Consumer medicine information

Ezetrol

Ezetimibe

BRAND INFORMATION

Brand name

Ezetrol

Active ingredient

Ezetimibe

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ezetrol.

SUMMARY CMI

EZETROL®

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 EZETROL?

EZETROL contains the active ingredient ezetimibe. EZETROL is used to help lower cholesterol levels.

For more information, see Section 1. Why am I using EZETROL? in the full CMI.

2. What should I know before I use EZETROL?

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

3. What if I am taking other medicines?

Some medicines may interfere with EZETROL 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 EZETROL?

  • The recommended dose is 10 mg once a day.
  • For the best effect take EZETROL at about the same time each day.

More instructions can be found in Section 4. How do I use EZETROL? in the full CMI.

5. What should I know while using EZETROL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking ezetimibe.
  • If you become pregnant while taking EZETROL, tell your doctor.
  • Have any blood tests your doctor requests to make sure EZETROL is right for you.
Things you should not do
  • Do not give EZETROL to anyone else, even if they have the same condition as you.
Driving or using machines
  • 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 EZETROL affects you.
Looking after your medicine
  • Keep EZETROL in a cool dry place where the temperature stays below 30°C.

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

6. Are there any side effects?

When EZETROL is used as the only cholesterol lowering medicine, common side effects are abdominal pain, diarrhea, flatulence and fatigue.

Allergic reactions to ezetimibe or other ingredients of EZETROL occur very rarely. Serious side effects are rare, but may need urgent medical attention.

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

EZETROL® (pronounced ez-eh-trol)

Active ingredient(s): ezetimibe

Consumer Medicine Information (CMI)

This leaflet provides important information about using EZETROL. 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 EZETROL.

Where to find information in this leaflet:

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

1. Why am I using EZETROL?

EZETROL contains the active ingredient ezetimibe. EZETROL helps to lower cholesterol levels.

EZETROL is used in people whose cholesterol levels are too high and when diet alone cannot lower these levels adequately.

EZETROL 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), EZETROL 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.

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.

How EZETROL works

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

EZETROL 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.

EZETROL 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), EZETROL 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 EZETROL for another reason. Ask your doctor if you have any questions about why EZETROL has been prescribed for you.

EZETROL is not addictive.

2. What should I know before I use EZETROL?

Warnings

Do not use EZETROL if:

  • you are allergic to 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. Always check the ingredients to make sure you can use this medicine.
  • 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 use EZETROL together with a statin if:

  • you have active liver disease
  • you are pregnant or breastfeeding

Do not use EZETROL together with fenofibrate if:

  • you have gall bladder disease

Check with your doctor if you:

  • have, or have had, any other medical conditions, including liver disease. If you are prescribed EZETROL with a statin, your doctor will do a blood test to make sure you have no problems with your liver.
  • take any medicines for any other condition
  • have allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

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?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. If there is a need to consider using EZETROL during pregnancy, your doctor will discuss the risks and benefits of taking it.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if EZETROL passes into breast milk.

Use in Children and Adolescents

  • EZETROL 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)
  • EZETROL 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 EZETROL is suitable for your child. Depending on the pubertal development of your child, EZETROL may not be suitable for him or her.

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 should not be taken with EZETROL including some fibrate medicines used to lower cholesterol levels.

e.g., gemfibrozil. However, the fibrate medicine fenofibrate can be taken with EZETROL.

Some medicines may interfere with EZETROL and affect how it works.

You may need different amounts of your medicine, or you may need to take different medicines or take your medicines at different times.

Medicines that may increase the effect of EZETROL include:

  • Ciclosporin, used to suppress the immune system.

Medicines that may reduce the effect of EZETROL include:

  • Bile acid sequestrants, such as colestyramine, used to lower cholesterol levels.

EZETROL may interfere with some medicines and affect how they work:

  • Warfarin or fluindione, used to prevent blood clots

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect EZETROL.

4. How do I use EZETROL?

How much to take

  • The recommended dose is 10mg taken once a day. Swallow EZETROL with a glass of water.
  • Take EZETROL only when prescribed by your doctor.
  • Follow the instructions provided and use EZETROL until your doctor tells you to stop.
  • EZETROL 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 EZETROL, your cholesterol levels may rise again.

When to take EZETROL

  • EZETROL can be taken at any time of the day, however, take it at about the same time each day.
  • Taking EZETROL 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 EZETROL with other cholesterol-lowering medicines, such as statins, to help you better control your cholesterol.
  • If you are taking a statin, EZETROL can be taken at the same time as the statin.
  • If you are taking a bile acid sequestrant, such as colestyramine, take your EZETROL either at least two hours before or four hours after taking the bile acid sequestrant.
  • It does not matter if you take EZETROL with or without food

If you forget to take EZETROL

EZETROL should be taken 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(s) 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 are not sure whether to skip the dose, talk to your doctor or pharmacist. If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you use too much EZETROL

If you think that you have used too much EZETROL, 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 EZETROL?

Things you should do

If you become pregnant while taking EZETROL, tell your doctor.

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

Remind any doctor, dentist or pharmacist you visit that you are taking EZETROL.

Things you should not do

  • Do not give EZETROL to anyone else, even if they have the same condition as you.
  • Have your blood fats checked when your doctor says, to make sure EZETROL 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how EZETROL affects you.

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

Looking after your medicine

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. Keep EZETROL in a cool dry place where the temperature stays below 30°C. Follow the instructions in the carton on how to take care of your medicine properly.

Store it 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
Muscle/skeleton-related:
  • muscle spasms
  • neck pain
  • back pain
  • pain in arms and legs
  • elevations in some laboratory tests of muscle function
Gastrointestinal-related:
  • nausea
  • diarrhoea
  • wind or excessive gas in the stomach or bowel
  • indigestion
  • heartburn
  • dry mouth
  • abdominal pain
  • constipation
Liver-related:
  • gallstones
  • inflammation of the gallbladder
  • elevations in some laboratory tests of liver function
Heart and circulation-related:
  • hot flush
  • high blood pressure
  • swelling, especially in the hands and feet
Skin-related:
  • itching
Metabolism and nutrition-related:
  • decreased appetite
  • • inflammation of the pancreas
Head and nervous system-related:
  • dizziness
  • headache
  • tingling or numbness of the hands or feet
Mood related:
  • depression
Respiratory related:
  • cough
General conditions:
  • unusual tiredness or weakness
  • fatigue
  • chest pain
  • 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
If you have these side effects, you may have had a serious allergic reaction to EZETROL. You may need urgent medical attention or hospitalisation.
These side effects are very rare.		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.
  • 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
  • On rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage.
Serious side effects are rare.		Tell your doctor immediately if you notice any of these side effects. These may be serious side effects and you may need urgent medical attention.

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

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 EZETROL contains

Active ingredient
(main ingredient)		10 mg ezetimibe per tablet
Other ingredients
(inactive ingredients)		lactose monohydrate
microcrystalline cellulose
povidone
croscarmellose sodium
sodium lauryl sulfate
magnesium stearate
Potential allergensEZETROL contains lactose It does not contain gluten, sucrose, tartrazine or any other azo dyes.

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

What EZETROL looks like

EZETROL is a white to off-white, capsule-shaped tablet with "414" marked on one side. (Aust R 91161).

There are 30 tablets in a pack.

Who distributes EZETROL

Organon Pharma Pty Limited
Building A 26 Talavera Road
Macquarie Park NSW 2113

This leaflet was prepared in October 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Ezetrol

Active ingredient

Ezetimibe

Schedule

S4

 

1 Name of Medicine

Ezetimibe.

2 Qualitative and Quantitative Composition

Each tablet of Ezetrol for oral administration contains 10 mg ezetimibe.

List of excipients with known effect.

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

3 Pharmaceutical Form

Ezetrol (ezetimibe) - 10 mg, white to off-white capsule shaped tablets, debossed with "414" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults (≥ 18 years).

Primary hypercholesterolaemia.

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

Homozygous familial hypercholesterolaemia (HoFH).

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

Homozygous sitosterolaemia (phytosterolaemia).

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

Prevention of cardiovascular disease.

Ezetrol, 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 postmenarche).

Heterozygous familial hypercholesterolaemia (HeFH).

Ezetrol coadministered 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).

Ezetrol coadministered 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 Ezetrol.

Use in patients with primary hypercholesterolemia.

The recommended dose of Ezetrol is 10 mg once daily, used alone or with a statin. Ezetrol can be administered at any time of the day, with or without food.
Ezetrol may be administered with a statin for incremental effect. For convenience, the daily dose of Ezetrol 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, Ezetrol 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 Ezetrol 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 Ezetrol or simvastatin is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate < 60 mL/min/1.73 m2, the dose of Ezetrol 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; 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 Ezetrol coadministered 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 Ezetrol coadministered with simvastatin in children and adolescent patients (10-17 years old) with nonfamilial 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 postmenarche).

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.
Ezetrol coadministered with simvastatin has not been studied in premenarchal girls or in prepubertal boys and is not recommended.
When Ezetrol 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.

Ezetrol 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 use; Section 4.8 Adverse Effects (Undesirable Effects), Paediatric (6 to 17 years of age) patients. There is no available data on use of Ezetrol in children < 6 years (see Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations)). The use of Ezetrol 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

Ezetrol is contraindicated in patients with hypersensitivity to any component of this medication.
When Ezetrol is to be administered with a statin, please refer to the product information for that particular statin.
Ezetrol in combination with fenofibrate is contraindicated in patients with gall bladder disease.
Therapy with Ezetrol in combination with a statin is contraindicated during pregnancy and lactation.
The combination of Ezetrol 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 Ezetrol is to be administered with a statin or fenofibrate, please refer to the product information for that particular product.

Liver enzymes.

In controlled coadministration trials in patients receiving Ezetrol with a statin, consecutive transaminase elevations (≥ 3 x the upper limit of normal (ULN)) have been observed. When Ezetrol is coadministered 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 (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 9000 patients with chronic kidney disease were randomised to receive Ezetrol 10 mg with simvastatin 20 mg daily (n = 4650) or placebo (n = 4620) (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (> 3 x ULN) was 0.7% for Ezetrol 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 Ezetrol 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 the ULN was 4 of 1674 (0.2%) patients administered Ezetrol alone vs. 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients coadministered Ezetrol and a statin vs. 4 of 929 (0.4%) patients administered a statin alone.
In postmarketing experience with Ezetrol, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetrol. However, rhabdomyolysis has been reported very rarely with Ezetrol monotherapy and very rarely with the addition of Ezetrol to agents known to be associated with increased risk of rhabdomyolysis. All patients starting therapy with Ezetrol should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Ezetrol 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 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 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 9000 patients with chronic kidney disease were randomised to receive Ezetrol 10 mg combined with simvastatin 20 mg daily (n = 4650) or placebo (n = 4620) (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for Ezetrol combined with simvastatin and 0.1% for placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).

Fibrates.

The coadministration 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 Ezetrol and ciclosporin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anticoagulants.

If Ezetrol 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, Ezetrol 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 Ezetrol coadministered 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 Ezetrol coadministered 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 Ezetrol coadministered 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 postmenarche. Doses greater than 10 mg Ezetrol 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 coadministered Ezetrol 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 Ezetrol coadministered 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 Ezetrol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.
Ezetrol coadministered with simvastatin has not been studied in premenarchal girls or in prepubertal boys and is not recommended.

Paediatric patients < 10 years of age.

Ezetrol is not recommended in children < 10 years of age.
Safety and effectiveness of Ezetrol in patients 6 to 10 years of age with heterozygous familial or nonfamilial hypercholesterolaemia have been evaluated in a 12 week controlled clinical trial. Children treated with Ezetrol had an adverse experience profile similar to that of adult patients treated with Ezetrol. 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 Ezetrol in combination with statins has not been studied in children < 10 years of age. Ezetrol 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 (ethinylestradiol and levonorgestrel), glipizide, tolbutamide or midazolam during coadministration. Cimetidine, coadministered 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 postrenal 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 historically 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 of 100 mg 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 coadministered 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 postmarketing reports of increased International Normalised Ratio in patients who had Ezetrol 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. Ezetrol should be used in pregnancy only if the potential benefit exceeds the potential risk. When Ezetrol 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. Ezetrol 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 Ezetrol may affect some patients' ability to drive or operate machinery. Individual responses to Ezetrol 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 Ezetrol 10 mg daily was administered alone, with a statin, or with fenofibrate in 3551 patients demonstrated: Ezetrol was generally well tolerated, adverse reactions were usually mild and transient, the overall incidence of side effects reported with Ezetrol was similar to that reported with placebo, and the discontinuation rate due to adverse experiences was comparable between Ezetrol and placebo.
There were no drug related adverse experiences reported occurring in ≥ 2% of patients taking Ezetrol alone (n = 1691).
The following drug related adverse experiences were reported occurring in ≥ 2% in patients taking Ezetrol coadministered 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 Ezetrol alone and at a greater incidence than placebo, or in patients taking Ezetrol coadministered with a statin and at a greater incidence than statin administered alone.

Ezetrol administered alone.

Investigations.

Uncommon: gamma-glutamyltransferase 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.

Ezetrol coadministered 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.

Ezetrol coadministered with fenofibrate.

Gastrointestinal disorders.

Common: abdominal pain.
In a coadministration 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 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 9000 patients treated with a fixed dose combination of Ezetrol 10 mg with simvastatin 20 mg daily (n = 4650) or placebo (n = 4620), 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 Ezetrol combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Ezetrol combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (> 3 x ULN) occurred in 0.7% of patients treated with Ezetrol 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 Ezetrol 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 (≥ 3 x 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 (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 Ezetrol coadministered 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 nonfamilial hypercholesterolaemia (n = 138), the safety and tolerability profile of the group treated with Ezetrol was similar to that of adult patients treated with Ezetrol. Elevations of ALT and/or AST (≥ 3 x 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 (≥ 10 x 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 use; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients).
Ezetrol 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 Ezetrol (0.5%) and placebo (0.3%). In coadministration trials, the incidence was 1.3% for patients treated with Ezetrol coadministered 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 Ezetrol administered alone or coadministered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.

Postmarketing experience.

The following adverse reactions have been reported in postmarketing 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; cholecystitis; drug-induced liver injury; 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 hypercholesterolaemia for up to 56 days, was generally well tolerated.
A few cases of overdosage with Ezetrol 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 of Ezetrol, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ezetrol (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, Ezetrol inhibited intestinal cholesterol absorption by 54%, compared with placebo. By inhibiting the absorption of intestinal cholesterol, Ezetrol reduces the delivery of cholesterol to the liver. Statins reduce cholesterol synthesis in the liver. Together these distinct mechanisms provide complementary cholesterol reduction. Ezetrol, 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, ethinylestradiol, or the fat soluble vitamins A and D.

Clinical trials.

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

Primary hypercholesterolaemia.

Monotherapy. In two multicentre, double blind, placebo controlled, 12 week studies in 1719 patients with primary hypercholesterolaemia, Ezetrol 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, Ezetrol 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.
Coadministration with a statin.

Ezetrol initiated concurrently with a statin.

In four, multicentre, double blind, placebo controlled, 12 week trials, in 1187 patients with hypercholesterolaemia, Ezetrol 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 Ezetrol 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 Ezetrol + statin doses, Ezetrol had a beneficial effect on total-C, Apo B, TG, and HDL-C (Table 4).

Ezetrol added to ongoing 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 Ezetrol 10 mg or placebo in addition to their ongoing 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 Ezetrol and placebo, respectively.
Ezetrol, added to ongoing 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.
Ezetrol 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 Ezetrol 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 Ezetrol plus atorvastatin coadministration 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 Ezetrol coadministration arm (22%) and patients on atorvastatin monotherapy (7%). At week 4, there was a significant difference in LDL-C reductions between coadministration patients (24%; Ezetrol + atorvastatin 10 mg) and monotherapy patients (9%; atorvastatin 20 mg). In the subgroup 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 Ezetrol 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 Ezetrol + simvastatin vs. 3% for simvastatin alone) and LDL-C reductions (24% for Ezetrol + 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 coadministration 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 coadministration. 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 postmenarchal 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 Ezetrol coadministered 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 coadministered Ezetrol and simvastatin (10 mg, 20 mg or 40 mg) or simvastatin alone (10 mg, 20 mg or 40 mg) for 6 weeks, coadministered Ezetrol and simvastatin 40 mg or 40 mg simvastatin alone for the next 27 weeks, and open label coadministered Ezetrol 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 Ezetrol and simvastatin groups would be greater than in the pooled simvastatin monotherapy groups. At week 6, coadministered Ezetrol 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 Tables 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 Ezetrol coadministered 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 Ezetrol coadministered 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 Ezetrol 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 nonfamilial hypercholesterolaemia were randomised to either Ezetrol 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, Ezetrol 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.
Ezetrol 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 Ezetrol 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), Ezetrol 10 mg administered with atorvastatin or simvastatin (40 mg), or Ezetrol 10 mg administered with atorvastatin or simvastatin (80 mg). Results are shown in Table 9. Ezetrol, 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.

Ezetrol in combination with simvastatin has been shown in the IMPROVE-IT trial (details below) to reduce the major cardiovascular events of nonfatal 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 revascularisation 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 coadministration 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, 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 = 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 = 11,594). 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 nonfatal myocardial infarction, documented unstable angina that required hospitalisation, or any coronary revascularisation procedure occurring at least 30 days after randomised treatment assignment) and nonfatal 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 nonfatal 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 nonsignificant increase in haemorrhagic 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 9438 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 a fixed dose combination of Ezetrol 10 mg with simvastatin 20 mg, placebo, or simvastatin 20 mg daily. The 1 year simvastatin arm was included to enable the comparison of Ezetrol combined with simvastatin to simvastatin alone with regard to safety and lipids. At 1 year the simvastatin only arm was rerandomised 1:1 to a fixed dose combination of Ezetrol 10 mg with simvastatin 20 mg or placebo. A total of 4650 patients were allocated to Ezetrol 10 mg combined with simvastatin 20 mg and 4620 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 Ezetrol 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 Ezetrol 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 Ezetrol combined with simvastatin (n = 4193) or placebo (n = 4191) groups. Secondary analyses included the same composite analysed for the full cohort randomised (at study baseline or at year 1) to Ezetrol combined with simvastatin (n = 4650) or placebo (n = 4620) as well as the components of this composite.
The primary endpoint analysis showed that Ezetrol combined with simvastatin significantly reduced the risk of MVE (749 patients with events in the placebo group vs. 639 in the Ezetrol 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 noncoronary cardiac deaths and haemorrhagic stroke) showed that Ezetrol combined with simvastatin significantly reduced the risk of MAE (526 (11.3%) of 4650 patients ever allocated to Ezetrol 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. Ezetrol 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. nondialysis, 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. Ezetrol combined with simvastatin significantly reduced the risk of stroke and any revascularisation, with nonsignificant numerical differences favouring Ezetrol combined with simvastatin for nonfatal MI and cardiac death.
No significant treatment effect of Ezetrol 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, Ezetrol 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, Ezetrol combined with simvastatin did not reduce the risk of progressing to endstage renal disease compared with placebo.
There were no significant differences between the Ezetrol 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 Ezetrol 10 mg with simvastatin 20 mg compared to either the lower dose combination (i.e. Ezetrol 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 Ezetrol 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 Ezetrol 10 mg (n = 30) or placebo (n = 7). Ezetrol 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 Ezetrol, the reduction in plant sterols was progressive over the course of the study.
Reductions in sitosterol and campesterol were consistent between patients taking Ezetrol 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 nonfat meals) had no effect on the oral bioavailability of ezetimibe when administered as Ezetrol 10 mg tablets. Ezetrol 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 < 6 years 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 Ezetrol. 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 (postrenal 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

Each 10 mg tablet contains croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium lauryl sulfate.

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 30°C. Store in the original package.

6.5 Nature and Contents of Container

Supplied in blister packs of 5, 10 and 30.

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 is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature.
Ezetrol, 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.

Its structural formula is:

CAS number.

The CAS registry number is 163222-33-1.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes