Consumer medicine information

Pharmacor Ezetimibe

Ezetimibe

BRAND INFORMATION

Brand name

Pharmacor Ezetimibe

Active ingredient

Ezetimibe

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pharmacor Ezetimibe.

SUMMARY CMI

PHARMACOR EZETIMIBE

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 PHARMACOR EZETIMIBE?

PHARMACOR EZETIMIBE is a cholesterol-lowering medicines known as HMG-CoA reductase inhibitors (or statins). It helps to lower cholesterol levels. For more information, see Section 1. Why am I using PHARMACOR EZETIMIBE? in the full CMI.

2. WHAT SHOULD I KNOW BEFORE I USE PHARMACOR EZETIMIBE?

Do not use if you have ever had an allergic reaction to PHARMACOR EZETIMIBE 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 PHARMACOR EZETIMIBE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may be affected by PHARMACOR EZETIMIBE, may affect how well it works, or may increase the risk of side effects with PHARMACOR EZETIMIBE. 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 PHARMACOR EZETIMIBE?

Take PHARMACOR EZETIMIBE only when prescribed by your doctor. The recommended dose is 10mg taken once a day, at any time of the day. More instructions can be found in Section 4. How do I use PHARMACOR EZETIMIBE? in the full CMI.

5. WHAT SHOULD I KNOW WHILE USING PHARMACOR EZETIMIBE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using PHARMACOR EZETIMIBE.
  • Keep all of your doctor's appointments so that your progress can be checked.
  • Your doctor will do regular checks to help prevent you from having side effects from the medicine. This includes blood tests to check your liver function and regular skin checks your doctor will also use these tests to decide when you should stop taking PHARMACOR EZETIMIBE.
Things you should not do
  • Do not give this medicine to anyone else, even if their condition seems similar to yours.
  • Do not use it to treat any other complaints unless your doctor tells you to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how PHARMACOR EZETIMIBE affects you.
  • Side effects have been reported that may affect your ability to drive or operate machinery. Be careful driving or operating machinery until you know how PHARMACOR EZETIMIBE affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your medicine in the original container until it is time to take it.
  • Store below 25°C. Store in dry place.

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

6. Are there any side effects?

PHARMACOR EZETIMIBE helps most people with high cholesterol, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects like swelling of the face, skin rash and hives, unexplained muscle aches etc. 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

PHARMACOR EZETIMIBE

Active ingredient(s): [Ezetimibe]

Consumer Medicine Information (CMI)

This leaflet provides important information about using PHARMACOR EZETIMIBE. 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 PHARMACOR EZETIMIBE.

Where to find information in this leaflet:

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

1. Why am I using PHARMACOR EZETIMIBE?

PHARMACOR EZETIMIBE helps to lower cholesterol levels. It is used in people whose cholesterol levels are too high and when diet alone cannot lower these levels adequately.

PHARMACOR EZETIMIBE may be taken alone or with other cholesterol-lowering medicines known as HMG-CoA reductase inhibitors (or statins), in addition to diet.

In people who have high levels of plant sterols in their blood (which doctors call sitosterolaemia), PHARMACOR EZETIMIBE helps to lower these levels.

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.

How PHARMACOR EZETIMIBE works

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

PHARMACOR EZETIMIBE works by decreasing the absorption of cholesterol in the small intestine. Statins lower cholesterol in a different way, by reducing the amount of cholesterol made in the liver.

PHARMACOR EZETIMIBE adds to the cholesterol-lowering effect of statins.

For patients with heart disease and a history of a heart attack or hospitalisation for unstable angina (chest pain), PHARMACOR EZETIMIBE combined with cholesterol-lowering medicines called statins reduces the risk of heart attack, stroke, surgery to increase heart blood flow, or hospitalisation for chest pain.

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

PHARMACOR EZETIMIBE is not addictive.

Use in Children and Adolescents

PHARMACOR EZETIMIBE 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).

PHARMACOR EZETIMIBE is not recommended in children under 10 years of age as there have been very few studies of its effects in these children.

Your doctor will assess whether if PHARMACOR EZETIMIBE is suitable for your child. Depending on the pubertal development of your child, PHARMACOR EZETIMIBE may not be suitable for him or her.

2. What should I know before i take PHARMACOR Ezetimibe?

Warnings

Do not take PHARMACOR EZETIMIBE if:

  • you have an allergy to PHARMACOR EZETIMIBE or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include skin rash, itchiness, shortness of breath, swelling of the face, lips, mouth, tongue or throat.
  • 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.

Do not take PHARMACOR EZETIMIBE together with a statin if:

  • you have active liver disease
  • you are pregnant or breast feeding.

Do not take PHARMACOR EZETIMIBE together with fenofibrate if:

  • you have gall bladder disease.

If you are not sure whether you should start taking PHARMACOR EZETIMIBE, talk to your doctor.

Before you start to take it

Tell your doctor if:

  1. you are pregnant or intend to become pregnant
If there is a need to consider using PHARMACOR EZETIMIBE during pregnancy, your doctor will discuss the risks and benefits of taking it.
  1. you are breast-feeding
It is not known if PHARMACOR EZETIMIBE passes into breast milk.
  1. you have, or have had, any medical conditions, including liver disease or liver problems
If you are prescribed PHARMACOR EZETIMIBE with a statin, your doctor will do a blood test to make sure you have no problems with your liver.
  1. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you take any PHARMACOR EZETIMIBE.

3. What if I am taking other medicines?

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

Some medicines should not be taken with PHARMACOR EZETIMIBE, including:

  • Certain fibrate medicines used to lower cholesterol levels, for example, gemfibrozil. However, the fibrate medicine fenofibrate can be taken with PHARMACOR EZETIMIBE.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking PHARMACOR EZETIMIBE.

Some medicines and PHARMACOR EZETIMIBE may interfere with each other, including:

  • Bile acid sequestrants, such as colestyramine, used to lower cholesterol levels.
  • Ciclosporin, used to suppress the immune system.
  • Warfarin or fluindione, used to prevent blood clots.

These medicines may be affected by PHARMACOR EZETIMIBE, may affect how well it works, or may increase the risk of side effects with PHARMACOR EZETIMIBE. You may need different amounts of your medicine, or you may need to take different medicines or take your medicines at different times.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking PHARMACOR EZETIMIBE.

4. How do I take PHARMACOR EZETIMIBE?

How much to take

Take PHARMACOR EZETIMIBE only when prescribed by your doctor.

The recommended dose is 10mg taken once a day, at any time of the day.

Swallow PHARMACOR EZETIMIBE with a glass of water.

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

When to take it

PHARMACOR EZETIMIBE may be taken at any time of the day.

It does not matter if you take PHARMACOR EZETIMIBE with or without food.

However, take it about the same time each day.

Taking PHARMACOR EZETIMIBE at the same time each day will have the best effect. It will also help you remember when to take the dose.

Your doctor may ask you to take PHARMACOR EZETIMIBE with other cholesterol-lowering medicines, such as statins, to help you better control your cholesterol.

If you are taking a statin, PHARMACOR EZETIMIBE can be taken at the same time as the statin.

If you are taking a bile acid sequestrant, such as cholestyramine, take your PHARMACOR EZETIMIBE either at least two hours before or four hours after taking the bile acid sequestrant.

How long to take it

PHARMACOR EZETIMIBE 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 PHARMACOR EZETIMIBE, your cholesterol levels may rise again.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your tablet(s) as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

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

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much PHARMACOR EZETIMIBE. Do this even if there are no signs of discomfort or poisoning.

5. WHAT SHOULD I KNOW WHILE USING PHARMACOR EZETIMIBE?

Things you should do

If you become pregnant while taking PHARMACOR EZETIMIBE, tell your doctor.

Have your blood fats checked when your doctor says, to make sure PHARMACOR EZETIMIBE 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 PHARMACOR EZETIMIBE.

If you are prescribed PHARMACOR EZETIMIBE with a statin, your doctor will do blood tests to check that there are no problems with your liver.

Things you must not do

Do not give PHARMACOR EZETIMIBE to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how PHARMACOR EZETIMIBE affects you.

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

High cholesterol can be treated in two main ways:

Lifestyle Changes -

this includes a cholesterol-lowering diet, increasing physical activity, and weight management. Ask your doctor for advice before increasing physical activity.

Medicines -

Cholesterol-lowering medicines are used together with lifestyle changes to help lower cholesterol.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PHARMACOR EZETIMIBE.

PHARMACOR EZETIMIBE helps most people with high cholesterol, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Less serious side effects

Less serious side effectsWhat to do
General
  • nausea
  • diarrhea
  • wind or excessive gas in the stomach or bowel
  • indigestion
  • heartburn
  • decreased appetite
  • dry mouth
  • abdominal pain
  • constipation
  • inflammation of the pancreas
  • dizziness
  • headache
  • tingling or numbness of the hands or feet
  • gallstones
  • inflammation of the gallbladder
  • elevations in some laboratory blood test of liver or muscle function
  • unusual tiredness or weakness
  • fatigue
  • muscle spasms
  • neck pain
  • chest pain
  • pain
  • pain in arms and legs
  • back pain
  • hot flush
  • high blood pressure
  • itching
  • swelling, especially in the hands and feet
  • depression
  • cough
Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

In adolescent patients (10 to 17 years of age) there have been no studies longer than one year of the effect of taking ezetimibe in combination with simvastatin on bone development, growth, social and emotional development, or fertility

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Serious side effects are rare.

Tell your doctor immediately or go to accident and emergency at your nearest hospital if you notice any of the following:

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 dizziness
  • skin rash and hives
  • severe skin problems
  • dark coloured urine
  • light coloured bowel motions
  • yellowing of the skin and eyes
  • joint pain
  • bleeding or bruising more easily than normal
  • steady abdominal pain with nausea and vomiting
  • unexplained muscle aches, tenderness or weakness, not caused by exercise
These may be serious side effects. If you have them, you may have had a serious allergic reaction to PHARMACOR EZETIMIBE. You may need urgent medical attention or hospitalisation. These side effects are very rare.

This may be a serious side effect. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage. You may need urgent medical attention.

After using PHARMACOR EZETIMIBE

Storage

Keep your tablets in the blister pack or bottle pack until it is time to take them.

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

Store below 25°C. Store in dry place.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking PHARMACOR EZETIMIBE or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

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 PHARMACOR EZETIMIBE contains

Active ingredient
(main ingredient)		10 mg ezetimibe per tablet
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • croscarmellose sodium
  • Sodium Lauryl Sulfate
  • crospovidone
  • microcrystalline cellulose
  • magnesium stearate
  • hypromellose

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

What PHARMACOR EZETIMIBE looks like

PHARMACOR EZETIMIBE comes as a white to off white capsule shaped, flat faced, beveled edge tablets, debossed with 'A25' on one side and plain on other side.

PHARMACOR EZETIMIBE tablets are packed in PVC/ACLAR-Alu Blister Pack and HDPE bottle with PP child resistant closure.

Pack size*:
10 tablets or 30 tablets in blister pack
30 tablets or 90 tablets in bottle pack

* Not all pack size may be marketed.

Supplier

PHARMACOR EZETIMIBE is supplied in Australia by:

PHARMACOR PTY. LTD
CHATSWOOD, NSW, 2067,
Australia

Australian Register Number:

PHARMACOR EZETIMIBE 10 mg - AUST R 276974

PHARMACOR EZETIMIBE 10 mg - AUST R 276975

This leaflet was prepared in 02/2024

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Pharmacor Ezetimibe

Active ingredient

Ezetimibe

Schedule

S4

 

1 Name of Medicine

Ezetimibe.

2 Qualitative and Quantitative Composition

Pharmacor Ezetimibe 10 mg tablets.

Each tablet of Pharmacor Ezetimibe for oral administration contains 10 mg ezetimibe.

List of excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Pharmacor Ezetimibe 10 mg tablets.

White to off white capsule shaped, flat faced, beveled edge tablets, debossed with 'A25' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults (≥ 18 years).

Primary hypercholesterolaemia.

Pharmacor Ezetimibe administered alone, or with an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia.

Homozygous familial hypercholesterolaemia (HoFH).

Pharmacor Ezetimibe, administered with a statin, is indicated for patients with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

Homozygous sitosterolaemia (phytosterolaemia).

Pharmacor Ezetimibe is indicated for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolaemia.

Prevention of cardiovascular disease.

Pharmacor Ezetimibe, is indicated for administration in combination with the maximum tolerated dose of a statin with proven cardiovascular benefit in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) 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).

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).

Pharmacor Ezetimibe co-administered with simvastatin (doses up to 40 mg) is indicated as an adjunctive therapy to diet in adolescent patients (10-17 years old) with heterozygous familial hypercholesterolaemia 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).

Pharmacor Ezetimibe co-administered with simvastatin (doses up to 40 mg) 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

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Pharmacor Ezetimibe.

Use in patients with primary hypercholesterolemia.

The recommended dose of Pharmacor Ezetimibe is 10 mg once daily, used alone or with a statin. Pharmacor Ezetimibe can be administered at any time of the day, with or without food.
Pharmacor Ezetimibe may be administered with a statin for incremental effect. For convenience, the daily dose of Pharmacor Ezetimibe may be taken at the same time as the statin, according to the dosing recommendations for the statin.

Use in patients with coronary heart disease and a history of acute coronary syndrome.

Combination therapy with a statin.

For incremental cardiovascular event reduction in patients with coronary heart disease, Pharmacor Ezetimibe 10 mg may be administered with a statin with proven cardiovascular benefit.

Use in patients with renal impairment/chronic kidney disease.

Monotherapy.

In patients with renal impairment, no dosage adjustment of Pharmacor Ezetimibe is necessary (see Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations)).

Combination therapy with simvastatin.

In patients with mild renal insufficiency (estimated GFR ≥ 60 mL/min/1.73 m2), no dosage adjustment of Pharmacor Ezetimibe or simvastatin is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate < 60 mL/min/1.73 m2, the dose of Pharmacor Ezetimibe is 10 mg and the dose of simvastatin is 20 mg once a day in the evening. Efficacy and safety at higher doses has not been evaluated in this CKD population (see Section 4.4 Special Warnings and Precautions for Use, Characteristics in patients (special populations); Section 5.1 Pharmacodynamic Properties, Clinical trials, Prevention of major vascular events in chronic kidney disease (CKD)).

Use in the elderly.

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

Paediatric use.

Initiation of treatment must be performed under review of a specialist.
Paediatric patients 10-17 years of age. The use of Pharmacor Ezetimibe co-administered with simvastatin in children and adolescent patients (10-17 years old) is recommended only for patients with Heterozygous Familial Hypercholesterolaemia (HeFH) or Homozygous Familial Hypercholesterolaemia (HoFH).
There are no clinical safety and efficacy data on the use of ezetimibe co-administered with 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).

No dosage adjustment is required (see Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations)). The clinical experience in paediatric and adolescents patient (aged 10-17 years old) is however limited and mostly includes children and adolescents (10-17 years old) with Heterozygous Familial Hypercholesterolaemia. There are also no long-term (> 1 year) safety data in this population.
Ezetimibe co-administered with simvastatin has not been studied in pre-menarchal girls or in pre-pubertal boys and is not recommended.
When Pharmacor Ezetimibe is administered with a statin, the dosage instructions for the statin in children should be followed.
Paediatric patients < 10 years of age.

Children < 10 years.

Ezetimibe is not recommended for use in children below 10 years of age. There are limited data on safety and efficacy in children 6-10 years of age. See Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients; Section 4.4 Special Warnings and Precautions for Use, Paediatric (6 to 17 years of age) patients; Section 4.8 Adverse Effects (Undesirable Effects), Paediatric (6 to 17 years of age) patients). There is no available data on use of ezetimibe in children < 6 years (see Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations)). The use of ezetimibe in combination with statins has not been studied in children < 10 years of age.

Hepatic insufficiency.

No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with ezetimibe is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score > 9) liver dysfunction (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations)).

4.3 Contraindications

Pharmacor Ezetimibe is contraindicated in patients with hypersensitivity to any component of this medication.
When Pharmacor Ezetimibe is to be administered with a statin, please refer to the Product Information for that particular statin.
Pharmacor Ezetimibe in combination with fenofibrate is contraindicated in patients with gall bladder disease.
Therapy with Pharmacor Ezetimibe in combination with a statin is contraindicated during pregnancy and lactation.
The combination of Pharmacor Ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

4.4 Special Warnings and Precautions for Use

When Pharmacor Ezetimibe is to be administered with a statin or fenofibrate, please refer to the Product Information for that particular product.

Liver enzymes.

In controlled co-administration trials in patients receiving ezetimibe with a statin, consecutive transaminase elevations (≥ 3 X the upper limit of normal [ULN]) have been observed. When Pharmacor Ezetimibe is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT), 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of 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 10 mg with simvastatin 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 combined with simvastatin and 0.6% for placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).

Skeletal muscle.

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of CPK > 10 X ULN was 4 of 1674 (0.2%) patients administered ezetimibe alone vs. 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ezetimibe and a statin vs. 4 of 929 (0.4%) patients administered a statin alone.
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis. All patients starting therapy with Pharmacor Ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Pharmacor Ezetimibe and any statin that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level > 10 times the ULN indicates myopathy.
In IMPROVE-IT, 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for ezetimibe/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥ 10 times ULN or two consecutive observations of CK ≥ 5 and < 10 times ULN. The incidence of rhabdomyolysis was 0.1% for ezetimibe/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness, pain or tenderness with a serum CK ≥ 10 times ULN with evidence of renal injury, ≥ 5 X ULN and < 10 X ULN on two consecutive occasions with evidence of renal injury or CK ≥ 10,000 IU/L without evidence of renal injury. (See Section 4.8 Adverse Effects (Undesirable Effects)).
In a clinical trial in which over 9,000 patients with chronic kidney disease were randomised to receive ezetimibe 10 mg combined with simvastatin 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 combined with simvastatin and 0.1% for placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).

Fibrates.

The co-administration of ezetimibe with fibrates, other than fenofibrate, has not been studied and is therefore not recommended. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Fenofibrate.

Fibrates may increase cholesterol excretion from the bile, and ezetimibe increased cholesterol in the gallbladder bile in a preclinical study in dogs. Given the potential for cholelithiasis, and the numerically higher incidence of cholecystectomies in patients administered ezetimibe and fenofibrate in a clinical study (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)), coadministration of ezetimibe and fenofibrate is not recommended in patients with pre-existing gallbladder disease (see Section 4.3 Contraindications).

Ciclosporin.

Caution should be exercised when initiating ezetimibe in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Pharmacor Ezetimibe and ciclosporin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anticoagulants.

If Pharmacor Ezetimibe 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).

Use in hepatic impairment.

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

Use in renal impairment.

(See Section 4.2 Dose and Method of Administration, Use in patients with renal impairment/chronic kidney disease; Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations), Renal insufficiency.)

Use in the elderly.

(See Section 4.2 Dose and Method of Administration, Use in the elderly; Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations), Geriatric patients.)

Paediatric use.

Paediatric patients 10 to 17 years of age.

The use of Pharmacor Ezetimibe co-administered with simvastatin in children and adolescent patients (10-17 years old) is recommended only for patients with Heterozygous Familial Hypercholesterolaemia (HeFH) or Homozygous Familial Hypercholesterolaemia (HoFH).
However, clinical efficacy/safety study experience in paediatric and adolescent patients (10-17 years old) has been mostly limited to patients with Heterozygous Familial Hypercholesterolaemia (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 co-administered with simvastatin in children and adolescents (10-17 years old) with hypercholesterolaemia other than Heterozygous Familial Hypercholesterolaemia have not been studied.
Safety and effectiveness of ezetimibe co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys and girls who were at least one year post-menarche. Doses greater than 10 mg ezetimibe with 40 mg simvastatin 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 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 (6 to 17 years of age) patients). Adolescent females should be counselled on appropriate contraceptive methods while on co-administered Pharmacor Ezetimibe and simvastatin therapy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
The safety and efficacy of ezetimibe co-administered with simvastatin doses 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 in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.
Ezetimibe co-administered with simvastatin has not been studied in pre-menarchal girls or in pre-pubertal boys and is not recommended.

Paediatric patients < 10 years of age.

Pharmacor Ezetimibe is not recommended in children < 10 years of age.
Safety and effectiveness of ezetimibe in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolaemia have been evaluated in a 12-week controlled clinical trial. Children treated with ezetimibe had an adverse experience profile similar to that of adult patients treated with ezetimibe. In this study, there was generally no detectable effect on growth or sexual maturation in either boys or girls. However, the effects of ezetimibe for a treatment period greater than 12 weeks on growth, sexual maturation, intellectual and psychosocial development have not been studied. The use of ezetimibe in combination with statins has not been studied in children < 10 years of age. ezetimibe has not been studied in patients younger than 6 years of age (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 (6 to 17 years of age) patients).

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

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.
Ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide or midazolam during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.

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.

Colestyramine.

Concomitant colestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55 %. The incremental LDL-C reduction due to adding ezetimibe to colestyramine may be lessened by this interaction.
Therefore, dosing of ezetimibe and a bile acid binding sequestrant should take place several hours apart. However, efficacy of such combination has not been studied.

Ciclosporin.

The effect of ciclosporin on ezetimibe was studied in eight post-renal transplant patients with creatinine clearance of > 50 mL/min who were 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 group of historical healthy volunteers (n=17) who had taken a single 10 mg dose of ezetimibe alone.
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 dose 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).

Fenofibrate.

In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.

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.

Statins.

No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin.

Anticoagulants.

Concurrent administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability and prothrombin time in a study of twelve healthy adult males administered a single dose of warfarin. 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).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Ezetimibe had no effects on fertility in male and female rats at doses up to 1000 mg/kg/day by oral gavage, corresponding to exposures of approximately 1 and 7 times the adult human exposure for ezetimibe and total ezetimibe respectively.
(Category B3)
No clinical data on exposed pregnancies are available. 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 of ezetimibe by oral gavage during organogenesis, corresponding to exposures of 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 of 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. Pharmacor Ezetimibe should be used in pregnancy only if the potential benefit exceeds the potential risk. When Pharmacor Ezetimibe is to be administered with a statin, please refer to the Product Information for that particular statin.
Ezetimibe in combination with statins in rats and rabbits resulted in higher exposures to ezetimibe and/or statins than either drug administered alone. Skeletal malfunctions (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. HMG-CoA reductase inhibitors (statins) are contraindicated during pregnancy, therefore, ezetimibe in combination with statins should not be used in pregnancy (see Section 4.3 Contraindications).
Embryofoetal studies in rats showed no adverse foetal effects of oral ezetimibe/fenofibrate doses corresponding to 5 times (total ezetimibe) and 38 times (fenofibric acid) the anticipated human plasma exposure at the maximum recommended doses. In similar studies in rabbits, a No Effect Level for embryotoxicity was established at ca. 90 times (total ezetimibe) and 32 times (fenofibric acid) anticipated human exposure levels.
 Studies in rats have shown that ezetimibe is excreted in milk. Ezetimibe had no effects on pup development in rats treated with up to 1000 mg/kg/day of ezetimibe during late pregnancy and lactation. Drug exposures (based on AUC) in pups were approximately 1.5% and 50% of maternal exposures for ezetimibe and total ezetimibe respectively. It is not known whether ezetimibe is excreted into human breast milk. Pharmacor Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

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 ezetimibe may affect some patients' ability to drive or operate machinery. Individual responses to Pharmacor Ezetimibe may vary (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical studies of 8 to 14 weeks duration in which ezetimibe 10 mg daily was administered alone, with a statin, or with fenofibrate in 3551 patients demonstrated: ezetimibe was generally well tolerated, adverse reactions were usually mild and transient, the overall incidence of side effects reported with ezetimibe was similar to that reported with placebo, and the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.
There were no drug-related adverse experiences reported occurring in ≥ 2% of patients taking ezetimibe alone (n = 1691).
The following drug-related adverse experiences were reported occurring in ≥ 2% in patients taking ezetimibe co-administered with a statin (n = 1675). See Table 1.
In addition, the following common or uncommon drug-related adverse experiences were reported in clinical trials in patients taking ezetimibe alone and at a greater incidence than placebo, or in patients taking ezetimibe co-administered with a statin and at a greater incidence than statin administered alone.

Ezetimibe administered alone.

Investigations.

Uncommon - gamma-glutamyl transferase increased; liver function test abnormal.

Respiratory, thoracic and mediastinal disorders.

Uncommon - cough.

Gastrointestinal disorders.

Common - abdominal pain; diarrhea; flatulence.
Uncommon - dyspepsia; gastroesophageal reflux disease.

Musculoskeletal and connective tissue disorders.

Uncommon - muscle spasms; neck pain.

Metabolism and nutrition disorders.

Uncommon - decreased appetite.

Vascular disorders.

Uncommon - hot flush; hypertension.

General disorders and administration site condition.

Common - fatigue.
Uncommon - chest pain; pain.

Ezetimibe co-administered with a statin.

Investigations.

Common - ALT and/or AST increased.

Nervous system disorders.

Common - headache.

Gastrointestinal disorders.

Uncommon - dry mouth; gastritis.

Skin and subcutaneous tissue disorders.

Uncommon - pruritus.

Musculoskeletal and connective tissue disorders.

Common - myalgia.
Uncommon - back pain; muscular weakness; pain in extremity.

General disorders and administration site condition.

Uncommon - asthenia; edema peripheral.

Ezetimibe co-administered with fenofibrate.

Gastrointestinal disorders.

Common - abdominal pain.
In a co-administration study with fenofibrate (see Section 5.1 Pharmacodynamic Properties, Clinical trials), in which 292 patients were exposed for ≥ 24 weeks and 120 exposed for ≥ 52 weeks, the incidence rate of cholecystectomy in the coadministration group was 1.7% (95% CI 0.6, 4.0) per 100 patient years compared to 0 (95% CI 0, 9.2) per 100 PY for the ezetimibe group and 0.6% (95% CI 0, 3.1) per 100 PY for the fenofibrate group. Longer term safety outcomes have not been studied.

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 hospitalizations 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 a fixed dose combination of ezetimibe 10 mg with simvastatin 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 combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with ezetimibe combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (> 3X ULN) occurred in 0.7% of patients treated with ezetimibe combined with 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 combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.

Paediatric (6 to 17 years of age) patients.

Paediatric patients 10-17 years of age.

In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (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 (≥ 10X ULN). No cases of myopathy were reported (see Section 4.4 Special Warnings and Precautions for Use, Paediatric (6 to 17 years of age) patients; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 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 co-administered with 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 (6 to 17 years of age patients).
The study was not of sufficient duration to detect long term adverse effects.

Paediatric patients < 10 years of age.

In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n=138), the safety and tolerability profile of the group treated with ezetimibe was similar to that of adult patients treated with ezetimibe. Elevations of ALT and/or AST (≥ 3 ULN, consecutive) were observed in 1.1% (1 patient) of the ezetimibe patients compared to 0% in the placebo group. There were no elevations of CPK (≥ 10X ULN). No cases of myopathy were observed. The duration of this study was 12 weeks and safety data from this study is therefore limited (see Section 4.4 Special Warnings and Precautions for Use, Paediatric (6 to 17 years of age) patients; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients).
Pharmacor Ezetimibe is not recommended in children < 10 years of age.

Laboratory values.

In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥ 3 X ULN, consecutive) was similar between ezetimibe (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with ezetimibe co-administered with a statin and 0.4% for patients treated with a statin alone. 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 CPK (≥ 10 X ULN) in patients treated with ezetimibe administered alone or co-administered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.

Post-marketing experience.

The following adverse reactions have been reported in post-marketing experience, regardless of causality assessment:
Hypersensitivity reactions, including anaphylaxis, angioedema, rash and urticaria; severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilic and systemic symptoms (DRESS) and erythema multiforme; arthralgia; myalgia; increased CPK; elevations of liver transaminases; hepatitis; thrombocytopenia; pancreatitis; nausea; dizziness; paraesthesia; depression; cholelithiasis; drug-induced liver injury; cholecystitis; constipation; asthenia and, very rarely myopathy/rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use).

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, was generally well tolerated.
A few cases of overdosage with ezetimibe have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacor Ezetimibe (ezetimibe) is in a class of lipid-modifying compounds that inhibit the intestinal absorption of cholesterol and related plant sterols.
Ezetimibe 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 sterols).
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 therefore inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe does not increase bile acid excretion (like bile acid sequestrants) and does not inhibit cholesterol synthesis in the liver (like statins).
In a 2-week clinical study in 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54 %, compared with placebo. By inhibiting the absorption of intestinal cholesterol, ezetimibe reduces the delivery of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Together these distinct mechanisms provide complementary cholesterol reduction. Ezetimibe, administered with a statin, reduces total-C, LDL-C, Apo B, and TG and increases HDL-C in patients with hypercholesterolaemia, beyond either treatment alone.
Clinical studies demonstrate that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis.
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.

Clinical trials.

Controlled clinical studies of varying designs were conducted with ezetimibe either as monotherapy or co-administration with a statin. Ezetimibe significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia.
Primary hypercholesterolemia.

Monotherapy.

In two, multicentre, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolaemia, ezetimibe 10 mg significantly lowered total-C, LDL-C, Apo B, and TG and increased HDL-C compared to placebo (see Table 2). 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.
Co-administration with a statin.

Ezetimibe initiated concurrently with a statin.

In four, multicentre, double-blind, placebo-controlled, 12-week trials, in 1187 patients with hypercholesterolaemia, ezetimibe 10 mg was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin. The greatest LDL-C reducing effect is seen with the lowest dose of each statin, with only a further 2-9% incremental reduction in LDL-C with each doubling of the dose. Comparatively, adding 10 mg of ezetimibe to a given dose of a statin is shown to achieve a greater reduction in LDL-C than that achieved with statin dose doubling. See Table 3.
In a pooled analysis of all ezetimibe + statin doses, ezetimibe had a beneficial effect on total-C, Apo B, TG, and HDL-C (Table 4).

Ezetimibe added to on-going statin therapy.

In a multicentre, double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.59 to 4.14 mmol/L, depending on baseline characteristics) were randomised to receive either ezetimibe 10 mg or placebo in addition to their on-going statin therapy.
Among statin-treated patients not at LDL-C goal at baseline (~82 %), LDL-C goal at study endpoint was achieved by 72% and 19% of patients randomised to ezetimibe and placebo, respectively.
Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, and TG and increased HDL-C, compared with placebo (Table 5). LDL-C reductions were consistent across all statins.
Ezetimibe or placebo added to statin therapy reduced median C-reactive protein by 10% or 0% from baseline, respectively.
In a multicentre, double-blind, 14 week study, 621 patients with hypercholesterolaemia receiving atorvastatin 10 mg daily with an LDL-C > 3.36 mmol/L were randomised to receive atorvastatin 20 mg or ezetimibe 10 mg added to atorvastatin 10 mg therapy. The atorvastatin dose could be titrated up to 80 mg in the atorvastatin arm and up to 40 mg in the ezetimibe plus atorvastatin co-administration arm, based on patients not attaining LDL-C goal (< 2.59 mmol/L). The mean baseline LDL-C was 4.84 mmol/L and approximately 60% of the patients had heterozygous familial hypercholesterolaemia (HeFH). At study end, there was a significant difference in attainment of LDL-C goal between patients in the ezetimibe co-administration arm (22%) and patients on atorvastatin monotherapy (7%). At week 4, there was a significant difference in LDL-C reductions between co-administration patients (24%; ezetimibe + atorvastatin 10 mg) and monotherapy patients (9 %; atorvastatin 20 mg). In the sub-group of patients with HeFH, similar results for LDL-C goal attainment and LDL-C reductions were achieved.
In a similarly designed study in 100 patients with hypercholesterolaemia receiving simvastatin 20 mg and not at LDL-C goal, the addition of ezetimibe 10 mg to simvastatin titration compared to titration of simvastatin alone produced similar advantages to those observed in the atorvastatin study described above. For example, significant differences in LDL-C goal attainment (27% for ezetimibe + simvastatin vs. 3% for simvastatin alone) and LDL-C reductions (24% for ezetimibe + simvastatin vs. 11% for simvastatin alone) were achieved.
Other studies. The use of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia demonstrated a numerically higher incidence of cholecystectomies in patients in the co-administration group compared with those in the monotherapy groups (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). Each drug contributed to lowering LDL-C, but the effects on triglycerides and HDL-C were related to fenofibrate and were not enhanced by co-administration. Longer term clinical outcomes such as mortality and morbidity were not investigated.
Clinical studies in paediatric (6 to 17 years of age) patients.

Paediatric patients 10 to 17 years of age.

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 heterozygous familial hypercholesterolaemia (HeFH) were randomised to receive either ezetimibe co-administered with 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 coadministered with simvastatin group compared to 5.7 mmol/L (range: 3.9-8.7 mmol/L) in the simvastatin monotherapy group. The patients received co-administered ezetimibe and simvastatin (10 mg, 20 mg or 40 mg) or simvastatin alone (10 mg, 20 mg or 40 mg) for 6 weeks, co-administered ezetimibe and simvastatin 40 mg or 40 mg simvastatin alone for the next 27 weeks, and open-label co-administered ezetimibe and simvastatin (10 mg, 20 mg or 40 mg) for 20 weeks thereafter.
The primary hypothesis was that the percent change in LDL-C from baseline to Week 6 in the pooled ezetimibe and simvastatin groups would be greater than in the pooled simvastatin monotherapy groups. At Week 6, co-administered ezetimibe and 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 6 and 7. 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 coadministered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group.
The clinical safety and efficacy of ezetimibe co-administered with simvastatin in children and adolescents (10-17 years old) with hypercholesterolaemia other than Heterozygous Familial Hypercholesterolaemia have not been studied.
The safety and efficacy of ezetimibe 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 in children and adolescents (10-17 years old) to reduce morbidity and mortality in adulthood has not been studied.

Paediatric patients < 10 years of age.

In a multicentre, double-blind, controlled study, 138 patients [59 boys (51 Tanner stage I and 6 Tanner stage II) and 79 girls (52 Tanner stage I, 22 Tanner stage II and 1 Tanner stage III)], 6 to 10 years of age (mean age 8.3 years) with heterozygous familial or non-familial hypercholesterolaemia were randomised to either ezetimibe 10 mg or placebo for 12 weeks. Inclusion in the study required 1) a baseline LDL-C > 4.1 and < 10.4 mmol/L (> 159 and < 400 mg/dL) and 2) a medical history and clinical presentation consistent with HeFH.
At week 12, ezetimibe significantly reduced total-C, LDL-C, Apo-B and non-HDL-C compared to placebo. Results for the two treatment groups were similar for TG and HDL-C. See Table 8.
Ezetimibe has not been studied in patients younger than 6 years of age.
Homozygous familial hypercholesterolaemia (HoFH). A study was conducted to assess the efficacy of ezetimibe in the treatment of HoFH. This double-blind, randomised, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomised to one of three treatment groups, atorvastatin or simvastatin (80 mg), ezetimibe 10 mg administered with atorvastatin or simvastatin (40 mg), or ezetimibe 10 mg administered with atorvastatin or simvastatin (80 mg). Results are shown in Table 9. Ezetimibe, administered with atorvastatin (40 or 80 mg) or simvastatin (40 or 80 mg), significantly reduced LDL-C compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg.
Prevention of cardiovascular disease. Ezetimibe in combination with simvastatin has been shown in the IMPROVE-IT trial (details below) 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 hospitalization and all coronary revascularization were unchanged. There was a small increase in the rate of haemorrhagic stroke that was not statistically significant. The incremental benefit is expected to be similar with co-administration of other statins shown to be effective in reducing the risk of cardiovascular events but this has not been demonstrated in studies similar to IMPROVE-IT.
The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was a multicenter, randomized, double-blind, active-control study of 18,144 patients enrolled within 10 days of hospitalization 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 randomized in a 1:1 ratio to receive either ezetimibe/simvastatin 10/40 mg (n=9067) or simvastatin 40 mg (n=9077) 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 hospitalization 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 hospitalization, or any coronary revascularization procedure occurring at least 30 days after randomized treatment assignment) and non-fatal stroke. The study demonstrated that treatment with ezetimibe when added to 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 10.) This incremental benefit is expected to be similar with coadministration of other statins shown to be effective in reducing the risk of cardiovascular events. Total mortality was unchanged in this high risk group (see Table 10).
There was an overall benefit for all strokes; however there was a small non-significant increase in heamorrhagic stroke in the ezetimibe-simvastatin group compared with simvastatin alone (see Table 10). The risk of haemorrhagic stroke for ezetimibe coadministered 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) > 3xULN were excluded. For the first year, patients were randomised in a ratio of 4:4:1, respectively, to a fixed dose combination of ezetimibe 10 mg with simvastatin 20 mg, placebo, or simvastatin 20 mg daily. The 1-year simvastatin arm was included to enable the comparison of ezetimibe combined with simvastatin to simvastatin alone with regard to safety and lipids. At 1 year the simvastatin-only arm was re-randomised 1:1 to a fixed dose combination of ezetimibe 10 mg with simvastatin 20 mg or placebo. A total of 4,650 patients were allocated to ezetimibe 10 mg combined with simvastatin 20 mg 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 10 mg combined with simvastatin 20 mg. At the midpoint of the study (2.5 years) mean LDL-C reduction in all randomised patients for ezetimibe combined with 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 nonfatal MI or cardiac death, stroke, or any revascularisation procedure) in only those patients initially randomised to the ezetimibe combined with 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 combined with simvastatin (n=4,650) or placebo (n=4,620) as well as the components of this composite.
The primary endpoint analysis showed that ezetimibe combined with simvastatin significantly reduced the risk of MVE (749 patients with events in the placebo group vs. 639 in the ezetimibe combined with 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 combined with simvastatin significantly reduced the risk of MAE (526 (11.3%) of 4650 patients ever allocated to ezetimibe combined with 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 combined with 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 11. Ezetimibe combined with simvastatin significantly reduced the risk of stroke and any revascularisation, with non-significant numerical differences favouring ezetimibe combined with simvastatin for nonfatal MI and cardiac death.
No significant treatment effect of ezetimibe combined with 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 combined with 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 combined with simvastatin did not reduce the risk of progressing to end-stage renal disease compared with placebo.
There were no significant differences between the ezetimibe combined with 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 10 mg with simvastatin 20 mg compared to either the lower dose combination (i.e. ezetimibe 10 mg with simvastatin 10 mg) or to treatment with statin alone (i.e. simvastatin 20 mg).
The effect of ezetimibe taken in combination with other statins in patients with CKD has not been studied.
Homozygous sitosterolaemia (phytosterolaemia). A study was conducted to assess the efficacy of ezetimibe in the treatment of homozygous sitosterolaemia. In this multicentre, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolaemia were randomised to receive ezetimibe 10 mg (n=30) or placebo (n=7). Ezetimibe significantly lowered the two major plant sterols, sitosterol and campesterol, by 21 % and 24 % from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ezetimibe, the reduction in plant sterols was progressive over the course of the study.
Reductions in sitosterol and campesterol were consistent between patients taking ezetimibe concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

5.2 Pharmacokinetic Properties

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.

Effect of food on oral absorption.

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. ezetimibe can be administered with or without food.

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.

Characteristics in patients (special populations).

Paediatric patients.

The absorption and metabolism of ezetimibe are similar between children and adolescents (≥ 10 years) and adults. Limited PK data are available in children aged ≥ 6 to 10 years of age. Pharmacokinetic data in the paediatric population < 6years of age are not available.

Geriatric patients.

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 is comparable between elderly and young subjects treated with ezetimibe. Therefore, no dosage adjustment is necessary in the elderly.

Hepatic insufficiency.

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.

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). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.
An additional patient in this study (post-renal transplant and receiving multiple medications, including ciclosporin) had a 12-fold greater exposure to total ezetimibe.

Gender.

Plasma concentrations for total ezetimibe are slightly higher (< 20 %) in women than in men. LDL-C reduction and safety profile is comparable between men and women treated with ezetimibe. Therefore, no dosage adjustment is necessary on the basis of gender.

Race.

Based on a meta-analysis of pharmacokinetic studies, there were no pharmacokinetic differences between Blacks and Caucasians.

5.3 Preclinical Safety Data

Genotoxicity.

Ezetimibe alone or in combination with a statin (simvastatin, lovastatin, pravastatin or atorvastatin) or fenofibrate did not cause gene mutation in bacteria or chromosomal damage in human peripheral lymphocytes or bone marrow cells in mice.

Carcinogenicity.

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 of 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. There are no carcinogenicity studies with ezetimibe/statin or ezetimibe/fenofibrate combinations.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Lactose monohydrate, microcrystalline cellulose, crospovidone, hypromellose, magnesium stearate, croscarmellose sodium.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C in a dry place.

6.5 Nature and Contents of Container

The tablets are packed in PVC/ACLAR-Alu Blister Pack and HDPE bottle with PP child resistant closure.

Pack size*.

10 tablets or 30 tablets in blister pack.
30 tablets or 90 tablets in bottle pack.
*Not all pack size 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

Pharmacor Ezetimibe is described chemically as 1-(4-fluorophenyl)-3(R)-[3-(4- fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4.

Chemical structure.


CAS number.

163222-33-1.
Description: Ezetimibe is a white, crystalline powder. Freely soluble in alcohol; soluble in acetonitrile; insoluble in aqueous solvents and nonpolar solvents like hexane and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes