. (AUST R 309732)
  • APO-EZETIMIBE/SIMVASTATIN 10/20-:
    Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets ‘336’ on one side and plain on other side. (AUST R 309770)
  • APO-EZETIMIBE/SIMVASTATIN 10/40 -:
    Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets ‘337’ on one side and plain on other side. (AUST R 309756)
  • APO-EZETIMIBE/SIMVASTATIN 10/80 -:
    Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets ‘338’ on one side and plain on other side. (AUST R 309758)

Available in Alu-Alu Blister packs of 5, 10 and 30

HDPE Bottle packs of 30

HDPE Bottle packs of 90, 500, 1000 (for dispensing use only).

Who distributes APO-EZETIMIBE/SIMVASTATIN

- Sponsor

Torrent Australasia Pty Ltd
Coleman & Greig L9/10 George St PARRAMATTA WESTFIELD NSW 2150

This leaflet was prepared in January 2023.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

APO-Ezetimibe/Simvastatin

Active ingredient

Ezetimibe; Simvastatin

Schedule

S4

 

1 Name of Medicine

Ezetimibe, simvastatin.

2 Qualitative and Quantitative Composition

APO-Ezetimibe/Simvastatin is available for oral use as tablets containing:
10 mg of ezetimibe and 10 mg of simvastatin (APO-Ezetimibe/Simvastatin 10/10);
10 mg of ezetimibe and 20 mg of simvastatin (APO-Ezetimibe/Simvastatin 10/20);
10 mg of ezetimibe and 40 mg of simvastatin (APO-Ezetimibe/Simvastatin 10/40);
10 mg of ezetimibe and 80 mg of simvastatin (APO-Ezetimibe/Simvastatin 10/80).

Excipients with known effect.

Contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Ezetimibe/Simvastatin 10/10 [10 mg ezetimibe/ 10 mg simvastatin].

Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets '335' on one side and plain on other side.

APO-Ezetimibe/Simvastatin 10/20 [10 mg ezetimibe/ 20 mg simvastatin].

Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets '336' on one side and plain on other side.

APO-Ezetimibe/Simvastatin 10/40 [10 mg ezetimibe/ 40 mg simvastatin].

Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets '337' on one side and plain on other side.

APO-Ezetimibe/Simvastatin 10/80 [10 mg ezetimibe/ 80 mg simvastatin].

Light pink to pink colored with mosaic appearance, capsule shaped biconvex uncoated tablets '338' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults (≥ 18 years).

Prevention of cardiovascular disease.

APO-Ezetimibe/Simvastatin is indicated in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) taking their maximum tolerated dose of simvastatin and in need of additional lowering of LDL-C in the expectation of a modest further reduction in the risk of cardiovascular events following at least one year of therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Primary hypercholesterolaemia.

APO-Ezetimibe/Simvastatin is indicated as adjunctive therapy to diet in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate:
Patients not appropriately controlled with a statin or ezetimibe alone;
Patients already treated with a statin and ezetimibe.

Homozygous familial hypercholesterolaemia (HoFH).

APO-Ezetimibe/Simvastatin is indicated in patients with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

Children and adolescents 10-17 years (pubertal status: boys Tanner Stage II and above and girls who are at least one year post-menarche).

Heterozygous familial hypercholesterolaemia (HeFH).

APO-Ezetimibe/Simvastatin is indicated as adjunctive therapy to diet in adolescent patients (10-17 years old) with HeFH where use of a combination product is appropriate:
Patients not appropriately controlled with a statin or ezetimibe alone;
Patients already treated with a statin and ezetimibe.

Homozygous familial hypercholesterolaemia (HoFH).

APO-Ezetimibe/Simvastatin is indicated in adolescent patients (10-17 years old) with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

4.2 Dose and Method of Administration

Dosage recommendations.

The patient should be placed on a standard cholesterol-lowering diet before receiving APO-Ezetimibe/Simvastatin and should continue on this diet during treatment with APO-Ezetimibe/Simvastatin. In patients with primary hypercholesterolaemia or mixed hyperlipidaemia, APO-Ezetimibe/Simvastatin can be administered within the range of 10/10 mg/day to 10/80 mg/day. The usual starting dose is 10/10 mg/day to 10/40 mg/day. The dosage should be individualised according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response. The 10/80 mg dose of APO-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 (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis). APO-Ezetimibe/Simvastatin should be taken as a single daily dose in the evening, with or without food. After initiation or titration of APO-Ezetimibe/Simvastatin, lipid levels may be analysed after 2 or more weeks and dosage adjusted, if needed.

Patients with coronary heart disease and a history of acute coronary syndrome.

In the cardiovascular events risk reduction study (IMPROVE-IT), the starting dose was 10/40 mg once a day in the evening. (See Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Patients with homozygous familial hypercholesterolaemia.

The recommended dosage for patients with HoFH is APO-Ezetimibe/Simvastatin 10/40 mg/day or 10/80 mg/day in the evening. The 10/80 mg dose should only be used when the benefits are expected to outweigh the potential risks (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).
APO-Ezetimibe/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 APO-Ezetimibe/Simvastatin, the dose of APO-Ezetimibe/Simvastatin should not exceed 10/40 mg/day (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Patients with renal impairment/chronic kidney disease.

In patients with mild renal insufficiency (estimated GFR ≥ 60 mL/min/1.73 m2) no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate < 60 mL/min/1.73 m2, the dose of APO-Ezetimibe/Simvastatin is 10/20 mg once a day in the evening. Efficacy and safety at higher doses has not been evaluated in this CKD population. (See Section 5.2 Pharmacokinetic Properties, Characteristics in special populations; Section 5.1 Pharmacodynamic Properties, Clinical trials.)

Use in the elderly.

No dosage adjustment is required for elderly patients (see Section 5.2 Pharmacokinetic Properties, Characteristics in special populations).

Paediatric use - heterozygous or homozygous familial hypercholesterolaemia.

Initiation of treatment must be performed under review of a specialist.
The use of APO-Ezetimibe/Simvastatin in children and adolescent patients (10-17 years old) is recommended only for patients with HeFH or HoFH.
There are no clinical safety and efficacy data on the use of APO-Ezetimibe/Simvastatin in children and adolescent patients (10-17 years old) with non-familial hypercholesterolaemia, or 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 10-17 years old) is limited and mostly includes children and adolescents (10-17 years old) with HeFH. 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 mg to a maximum of 10/40 mg/day (see Section 5.2 Pharmacokinetic Properties, Characteristics in special populations).

Children < 10 years.

APO-Ezetimibe/Simvastatin is not recommended for use in children below age 10 due to very limited data on safety and efficacy (see Section 5.2 Pharmacokinetic Properties, Characteristics in special populations; Section 4.4 Special Warnings and Precautions for Use, Paediatric use). APO-Ezetimibe/Simvastatin has not been studied in pre-menarchal girls or in pre-pubertal boys and is not recommended in children < 10 years.

Hepatic insufficiency.

No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6). Treatment with APO-Ezetimibe/Simvastatin 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 Special Warnings and Precautions for Use, Use in hepatic impairment; Section 5.2 Pharmacokinetic Properties, Characteristics in special populations).

Co-administration with other medicines.

Dosing of APO-Ezetimibe/Simvastatin should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant.
In patients taking amiodarone, verapamil, diltiazem, ≥ 1 g/day of niacin, or products containing elbasvir or grazoprevir concomitantly with APO-Ezetimibe/Simvastatin, the dose of APO-Ezetimibe/Simvastatin should not exceed 10/20 mg/day (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients taking amlodipine concomitantly with APO-Ezetimibe/Simvastatin, the dose of APO-Ezetimibe/Simvastatin should not exceed 10/40 mg/day (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The safety and effectiveness of APO-Ezetimibe/Simvastatin administered with fibrates have not been studied. Therefore, the concomitant use of APO-Ezetimibe/Simvastatin and fibrates should be avoided. Concomitant use of gemfibrozil is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Because the incidence of myopathy when simvastatin is co-administered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products is higher in Chinese than in non-Chinese patients, co-administration of APO-Ezetimibe/Simvastatin with lipid-modifying doses of niacin-containing products is not recommended in Asian patients (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis, Drug interactions).

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
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 drugs containing cobicistat (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of gemfibrozil, ciclosporin, or danazol (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant use with fusidic acid (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 CK above 10X 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 Interactions with Other Medicines and Other Forms of Interactions). Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
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 major, large, long-term clinical trial (SEARCH) 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 SEARCH, 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 all the myopathy cases occur 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 APO-Ezetimibe/Simvastatin should only be used in patients at high risk for cardiovascular complications who have not achieve their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking APO-Ezetimibe/Simvastatin 10/80 mg for whom an interacting agent is needed, a lower dose of APO-Ezetimibe/Simvastatin or an alternative statin-ezetimibe regimen with less potential for drug-drug interactions should be used (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).
All patients starting therapy with APO-Ezetimibe/Simvastatin, or whose dose of APO-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. APO-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 treatment, muscle symptoms and CK increases resolved (see Section 4.8 Adverse Effects (Undesirable Effects)). Periodic CK determinations may be considered in patients starting therapy with APO-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 APO-Ezetimibe/Simvastatin merit closer monitoring. Therapy with APO-Ezetimibe/Simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
In the IMProved Reduction of Outcomes: Ezetimibe/Simvastatin Efficacy International Trial (IMPROVE-IT), 18,144 patients with CHD were randomised to receive ezetimibe/simvastatin tablet 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 tablet 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 tablet 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 Adverse Effects (Undesirable Effects)).
In a clinical trial in which over 9,000 patients with chronic kidney disease were randomised to receive ezetimibe/simvastatin tablet 10/20 mg daily (n=4,650) or placebo (n=4,620) (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for ezetimibe/simvastatin tablet and 0.1% for placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 population assessed in this clinical trial was Chinese, caution should be used when prescribing APO-Ezetimibe/Simvastatin to any Asian patients and the lowest dose necessary should be employed.

Drug interactions.

Because APO-Ezetimibe/Simvastatin contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of APO-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, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, or drugs containing cobicistat) is contraindicated. If short-term treatment with potent CYP3A4 inhibitors is unavoidable, therapy with APO-Ezetimibe/Simvastatin should be suspended during the course of treatment (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gemfibrozil, ciclosporin or danazol.

Concomitant use of these drugs with APO-Ezetimibe/Simvastatin is contraindicated (see Section 4.3 Contraindications).

Fusidic acid.

Patients on fusidic acid treated concomitantly with simvastatin may have an increased risk of myopathy/rhabdomyolysis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Fusidic acid must not be co-administered with statins (see Section 4.3 Contraindications). In patients where the use of systemic fusidic acid is considered essential, APO-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. APO-Ezetimibe/Simvastatin therapy may be reintroduced seven days after the last dose of fusidic acid.
Other medicines.

Amiodarone.

In a large 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, the dose of APO-Ezetimibe/Simvastatin should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Calcium channel blockers.

Verapamil or diltiazem: Co-administration of verapamil increased the incidence of 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 APO-Ezetimibe/Simvastatin should not exceed 10/20 mg daily in patients receiving concomitant medication with verapamil or diltiazem (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Amlodipine: In a clinical trial, patients on amlodipine treated concomitantly with simvastatin 80 mg had a slightly increased risk of myopathy. The dose of APO-Ezetimibe/Simvastatin should not exceed 10/40 mg daily in patients receiving concomitant medication with amlodipine (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Lomitapide.

The dose of APO-Ezetimibe/Simvastatin should not exceed 10/40 mg daily in patients with HoFH receiving concomitant medication with lomitapide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Moderate inhibitors of CYP3A4.

Patients taking other medicines labelled as having a moderate inhibitor effect on CYP3A4 concomitantly with APO-Ezetimibe/Simvastatin, particularly higher APO-Ezetimibe/Simvastatin doses, may have an increased risk of myopathy. When co-administering APO-Ezetimibe/Simvastatin with a moderate inhibitor of CYP3A4, a dose adjustment of APO-Ezetimibe/Simvastatin may be necessary.

Inhibitors of breast cancer resistance protein (BCRP).

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 APO-Ezetimibe/Simvastatin may be necessary. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of APO-Ezetimibe/Simvastatin should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Other fibrates.

The safety and effectiveness of APO-Ezetimibe/Simvastatin administered with fibrates have not been studied. Therefore, the concomitant use of APO-Ezetimibe/Simvastatin and fibrates should be avoided. Concomitant use of gemfibrozil is contraindicated (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Niacin (≥ 1 g/day).

The dose of APO-Ezetimibe/Simvastatin should not exceed 10/20 mg daily in patients receiving concomitant medication with niacin (nicotinic acid) ≥ 1 g/day. Cases of 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 European/Non-Chinese patients, co-administration of APO-Ezetimibe/Simvastatin with lipid-modifying doses (≥ 1 g/day) of niacin is not recommended in Asian patients (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 be given to suspending ezetimibe/simvastatin temporarily in patients taking daptomycin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anticoagulants.

If APO-Ezetimibe/Simvastatin is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Prescribing recommendations for interacting agents are summarised in Table 1 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).

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 IMPROVE-IT, 18,144 patients with CHD were randomised 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 consecutive elevations of transaminases (≥ 3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for simvastatin. (See Section 4.8 Adverse Effects (Undesirable Effects)).
In a controlled clinical study in which over 9,000 patients with chronic kidney disease were randomised to receive ezetimibe/simvastatin 10/20 mg daily (n=4,650) or placebo (n=4,620) (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 Adverse Effects (Undesirable Effects)).
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 drug should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see Section 4.4 Special Warnings and Precautions for Use, 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 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 necrotising myopathy.

There have been rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatinine kinase, which persists despite discontinuation of statin treatment.

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 Adverse Effects (Undesirable Effects)). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected that 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.

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.

Use in hepatic impairment.

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, APO-Ezetimibe/Simvastatin is not recommended in these patients (see Section 5.2 Pharmacokinetic Properties, Characteristics in special populations).

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Patients with renal impairment/chronic kidney disease.

Use in the elderly.

No dosage adjustment is required for elderly patients (see Section 5.2 Pharmacokinetic Properties, Characteristics in special populations). Because advanced age (≥ 65 years) is a predisposing factor for myopathy, APO-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.

Paediatric use.

The use of APO-Ezetimibe/Simvastatin in children and adolescent patients (10-17 years old) is recommended only for patients with HeFH or HoFH.
However, clinical efficacy/safety study experience in paediatric and adolescent patients (aged 10 to 17 years) has been mostly limited to patients with HeFH (see Section 5.1 Pharmacodynamic Properties, Clinical trials). 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 (10-17 years old) with hypercholesterolaemia other than HeFH have not been studied.
Safety and effectiveness of ezetimibe/simvastatin in patients 10 to 17 years of age with HeFH 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 generally 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 Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (10 to 17 years of age) patients). Adolescent females should be counselled on appropriate contraceptive methods while on ezetimibe/simvastatin therapy (see Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
The safety and efficacy of ezetimibe/simvastatin doses above 10/40 mg daily have not been studied in children and adolescents (10-17 years old) and are not recommended. The long-term efficacy of therapy with ezetimibe/simvastatin in children and adolescents (10-17 years old) to reduce morbidity and mortality in adulthood has not been studied.
Ezetimibe/simvastatin has not been studied in pre-menarchal girls or in pre-pubertal boys and is not recommended in children < 10 years of age.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory values.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ezetimibe/simvastatin.

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 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs 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 drugs metabolised by CYP3A4.
Potent inhibitors of CYP3A4 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 drugs containing cobicistat) is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gemfibrozil, ciclosporin or danazol.

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

Ciclosporin.

In a study of eight post-renal transplant patients with creatinine clearance of > 50 mL/min on a stable dose of ciclosporin, 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).
In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including ciclosporin, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls.
In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of ciclosporin on Day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100 mg dose of ciclosporin alone (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). The pharmacokinetic interactions between ezetimibe at steady-state and ciclosporin also at steady-state have not been studied.

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of simvastatin with fusidic acid. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins. Where the use of fusidic acid is considered essential, ezetimibe/simvastatin should be discontinued throughout the duration of fusidic acid treatment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Other drug interactions.

Amiodarone.

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone with ezetimibe/simvastatin (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). During co-administration of amiodarone and simvastatin 80 mg in a large clinical trial, the risk of myopathy was approximately 6% (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cholestyramine.

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding ezetimibe/simvastatin to cholestyramine may be lessened by this interaction.

Calcium channel blockers.

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Lomitapide.

The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of lomitapide (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

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 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

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 Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Inhibitors of breast cancer resistance protein (BCRP).

Simvastatin is a substrate of the efflux transporter BCRP. 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. When co-administering simvastatin with an inhibitor of BCRP, a dose adjustment of ezetimibe/simvastatin may be necessary (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Fibrates.

Concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold; however, this increase is not considered clinically significant. The safety and effectiveness of ezetimibe/simvastatin administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a pre-clinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of ezetimibe/simvastatin with fibrates is not recommended until use in patients is studied.

Niacin.

In a study of 15 healthy adults, concomitant ezetimibe/simvastatin (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%, 90% Confidence Interval (CI), -28 to 105) and nicotinuric acid (19%, 90% CI, -1 to 43) [n=13] administered as NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%, 90% CI, -2 to 22), total ezetimibe (26%, 90% CI, 10 to 44), simvastatin (20%, 90% CI, 3 to 40) and simvastatin acid (35%, 90% CI, -3 to 88) [n=15].
Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Colchicine.

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

Daptomycin.

The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin (see Section 4.4 Special Warnings and Precautions for Use, Drug interactions).

Grapefruit juice.

Contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolised by CYP3A4. The effect of typical consumption (one 250 mL glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, because larger quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during ezetimibe/simvastatin therapy (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Coumarin derivatives.

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalised Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting ezetimibe/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 ezetimibe/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.
Concomitant administration of ezetimibe (10 mg once daily) for 11 days had no significant effect on bioavailability of a single dose 25 mg warfarin, administered on day 7, and prothrombin time in a cross-over study of twelve healthy adult males. There have been post-marketing reports of increased International Normalised Ratio in patients who had ezetimibe added to warfarin or fluindione. Most of these patients were also on other medications (see Section 4.4 Special Warnings and Precautions for Use).
The effect of ezetimibe/simvastatin on the prothrombin time has not been studied.

Antacids.

Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.

Digoxin.

Concomitant administration of simvastatin and digoxin in normal volunteers resulted in a slight elevation (less than 0.3 nanogram/mL) in plasma drug concentrations (as measured by a digoxin radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Ezetimibe/simvastatin.

There are no human data addressing the effects of ezetimibe/simvastatin combinations on fertility. In animal reproductive/fertility studies, no effect on pregnancy rates was observed in rats treated orally with ezetimibe/simvastatin at up to 1000/12.5 mg/kg. These doses correspond to exposure levels (based on AUC) approximately 1x (free ezetimibe), 20x (total ezetimibe), 0.8x (simvastatin), and 72x (hydroxysimvastatin) that expected in humans over the ezetimibe/simvastatin combination dose range (10/10 mg to 10/80 mg).

Effects on spermatogenesis and testosterone.

Simvastatin.

In several studies of over 800 men with hypercholesterolaemia treated with simvastatin 20 mg to 80 mg per day for 12 to 48 weeks, basal testosterone levels were mildly decreased during simvastatin therapy, but there were no consistent changes in LH and FSH. In 86 men treated with simvastatin 20 mg to 80 mg per day, there was no impairment of hCG-stimulated testosterone secretion.
Testicular degeneration has been seen in two dog safety studies with simvastatin. Special studies designed to further define the nature of these changes have not met with success since the effects are poorly reproducible and unrelated to dose, serum cholesterol levels, or duration of treatment. Simvastatin has been administered for up to two years to dogs at a dose of 50 mg/kg/day without any testicular effects.
(Category D)
Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.

Ezetimibe/simvastatin.

APO-Ezetimibe/Simvastatin is contraindicated during pregnancy. HMG-CoA reductase inhibitors, including simvastatin, a component of APO-Ezetimibe/Simvastatin, are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor, or medicines containing an HMG-CoA reductase inhibitor, therapy during pregnancy.
Atherosclerosis is a chronic process, and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia.
The safety of ezetimibe/simvastatin combinations in pregnant women has not been established.
Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for foetal development, including synthesis of steroids and cell membranes. Because of the ability of HMG-CoA reductase inhibitors to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, APO-Ezetimibe/Simvastatin, which contains simvastatin, is contraindicated during pregnancy. APO-Ezetimibe/Simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, APO-Ezetimibe/Simvastatin should be discontinued and the patient informed of the potential hazard to the foetus (see Section 4.3 Contraindications).
Ezetimibe in combination with statins in rats and rabbits resulted in higher exposures to ezetimibe and/or statins than either drug administered alone. Skeletal malformations (hemivertebrae in rats and shortened/filamentous tail associated with fused and reduced number of caudal vertebrae in rabbits) and other less severe foetal abnormalities were observed in rats and rabbits dosed with ezetimibe/statin combinations during organogenesis.

Simvastatin.

In two series of 178 and 134 cases where pregnant women took an HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy serious foetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetus occurring after a pregnant woman is exposed to a HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in women exposed to a HMG-CoA reductase inhibitor is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist.
Maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, APO-Ezetimibe/Simvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with APO-Ezetimibe/Simvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see Section 4.3 Contraindications).

Ezetimibe.

No clinical data on exposed pregnancies are available for ezetimibe. Ezetimibe crossed the placenta in rats and rabbits. There was no evidence of foetal abnormalities in rats dosed with up to 1000 mg/kg/day ezetimibe by oral gavage during organogenesis, corresponding to exposures about 1 and 7 times the adult human exposure for ezetimibe and total ezetimibe respectively, based on AUC. There was an increase in the incidence of extra thoracic ribs in rabbits at doses of 250 to 1000 mg/kg/day, corresponding to exposures 0.5 to 1 times and 100 to 150 times the adult human exposure for ezetimibe and total ezetimibe, respectively. The relevance of this finding to humans is not known.
 There are no human or animal data addressing the use of ezetimibe/simvastatin combinations during lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking APO-Ezetimibe/Simvastatin should not breastfeed their infants (see Section 4.3 Contraindications).

Ezetimibe.

Studies in rats showed that ezetimibe is excreted in milk. Ezetimibe had no effects on pup development in rats treated with up to 1000 mg/kg/day ezetimibe during late pregnancy and lactation. Drug exposures (based on AUC) in pups were approximately 1.5% (free ezetimibe) and 50% (total ezetimibe) of maternal exposures. It is not known whether ezetimibe is excreted into human breast milk.

Simvastatin.

Animal studies have shown that weight gain during lactation is reduced in the offspring of rats dosed with simvastatin at dosages of 12.5 to 25 mg/kg/day. There is no information from animal studies on whether simvastatin or its metabolites are excreted in breast milk.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects that have been reported with APO-Ezetimibe/Simvastatin may affect some people's ability to drive or operate machinery. Individual responses to APO-Ezetimibe/Simvastatin may vary (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Ezetimibe/simvastatin (or co-administration of ezetimibe and simvastatin equivalent to APO-Ezetimibe/Simvastatin) has been evaluated for safety in approximately 12,000 patients in clinical trials. Ezetimibe/simvastatin was generally well tolerated.
The following common (≥ 1/100, < 1/10) or uncommon (≥ 1/1000, < 1/100) drug-related adverse experiences were reported in patients taking ezetimibe/simvastatin (n=2404) and at a greater incidence than placebo (n=1340):

Investigations.

Common: ALT and/or AST increased; blood CK increased.
Uncommon: blood bilirubin increased; blood uric acid increased; gamma-glutamyltransferase increased; international normalised ratio increased; protein urine present; weight decreased.

Nervous system disorders.

Uncommon: dizziness; headache.

Gastrointestinal disorders.

Uncommon: abdominal pain; abdominal discomfort; abdominal pain upper; dyspepsia; flatulence; nausea; vomiting.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus; rash.

Musculoskeletal and connective tissue disorders.

Uncommon: arthralgia; muscle spasms; muscular weakness; musculoskeletal discomfort; neck pain; pain in extremity.

General disorders and administration site conditions.

Uncommon: asthenia; fatigue; malaise; oedema peripheral.

Psychiatric disorders.

Uncommon: sleep disorder.
The following common (≥ 1/100, < 1/10) or uncommon (≥ 1/1000, < 1/100); drug-related adverse experiences were reported in patients taking ezetimibe/simvastatin (n=9595) and at a greater incidence than statins administered alone (n=8883):

Investigations.

Common: ALT and/or AST increased.
Uncommon: blood bilirubin increased; blood CK increased; gamma-glutamyltransferase increased.

Nervous system disorders.

Uncommon: headache; paresthaesia.

Gastrointestinal disorders.

Uncommon: abdominal distension; diarrhoea; dry mouth; dyspepsia; flatulence; gastro-oesophageal reflux disease; vomiting.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus; rash; urticaria.

Musculoskeletal and connective tissue disorders.

Common: myalgia.
Uncommon: arthralgia; back pain; muscle spasms; muscular weakness; musculoskeletal pain; pain in extremity.

General disorders and administration site conditions.

Uncommon: asthenia; chest pain; fatigue; oedema peripheral.

Psychiatric disorders.

Uncommon: insomnia.

Paediatric (10 to 17 years of age) patients.

In a study involving adolescent (10 to 17 years of age) patients with HeFH (n=248), elevations of ALT and/or AST (≥ 3X ULN, consecutive) were observed in 3% (4 patients) of the ezetimibe/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (≥ 10 X ULN). No cases of myopathy were reported (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (10 to 17 years of age) patients).
In this limited controlled study, there was generally 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 Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (10 to 17 years of age) patients).
The study was not of sufficient duration to detect long term adverse events.

Laboratory values.

In controlled clinical co-administration trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥ 3 X ULN, consecutive) was 1.7% for patients treated with ezetimibe/simvastatin. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment (see Section 4.4 Special Warnings and Precautions for Use).
Clinically important elevations of CK (≥ 10 X ULN) were seen in 0.2% of the patients treated with ezetimibe/simvastatin.

Patients with coronary heart disease.

In the IMPROVE-IT study (see Section 5.1 Pharmacodynamic Properties, Clinical trials), involving 18,144 patients treated with either ezetimibe/simvastatin 10/40 mg (n=9067; of whom 6% were uptitrated to ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (n=9077; of whom 27% were uptitrated to simvastatin 80 mg), the safety profiles were similar during a median follow-up period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for patients treated with ezetimibe/simvastatin and 10.1% for patients treated with simvastatin. 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. The incidence of consecutive elevations of transaminases (≥ 3 X ULN) was 2.5% for ezetimibe/simvastatin and 2.3% for simvastatin (see Section 4.4 Special Warnings and Precautions for Use). Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to ezetimibe/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalisations was 1.5% in both treatment groups. Cancer (defined as any new malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.

Patients with chronic kidney disease.

In the Study of Heart and Renal Protection (SHARP) (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Prevention of major vascular events in chronic kidney disease (CKD)), involving over 9,000 patients treated with ezetimibe/simvastatin 10/20 mg daily (n=4,650) or placebo (n=4,620), the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients treated with ezetimibe/simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with ezetimibe/simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (> 3 X ULN) occurred in 0.7% of patients treated with ezetimibe/simvastatin compared with 0.6% of patients treated with placebo (see Section 4.4 Special Warnings and Precautions for Use). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for ezetimibe/simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.

Post-marketing experience.

The adverse reactions reported for ezetimibe/simvastatin are consistent with those previously reported with ezetimibe and/or simvastatin.
Additional adverse events reported commonly with ezetimibe during clinical trials:

Gastrointestinal disorders.

Gastritis.

Investigations.

Liver function test abnormal.

Respiratory, thoracic and mediastinal disorders.

Cough.

Metabolism and nutrition disorders.

Decreased appetite.

Vascular disorders.

Hot flush; hypertension.

General disorders and administration site conditions.

Pain.
Additional adverse events reported rarely, regardless of causality assessment, with ezetimibe during post-marketing use:

Blood and lymphatic system disorders.

Thrombocytopenia.

Hepato-biliary disorders.

Cholelithiasis, cholecystitis, hepatitis.

Musculoskeletal, connective tissue and bone disorders.

Very rarely myopathy/rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use).

Psychiatric disorders.

Depression.

Skin and subcutaneous tissue disorders.

Hypersensitivity reactions, including rash and urticaria (rare [≥ 1/10,000, < 1/1000]) and anaphylaxis and angioedema (very rare [< 1/10,000]), erythema multiforme.

Gastrointestinal disorders.

Pancreatitis (very rare).

Laboratory values.

Increased CPK; elevations of liver transaminases.
Additional adverse events reported rarely with simvastatin during clinical studies and/or post-marketing use:

Blood and lymphatic system disorders.

Rare: anaemia.

Gastrointestinal disorders.

Rare: constipation, pancreatitis.

Hepatic disorders.

Rare: hepatitis/jaundice and very rarely, fatal and non-fatal hepatic failure.

Eye disorder.

Rare: vision blurred, visual impairment.

Skin and subcutaneous tissue disorders.

Very rare: lichenoid drug eruptions.

Reproductive system and breast disorders.

Rare: erectile dysfunction. Very rare: gynaecomastia.

Musculoskeletal, connective tissue and bone disorders.

Rare: muscle cramps, myopathy, rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis). Very rare: muscle rupture.
There have been very rare reports of immune-mediated necrotising myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterised by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment: muscle biopsy showing necrotising myopathy without significant inflammation; improvement with immunosuppressive agents (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Nervous system disorders.

Peripheral neuropathy.

Respiratory, thoracic and mediastinal disorders.

Interstitial lung disease.

Skin and subcutaneous tissue disorders.

Alopecia.
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.
There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. 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).

Laboratory values.

Elevated alkaline phosphatase and gamma-glutamyl transpeptidase have been reported with simvastatin.
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Ezetimibe/simvastatin.

No specific treatment of overdosage with ezetimibe/simvastatin can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Co-administration of ezetimibe (1000 mg/kg) and simvastatin (1000 mg/kg) was well-tolerated in acute, oral toxicity studies in mice and rats. No clinical signs of toxicity were observed in these animals. The estimated oral LD50 for both species was ezetimibe ≥ 1000 mg/kg/simvastatin ≥ 1000 mg/kg.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Ezetimibe.

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, and 40 mg/day to 13 patients with homozygous sitosterolemia for 26 weeks, was generally well tolerated.
A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Simvastatin.

A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ezetimibe/simvastatin.

Plasma cholesterol homeostasis depends on the balance between intestinal absorption and endogenous synthesis. APO-Ezetimibe/Simvastatin contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe/simvastatin reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.

Ezetimibe.

Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.
In a 2-week clinical study in 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

Simvastatin.

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolysed in the liver to the corresponding active β-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 trials.

In controlled clinical studies, ezetimibe/simvastatin significantly reduced 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 increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia.
Prevention of cardiovascular disease.

Ezetimibe/simvastatin.

In brief, ezetimibe/simvastatin has been shown in the IMPROVE-IT trial to reduce the major cardiovascular events of non-fatal myocardial infarction and stroke in patients with coronary heart disease and a history of Acute Coronary Syndrome. Total mortality, cardiovascular mortality and rates of unstable angina requiring hospitalisation and all coronary revascularisations were unchanged. There was a small increase in the rate of haemorrhagic stroke that was not statistically significant.
The IMProved Reduction of Outcomes: Ezetimibe/simvastatin Efficacy International Trial (IMPROVE-IT) was a multicentre, randomised, double-blind, active-control study of 18,144 patients enrolled within 10 days of hospitalisation for acute coronary syndrome (ACS; either acute myocardial infarction [MI] or unstable angina [UA]). Patients had an LDL-C ≤ 3.2 mmol/L (≤ 125 mg/dL) at the time of presentation with ACS if they had not been taking lipid-lowering therapy, or ≤ 2.6 mmol/L (≤ 100 mg/dL) if they had been receiving lipid-lowering therapy. All patients were randomised in a 1:1 ratio to receive either ezetimibe/simvastatin 10/40 mg (n=9,067) or simvastatin 40 mg (n=9,077) and followed for a median of 6.0 years.
Patients had a mean age of 63.6 years; 76% were male, 84% were Caucasian, and 27% were diabetic. The average LDL-C value at the time of study qualifying event was 2.1 mmol/L (80 mg/dL) for those on lipid-lowering therapy (n=6390) and 2.6 mmol/L (101 mg/dL) for those not on previous lipid-lowering therapy (n=11594). Prior to the hospitalisation for the qualifying ACS event, 34% of the patients were on statin therapy. At one year, the average LDL-C for patients continuing on therapy was 1.4 mmol/L (53.2 mg/dL) for the ezetimibe/simvastatin group and 1.8 mmol/L (69.9 mg/dL) for the simvastatin monotherapy group. Lipid values were generally obtained for patients who remained on study therapy.
The primary endpoint was a composite consisting of cardiovascular death, major coronary events (MCE; defined as non-fatal myocardial infarction, documented unstable angina that required hospitalisation, or any coronary revascularisation procedure occurring at least 30 days after randomised treatment assignment) and non-fatal stroke. The study demonstrated that treatment with ezetimibe/simvastatin provided incremental benefit in reducing the primary composite endpoint of cardiovascular death, MCE, and non-fatal stroke compared with simvastatin alone (relative risk reduction of 6.4%, p=0.016). The primary endpoint occurred in 2572 of 9067 patients (7-year Kaplan-Meier [KM] rate 32.72%) in the ezetimibe/simvastatin group and 2742 of 9077 patients (7-year KM rate 34.67%) in the simvastatin alone group. (See Figure 1 and Table 2). Total mortality was unchanged in this high risk group (see Table 2).
There was an overall benefit for all strokes; however, there was a small non-significant increase in haemorrhagic stroke in the ezetimibe/simvastatin group compared with simvastatin alone (see Table 2). The risk of haemorrhagic stroke for ezetimibe co-administered with higher potency statins in long-term outcome studies has not been evaluated.
The treatment effect of ezetimibe/simvastatin was generally consistent with the overall results across many subgroups, including sex, age, race, medical history of diabetes mellitus, baseline lipid levels, prior statin therapy, prior stroke, and hypertension.
Prevention of major vascular events in chronic kidney disease (CKD). The Study of Heart and Renal Protection (SHARP) was a multinational, randomised, placebo-controlled, double-blind study conducted in 9,438 patients with chronic kidney disease, a third of whom were on dialysis at baseline. Patients with a definite history of myocardial infarction (MI) or coronary revascularisation procedure, existing or planned renal transplant, recent acute uraemic emergency, evidence of active inflammatory muscle disease or creatine kinase (CK) > 3 x ULN were excluded. For the first year, patients were randomised in a ratio of 4:4:1, respectively, to ezetimibe/simvastatin 10/20, placebo, or simvastatin 20 mg daily. The 1-year simvastatin arm was included to enable the comparison of ezetimibe/simvastatin to simvastatin alone with regard to safety and lipids. At 1 year the simvastatin-only arm was re-randomised 1:1 to ezetimibe/simvastatin 10/20 or placebo. A total of 4,650 patients were allocated to ezetimibe/simvastatin 10/20 and 4,620 to placebo, and followed for a median of 4.9 years. Patients had a mean age of 62 (ranging in age from 39 to 94.5 years old); 63% were male, 72% were Caucasian, and 23% were diabetic; and, for those not on dialysis, the median serum creatinine was 0.22 mmol/L and the mean estimated glomerular filtration rate (eGFR) was 26.5 mL/min/1.73 m2, with 94% of patients having an eGFR < 45 mL/min/1.73 m2. There were no lipid entry criteria. Mean LDL-C at baseline was 2.8 mmol/L. As of the 1-year measurement, LDL-C was reduced 26% relative to placebo by simvastatin 20 mg alone and 38% for ezetimibe/simvastatin 10/20. At the midpoint of the study (2.5 years) mean LDL-C reduction for ezetimibe/simvastatin relative to placebo was 32%. All lipid measurements included patients no longer taking study medication.
The SHARP protocol-specified primary comparison was an intention-to-treat analysis of "major vascular events" (MVE; defined as non-fatal MI or cardiac death, stroke, or any revascularisation procedure) in only those patients initially randomised to the ezetimibe/simvastatin (n=4,193) or placebo (n=4,191) groups. Secondary analyses included the same composite analysed for the full cohort randomised (at study baseline or at year 1) to ezetimibe/simvastatin (n=4,650) or placebo (n=4,620), as well as the components of this composite.
The primary endpoint analysis showed that ezetimibe/simvastatin significantly reduced the risk of MVE (749 patients with events in the placebo group vs 639 in the ezetimibe/simvastatin group) with an absolute risk reduction of 2.3% (number needed to treat, 43) and a relative risk reduction of 16% (p=0.001) (see Figure 2). An analysis of major atherosclerotic events (MAE, a subset of the MVE composite that excluded non-coronary cardiac deaths and haemorrhagic stroke) showed that ezetimibe/simvastatin significantly reduced the risk of MAE (526 (11.3%) of 4650 patients ever allocated to ezetimibe/simvastatin and 619 (13.4%) of 4620 patients ever allocated to placebo), corresponding to an absolute risk reduction of 2.1% (number needed to treat, 48) and a relative risk reduction of 17% (p=0.002).
The risk reduction for the MVE composite was directionally consistent (i.e. ezetimibe/simvastatin numerically superior to placebo) with that of the entire cohort of patients for the following key baseline predefined subgroups: age, gender, dialysis vs non-dialysis, eGFR, diabetes, pre-existing atherosclerotic disease, blood pressure, or tertiles of baseline LDL-C.
Compliance rates with placebo and study medication declined over the course of the study. For example, at 20-25 months of follow-up, 68% of patients allocated to ezetimibe/simvastatin and 67% of patients allocated to placebo were taking 80% or more of the study medication, while at 44-49 months, compliance had fallen to 60% and 56%, respectively.
The individual components of MVE in all randomised patients are presented in Table 3. Ezetimibe/simvastatin significantly reduced the risk of stroke and any revascularisation, with non-significant numerical differences favouring ezetimibe/simvastatin for non-fatal MI and cardiac death.
No significant treatment effect of ezetimibe/simvastatin on MVE was found in the subgroup of patients on dialysis at baseline compared with those not on dialysis at baseline. Among 3023 patients on dialysis at baseline, ezetimibe/simvastatin reduced the risk of MVE by 6% (RR 0.94: 95% CI 0.80-1.09) compared with 22% (RR 0.78: 95% CI 0.69-0.89) among 6247 patients not on dialysis at baseline (interaction p=0.08).
Among patients not on dialysis at baseline, ezetimibe/simvastatin did not reduce the risk of progressing to end-stage renal disease compared with placebo.
There were no significant differences between the ezetimibe/simvastatin and placebo groups on all cause mortality, or on any specific cause of death.
The study design precluded drawing conclusions regarding the independent contribution of either ezetimibe or simvastatin to the observed effect and was not able to provide evidence of efficacy for the combination of ezetimibe/simvastatin 10/20 compared to either the lower dose combination (i.e. ezetimibe/simvastatin 10/10) or to treatment with statin alone (i.e. simvastatin 20 mg).
Primary hypercholesterolaemia.

Ezetimibe/simvastatin.

Five multicentre, double-blind studies conducted with ezetimibe/simvastatin in patients with primary hypercholesterolaemia are reported: two were comparisons with simvastatin and two were comparisons with atorvastatin and one was a comparison with rosuvastatin.
In a multicentre, double-blind, placebo-controlled, 12-week trial, 887 hypercholesterolaemic patients were randomised to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or co-administered ezetimibe and simvastatin equivalent to ezetimibe/simvastatin (10/10, 10/20, 10/40, and 10/80). Ezetimibe/simvastatin significantly lowered total-C, LDL-C, Apo B, TG, non-HDL-C, and C-reactive protein compared to all doses of simvastatin. The effects of ezetimibe/simvastatin on HDL-C were similar to the effects seen with simvastatin. Further analysis showed ezetimibe/simvastatin significantly increased HDL-C compared with placebo. (See Table 4 [mean absolute change] and Table 5 [mean percent change]).
In a similarly designed study, results for all lipid parameters were generally consistent. In a pooled analysis of these two studies, the incremental reduction of LDL-C concentration with the combination tablet was generally consistent across subgroups tested, including risk factor status, age, and baseline lipid profile. In addition, the lipid response to ezetimibe/simvastatin was similar in patients with TG levels greater than or less than 2.3 mmol/L (200 mg/dL).
In a multicentre, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C ≥ 3.4 mmol/L (130 mg/dL) were randomised to one of four treatment groups: co-administered ezetimibe and simvastatin equivalent to ezetimibe/simvastatin (10/10, 10/20, and 10/40), or simvastatin 20 mg. Patients not reaching an LDL-C < 2.6 mmol/L (100 mg/dL) had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg. At Week 5, the LDL-C reductions with ezetimibe/simvastatin 10/10, 10/20 , or 10/40 were significantly larger than with simvastatin 20 mg. In addition, at Week 5, significantly more patients receiving ezetimibe/simvastatin 10/10, 10/20, or 10/40 attained LDL-C target compared to those receiving simvastatin 20 mg (see Table 6 [mean absolute change] and Table 7 [mean percent change]). Week 5 results for LDL-C reduction and percentage attaining LDL-C target were consistent with the end of study results (Week 23).
In a multicentre, double-blind, 6-week study, 1902 patients with primary hypercholesterolaemia, who had not met their NCEP ATP III target LDL-C goal, were randomised to one of eight treatment groups: ezetimibe/simvastatin (10/10, 10/20, 10/40 or 10/80) or atorvastatin (10 mg, 20 mg, 40 mg or 80 mg). When patients receiving all doses of ezetimibe/simvastatin were compared to those receiving all doses of atorvastatin, ezetimibe/simvastatin lowered total-C, LDL-C, Apo B and non-HDL-C, and increased HDL-C significantly more than atorvastatin. The effects of ezetimibe/simvastatin on TG were similar to the effects seen with atorvastatin (see Table 8 [mean absolute change] and Table 9 [mean percent change]).
In a multicentre, double-blind, 24-week, forced titration study, 788 patients with primary hypercholesterolaemia, who had not met their NCEP ATP III target LDL-C goal, were randomised to receive co-administered ezetimibe and simvastatin equivalent to ezetimibe/simvastatin (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, ezetimibe/simvastatin lowered LDL-C to a greater degree than atorvastatin (see Table 10 [mean absolute change] and Table 11 [mean percent change]).
In a multicentre, double-blind, 6-week study, 2959 patients with hypercholesterolaemia, who had not met their NCEP ATP III target LDL-C goal, were randomised to one of six treatment groups: ezetimibe/simvastatin (10/20, 10/40 or 10/80) or rosuvastatin (10 mg, 20 mg or 40 mg). When patients receiving all doses of ezetimibe/simvastatin were compared to those receiving all doses of rosuvastatin, ezetimibe/simvastatin lowered total-C, LDL-C, Apo B and non-HDL-C significantly more than rosuvastatin. The effects of ezetimibe/simvastatin on HDL-C were similar to the effects seen with rosuvastatin (see Table 12 [mean absolute change] and Table 13 [mean percent change]).
In a double-blind, placebo-controlled, 8-week study, 240 patients with hypercholesterolaemia already receiving simvastatin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.6 to 4.1 mmol/L [100 to 160 mg/dL], depending on baseline characteristics) were randomised to receive either ezetimibe 10 mg or placebo in addition to their on-going simvastatin therapy. Among simvastatin-treated patients not at LDL-C goal at baseline (~80%), significantly more patients randomised to ezetimibe co-administered with simvastatin achieved their LDL-C goal at study endpoint compared to patients randomised to placebo co-administered with simvastatin, 76% and 21.5%, respectively. The additional corresponding LDL-C reductions for ezetimibe or placebo co-administered with simvastatin were also significantly different (27% or 3%, respectively). In addition, ezetimibe co- administered with simvastatin significantly decreased total-C, Apo B, and TG compared with placebo co-administered with simvastatin.
In a multicentre, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks with a mean LDL-C of 2.4 mmol/L (93 mg/dL), were randomised to receive either simvastatin 40 mg or the co-administered active ingredients equivalent to ezetimibe/simvastatin 10/20.
Ezetimibe/simvastatin 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg in further reducing LDL-C (-21% and 0%, respectively), total-C (-14% and -1%, respectively), Apo B (-14% and -2%, respectively), and non-HDL-C (-20% and -2%, respectively) beyond the reductions observed with simvastatin 20 mg. Results for HDL-C and TG between the two treatment groups were not significantly different. Results were not affected by type of thiazolidinedione treatment.
ENHANCE study. This randomised, double-blind trial recruited 720 patients with HeFH. The primary variable was the mean change in carotid intima media thickness (cIMT) from baseline to endpoint. Patients were treated with either simvastatin alone, 80 mg simvastatin daily or ezetimibe 10 mg in combination with simvastatin 80 mg once daily for up to two years. The mean cIMT increased by 0.0058 mm following simvastatin and 0.0111 mm following combined therapy with ezetimibe and simvastatin. The difference between treatments was not statistically significant - p-value 0.29 based on ANCOVA model. The reason for the lack of difference between treatment groups in the change in cIMT is unknown.
The combination had a significantly greater effect on lipid parameters compared with simvastatin alone. Mean LDL-cholesterol decreased by 56% following ezetimibe/simvastatin compared with 39% reduction following simvastatin alone (p < 0.01, based on ANOVA model). There were statistically greater reductions in total-C, Apo B, TG, campesterol and sitosterol following ezetimibe/simvastatin. Clinical outcome was not an objective of the ENHANCE trial.
Clinical studies in paediatric (10 to 17 years of age) patients. In a multicentre, double-blind, controlled study, 142 boys and 106 post-menarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% Multiracial) with HeFH were randomised to receive either co-administered ezetimibe and simvastatin equivalent to ezetimibe/simvastatin or simvastatin alone. Inclusion in this study required: 1) a baseline LDL-C level between 4.1 and 10.4 mmol/L (160 and 400 mg/dL); and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 5.8 mmol/L (range: 4.2-9.1 mmol/L) in the ezetimibe co-administered with simvastatin group compared to 5.7 mmol/L (range: 3.9-8.7 mmol/L) in the simvastatin monotherapy group. The patients received ezetimibe/simvastatin (10/10, 10/20 or 10/40) or simvastatin alone (10 mg, 20 mg or 40 mg) for 6 weeks, ezetimibe/simvastatin 10/40 or simvastatin 40 mg alone for the next 27 weeks, and open-label ezetimibe/simvastatin (10/10, 10/20 or 10/40) for 20 weeks thereafter.
The primary hypothesis was that the percent change in LDL-C from baseline to Week 6 in the pooled ezetimibe/simvastatin groups would be greater than in the pooled simvastatin monotherapy groups. At Week 6, ezetimibe/simvastatin (all doses) lowered LDL-C significantly more than simvastatin (all doses) alone (49% vs 34% respectively). The results of the study at Week 6 are summarised in Table 14 and Table 15. Results at Week 33 were consistent with those at Week 6. At Week 53, the end of the open-label extension, the effects on lipid parameters were maintained.
From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.
The clinical safety and efficacy of ezetimibe/simvastatin in children and adolescents (10-17 years old) with hypercholesterolaemia other than HeFH have not been studied.
The safety and efficacy of ezetimibe 10 mg co-administered with doses of simvastatin above 40 mg daily have not been studied in children and adolescents (10-17 years old) and are not recommended. The long-term efficacy of therapy with ezetimibe/simvastatin in children and adolescents (10-17 years old) to reduce morbidity and mortality in adulthood has not been studied.

Ezetimibe.

In two multicentre, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered total-C (13%), LDL-C (19%), Apo B (14%), and TG (8%) and increased HDL-C (3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, race, and baseline LDL-C. In addition, ezetimibe had no effect on the plasma concentrations of the fat-soluble vitamins A, D, and E, had no effect on prothrombin time, and did not impair adrenocortical steroid hormone production.

Simvastatin.

Ezetimibe/simvastatin contains simvastatin. In two large placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (n=4,444 patients) and the Heart Protection Study (n=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce the risk of total mortality by reducing CHD deaths, the risk of non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularisation procedures.
Homozygous familial hypercholesterolemia (HoFH). A double-blind, randomised, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analysed from a subgroup of patients (n=14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Co-administered ezetimibe and simvastatin equivalent to ezetimibe/simvastatin (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients co-administered ezetimibe and simvastatin equivalent to ezetimibe/simvastatin (10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.

5.2 Pharmacokinetic Properties

Ezetimibe.

Absorption.

After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe 10 mg tablets.

Distribution.

Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.

Metabolism.

Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Excretion.

Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the faeces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Simvastatin.

Absorption.

The availability of the β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction. The major metabolites of simvastatin present in human plasma are the β-hydroxyacid and four additional active metabolites.
Relative to the fasting state, the plasma profiles of both active and total inhibitors were not affected when simvastatin was administered immediately before a test meal.

Distribution.

Both simvastatin and the β-hydroxyacid are bound to human plasma proteins (95%).
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the above pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours post-dose.

Metabolism.

Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.
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 its primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the systemic circulation is low.
Following an intravenous injection of the β-hydroxyacid metabolite, its half-life averaged 1.9 hours.
In dose proportionality studies utilising doses of simvastatin of 5 mg, 10 mg, 20 mg, 60 mg, 90 mg and 120 mg there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose.

Excretion.

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 drug equivalents excreted in bile as well as unabsorbed drug. Following an intravenous injection of the β-hydroxyacid metabolite an average of only 0.3% of the IV dose was excreted in urine as inhibitors.

Characteristics in special populations.

Paediatric patients.

Ezetimibe.

The absorption and metabolism of ezetimibe are similar between children and adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the paediatric population < 10 years of age are not available.

Simvastatin.

The pharmacokinetics of simvastatin has not been studied in the paediatric population.
Elderly patients.

Ezetimibe.

Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥ 65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe (see Section 4.4 Special Warnings and Precautions for Use).
Hepatic insufficiency.

Ezetimibe.

After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score > 9) hepatic insufficiency, ezetimibe is not recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use).
Renal insufficiency.

Ezetimibe.

After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤ 30 mL/min/1.73 m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9).
An additional patient in this study (post-renal transplant and receiving multiple medications, including ciclosporin) had a 12-fold greater exposure to total ezetimibe.

Simvastatin.

In a study of patients with severe renal insufficiency (creatinine clearance < 30 mL/min), the plasma concentrations of total inhibitors after a single dose of a related HMG-CoA reductase inhibitor were approximately two-fold higher than those in healthy volunteers.
Gender. Plasma concentrations for total ezetimibe are slightly higher (< 20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe.
Race. Based on a meta-analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between Blacks and Caucasians.

5.3 Preclinical Safety Data

Genotoxicity.

Ezetimibe/simvastatin.

Ezetimibe alone or in combination with simvastatin did not cause gene mutation in bacteria or chromosomal damage in human peripheral lymphocytes or bone marrow cells in mice.

Carcinogenicity.

Ezetimibe/simvastatin.

Carcinogenicity studies with ezetimibe/simvastatin combinations have not been performed.

Ezetimibe.

Two-year dietary studies with ezetimibe alone in mice and rats showed no evidence of carcinogenic potential. The highest ezetimibe dose (500 mg/kg/day) in mice corresponds to exposure levels approximately 4 and ≥ 150 times the adult human exposure for ezetimibe and total ezetimibe, respectively, based on AUC. Exposures in rats at the highest dose (1500 mg/kg/day in males and 500 mg/kg/day in females) correspond to approximately 2 and 14 times the adult human exposure for ezetimibe and total ezetimibe, respectively.

Simvastatin.

Carcinogenicity studies have been conducted in mice at oral doses ranging from 1 to 400 mg/kg/day and in rats at doses of 1 to 100 mg/kg/day. Hepatocellular adenomas and carcinomas were observed in both sexes of both species at doses greater than 25 mg/kg/day. Plasma drug levels in rats at this no-effect dose level, expressed as the AUC for enzyme inhibitory activity, were 3 to 11 times greater than those in humans at the maximum recommended dose, whereas serum levels at the no-effect level in mice were similar to those in humans. Additional findings in mice were increased incidences of pulmonary adenomas at doses greater than 25 mg/kg/day, and of Harderian gland adenomas at 400 mg/kg/day. In rats, the incidence of thyroid follicular adenoma was increased in females at doses greater than 5 mg/kg/day and in males at doses greater than 25 mg/kg/day. These thyroid tumours were associated with focal cystic follicular hyperplasia and may be a secondary effect reflective of a simvastatin-mediated enhancement of thyroid hormone clearance by the liver.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose, croscarmellose sodium, citric acid monohydrate, ascorbic acid, butylated hydroxyanisole, and propyl gallate, ferric oxide red and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store below 25°C. Store in original packaging.

6.5 Nature and Contents of Container

Alu-Alu blister packs of 5, 10 and 30.
HDPE bottle packs of 30.
HDPE bottle packs of 90, 500 and 1000 (for dispensing use only).
Not all pack types or pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Ezetimibe.

The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4- hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3 and its molecular weight is 409.4.
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water.

Chemical structure.


CAS number.

163222-33-1.

Simvastatin.

Simvastatin, an inactive lactone, is hydrolysed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a- hexahydro-3,7- dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S- [1α,3α,7β,8β(2S*,4S*),-8aβ]]. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57.
Simvastatin is a white to off-white, non-hygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Chemical structure.


CAS number.

79902-63-9.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes