Consumer medicine information

Lipex

Simvastatin

BRAND INFORMATION

Brand name

Lipex

Active ingredient

Simvastatin

Schedule

SUMMARY CMI

LIPEX^®

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 LIPEX?

LIPEX contains the active ingredient simvastatin. LIPEX helps to lower cholesterol and triglyceride levels.

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

2. What should I know before I use LIPEX?

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

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

For more information, see Section 2. What should I know before I use LIPEX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with LIPEX 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 LIPEX?

Take LIPEX once a day in the evening.
Your doctor will tell you how many tablets you need to take each day.

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

5. What should I know while using LIPEX?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using LIPEX. Have your blood fats checked when your doctor says, to make sure LIPEX is working If you are about to have elective surgery, tell your doctor that you are taking LIPEX.
Things you should not do	Grapefruit juice should be avoided while taking LIPEX. Grapefruit juice contains one or more components that alter the metabolism of some medicines, including LIPEX
Driving or using machines	LIPEX may cause dizziness in some people. Make sure you know how you react to LIPEX before you drive a car or operate machinery
Drinking alcohol	Avoid drinking large quantities of alcohol. Tell your doctor if you drink alcohol. Drinking large quantities of alcohol may increase your chance of LIPEX causing liver problems
Looking after your medicine	Keep LIPEX in a cool dry place where the temperature stays below 30°C

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

6. Are there any side effects?

Common side effects of LIPEX are constipation, diarrhoea, wind, stomach upset or pain, feeling sick (nausea), headache, trouble sleeping, rash.

Allergic reactions to LIPEX occur 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

LIPEX^®

Active ingredient(s): simvastatin

Consumer Medicine Information (CMI)

This leaflet provides important information about using LIPEX. 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 LIPEX.

Where to find information in this leaflet:

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

1. Why am I using LIPEX?

LIPEX contains the active ingredient simvastatin. LIPEX helps to lower cholesterol and triglyceride levels.

LIPEX is used to in people who have coronary heart disease (CHD) or who are at high risk of CHD (for example, if they have diabetes, a history of stroke, or other blood vessel disease).

LIPEX may be used in these people, regardless of their cholesterol level to:

help prolong life by reducing the risk of a heart attack
reduce the risk of stroke
reduce the need for surgery to increase blood flow to the heart
reduce the need for hospitalisation due to angina.

Cholesterol

Everyone has cholesterol and triglycerides in their blood. They are types of blood fat needed by the body for many things, including building cell walls, making bile acids (which help to digest food) and certain hormones. However, too much cholesterol can be a problem.

Your body makes cholesterol, but it also comes from food.

Normally the body balances the cholesterol it makes with the cholesterol it gets from food. This means if more cholesterol comes from food, less is made by the body. However, if you eat a diet high in fat, your body may not keep this balance and your cholesterol levels rise.

High cholesterol is more likely to occur with certain diseases or if you have a family history of high cholesterol.

When you have high levels of cholesterol, it may 'stick' to the inside of your blood vessels instead of being carried to the parts of the body where it is needed. Over time, this can form hard areas, called plaque, on the walls of blood vessels, making it more difficult for the blood to flow. This blocking of your blood vessels can lead to coronary heart disease (such as heart attack and angina), and stroke.

In people with CHD, LIPEX may slow down the hardening of blood vessels and reduce the risk of developing new plaques.

There are different types of cholesterol, called LDL and HDL cholesterol. LDL cholesterol is the 'bad' cholesterol that can block your blood vessels. HDL cholesterol, on the other hand, is the 'good' cholesterol that is thought to remove the bad cholesterol from the blood vessels.

Triglycerides

Triglycerides are an energy source for the body. However, as with cholesterol, too much triglycerides can be a problem.

How LIPEX works

LIPEX belongs to a group of medicines known as HMG-CoA reductase inhibitors. It works by reducing the amount of cholesterol made by the liver. In terms of good and bad cholesterol, LIPEX reduces the bad cholesterol and raises the good cholesterol.

LIPEX does not reduce the cholesterol and triglycerides that come from fat in food.

Therefore, when you are taking LIPEX, you also need to follow a low fat diet and other measures, such as exercise and weight control.

In most people, there are no symptoms of high cholesterol or triglycerides. Your doctor can measure your cholesterol and triglycerides with a simple blood test.

Safety and effectiveness have been studied in 10-17 year old boys and in girls, who had started their menstrual period at least one year before (see How to take LIPEX). LIPEX has not been studied in children under the age of 10 years. For more information, talk to your doctor..

2. What should I know before I use LIPEX?

Warnings

Do not use LIPEX if:

you are allergic to simvastatin, 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 tongue or face, or painful joints.
Always check the ingredients to make sure you can use this medicine.
you have liver disease
you have had muscle pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides
the packaging is torn or shows signs of tampering

Check with your doctor if you:

have unexplained muscle pain, tenderness or weakness not caused by exercise. This is because on rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage that can lead to death. Your doctor may do a blood test to check for certain muscle problems.
are Asian
have ever had liver disease. Your doctor will do a blood test to make sure you have no problems with your liver.
have kidney disease
drink alcohol regularly
have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.
have or have had myasthenia gravis (a disease causing general muscle weakness including in some cases muscles used for breathing) or ocular myasthenia (a disease causing eye muscle weakness) as statins may lead to occurrence of myasthenia or aggravate the condition.
have any other medical conditions
take any medicines for any other condition

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

Pregnancy and breastfeeding

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

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

LIPEX should not be used during pregnancy or while breast-feeding.

Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to the baby.

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 LIPEX as they may increase the risk of muscle side effects with LIPEX.

It is particularly important to tell your doctor if you are taking:

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

If you are taking any of the above, your doctor may suggest stopping LIPEX temporarily or permanently

Some medicines and LIPEX may interfere with each other. Because taking LIPEX with any of the following drugs can increase the risk of muscle problems (see Side Effects), it is particularly important to tell your doctor if you are taking:

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

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

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

You should also tell any doctor who is prescribing a new medication for you that you are taking LIPEX.

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

4. How do I use LIPEX?

How much to take

Take LIPEX only when prescribed by your doctor.
Your doctor will tell you how many tablets you need to take each day. This depends on your cholesterol and triglyceride levels and other factors, such as kidney disease.
For adults, the recommended starting dose is 10mg or 20 mg per day, taken in the evening, which may need to be increased up to 80 mg daily to have the best effect.
Because of the increased risk of muscle problems, the 80 mg dose is only for patients at high risk of heart disease problems who have not reached their cholesterol goal on lower doses.
People with CHD or risk factors for CHD are usually started on 40 mg per day, taken in the evening.
For children (10-17 years old), the recommended usual starting dose is 10 mg a day in the evening. The maximum recommended dose is 40 mg a day.
Swallow LIPEX with a glass of water.
Follow the instructions provided and use LIPEX until your doctor tells you to stop.
LIPEX 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 LIPEX, your cholesterol levels may rise again.

When to take LIPEX

Take LIPEX once a day in the evening.
The liver produces its greatest amount of cholesterol when the body is at rest and when there is no dietary intake. For most people this is at night when asleep. Therefore, LIPEX is more effective when taken in the evening. A good time would be after your evening meal. However, it does not matter whether you take it before or after food.
Take LIPEX at about the same time each evening.
Taking your tablet(s) at the same time each evening will have the best effect. It will also help you remember when to take the tablets.

If you forget to use LIPEX

LIPEX should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your tablet(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 LIPEX

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

Call your doctor straight away and stop taking LIPEX if you become pregnant while you are taking LIPEX.

Things you should do

Have your blood fats checked when your doctor says, to make sure LIPEX is working.
If you are about to be started on any new medicine tell your doctor and pharmacist that you are taking LIPEX.
If you are about to have elective surgery, tell your doctor that you are taking LIPEX.
Your doctor may suggest stopping the tablets a few days before surgery.

Remind any doctor, dentist or pharmacist you visit that you are using LIPEX.

Things you should not do

Do not give LIPEX to anyone else, even if they have the same condition as you.
Grapefruit juice should be avoided while taking LIPEX.
Grapefruit juice contains one or more components that alter the metabolism of some medicines, including LIPEX

Changes to lifestyle that may help reduce the chance of coronary heart disease

Lowering high cholesterol can help reduce your chances of having coronary heart disease (CHD). However, your chances of having CHD may be increased by several other factors including high blood pressure, cigarette smoking, diabetes, excess weight, family history of CHD, being a male and being a woman who has reached menopause.

Some self help measures suggested below may help your condition and help reduce your chances of having CHD. Talk to your doctor, pharmacist, or dietician about these measures and for more information.

Diet

continue the low fat diet recommended by your doctor, dietician or pharmacist.

Weight

your doctor may advise you to lose weight if you are overweight.

Exercise

make exercise a part of your routine - walking is good. Ask your doctor for advice before starting exercise.

Smoking

your doctor may advise you to stop smoking or at least cut down.

Driving or using machines

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

LIPEX generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, LIPEX may cause dizziness in some people. Make sure you know how you react to LIPEX before you drive a car or operate machinery.

Drinking alcohol

Avoid drinking large quantities of alcohol.

Drinking large quantities of alcohol may increase your chance of LIPEX causing liver problems.

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effects

What to do

Gastrointestinal-related:

constipation, diarrhoea, wind
stomach upset or pain, feeling sick (nausea)

Muscle/skeleton-related:

muscle cramps
muscle rupture (very rare)

Eye-related:

blurred vision and impaired vision

Skin-related:

hair loss
rash that occurs on the skin or sores in the mouth (lichenoid drug eruptions) (very rare)

Head and nervous system-related:

headache
dizziness
poor memory, memory loss, confusion
tingling in the hands and feet

Mood-related:

trouble sleeping
feelings of depression

Reproductive system or breast-related:

erectile dysfunction
gynaecomastia (breast enlargement in men) (very rare)

Respiratory-related:

breathing problems including persistent cough and/or shortness of breath or fever

Blood-related:

signs of anaemia, such as tiredness, being short of breath, and looking pale

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
Muscle/skeleton-related: aching muscles, muscle tenderness or weakness, not caused by exercise (in very rare cases this may not go away after stopping LIPEX) brown/black coloured urine muscle rupture (very rare) On rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage that can lead to death. The risk of muscle problems is greater for: patients taking higher doses of LIPEX, particularly the 80 mg dose older patients (65 years of age and older) female patients patients with abnormal kidney function patients with thyroid problems. Liver-related: Liver problems can also occur and may be serious. Your doctor will do blood tests to check your liver. Symptoms of liver problems include: feeling tired or weak loss of appetite upper belly pain dark urine yellowing of your skin or the whites of your eyes	Tell your doctor immediately if you notice any of these side effects.
Allergic reaction: swelling of the face, lips, mouth, tongue, and/or throat that may cause difficulty in swallowing or breathing shortness of breath	Tell your doctor immediately or go to accident and emergency at your nearest hospital if you notice any of these side effects.
Blood-related: bruising more easily than normal Skin-related: skin rash, itchiness pinkish, itchy swellings on the skin, also called hives or nettlerash Muscle/skeleton-related: painful, swollen joints weakness in your arms or legs that worsens after periods of activity, double vision or drooping of your eyelids, difficulty swallowing, or shortness of breath (symptoms of myasthenia). Reproductive system or breast-related: larger breasts than normal in men General conditions: fever, generally feeling unwell	Tell your doctor immediately if you notice any of these side effects. These may be serious side effects of LIPEX. Some of these may be symptoms of an allergic reaction to LIPEX. You may need urgent medical attention.

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 LIPEX contains

Active ingredient (main ingredient)	simvastatin 5, 10, 20, 40 or 80 mg per tablet
Other ingredients (inactive ingredients)	butylated hydroxyanisole ascorbic acid citric acid monohydrate cellulose starch - pregelatinised maize magnesium stearate lactose monohydrate hypromellose titanium dioxide talc carnauba wax hyprolose iron oxide yellow CI77492 (5 mg, 10 mg, 20 mg and 80 mg tablets) iron oxide red CI77491 (10 mg, 20 mg, 40 mg and 80 mg tablets)
Potential allergens	LIPEX 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 LIPEX looks like

LIPEX comes in four types of tablets:

LIPEX 10 mg - peach coloured, oval-shaped tablet with "MSD 735" marked on one side (AUST R 11616)

LIPEX 20 mg - tan coloured, oval-shaped tablet with "MSD 740" marked on one side (AUST R 11617)

LIPEX 40 mg - brick-red coloured, oval-shaped tablet with "MSD 749" marked on one side (AUST R 59273)

LIPEX 80 mg - brick-red coloured, capsule-shaped tablet with "543" marked on one side and "80" on the other (AUST R 65524)

A starter pack of LIPEX contains 5 tablets. A trade pack of LIPEX contains 30 tablets.

Who distributes LIPEX

Organon Pharma Pty Ltd
Level 5, 66 King St
Sydney NSW 2000
Australia

This leaflet was prepared in February 2025.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Lipex

Active ingredient

Simvastatin

Schedule

1 Name of Medicine

Simvastatin.

2 Qualitative and Quantitative Composition

Simvastatin is a white crystalline powder, practically insoluble in water and freely soluble in chloroform, methanol and ethanol.
Each tablet for oral administration contains either 10 mg, 20 mg, 40 mg or 80 mg of simvastatin.

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

Lipex (simvastatin) - 10 mg, peach coloured, oval shaped, film-coated tablets, marked 'MSD 735'.
Lipex (simvastatin) - 20 mg, tan coloured, oval-shaped, film-coated tablets, marked 'MSD 740'.
Lipex (simvastatin) - 40 mg, brick red coloured, oval, film-coated tablets, one side engraved with 'MSD 749', other side plain.
Lipex (simvastatin) - 80 mg, brick red, capsule shaped, convex, film-coated tablets, one side engraved with '543', other side engraved '80'.

4 Clinical Particulars

4.1 Therapeutic Indications

Lipex is indicated as an adjunct to diet for treatment of hypercholesterolaemia.
Prior to initiating therapy with Lipex, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, alcoholism) should be identified and treated.
Lipex is indicated in patients at high risk of CHD (with or without hypercholesterolaemia) including patients with diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or with existing CHD to reduce the risk of cardiovascular death, major cardiovascular events including stroke, and hospitalisation due to angina pectoris.
These effects do not replace the need to independently control known causes of cardiovascular mortality and morbidity such as hypertension, diabetes and smoking.
Lipex is indicated as an adjunct to diet in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heterozygous familial hypercholesterolaemia (HeFH).
Prior to initiating therapy with Lipex, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, alcoholism) should be identified and treated.

4.2 Dose and Method of Administration

The dosage range for Lipex is 10-80 mg/day, given as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80 mg dose of Lipex should only be used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Patients at high risk of coronary heart disease (CHD) or with existing CHD.

The usual starting dose of Lipex is 40 mg/day given as a single dose in the evening in patients at high risk of CHD (with or without hypercholesterolaemia), i.e. patients with diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or with existing CHD. Drug therapy can be initiated simultaneously with diet and exercise.

Hypercholesterolaemia and combined hyperlipidaemia (patients who are not in the risk categories above).

The patient should be placed on a standard cholesterol-lowering diet before receiving Lipex and should continue on this diet during treatment with Lipex.
The recommended starting dose is 10 to 20 mg per day in the evening. Therapy should be individualised according to the patient's response.

Concomitant therapy.

Lipex is effective alone or in combination with bile acid sequestrants.
In patients taking fibrates other than gemfibrozil (see Section 4.3 Contraindications) or fenofibrate, the dose of Lipex should not exceed 10 mg/day.
In patients taking amiodarone, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with Lipex, the dose of Lipex should not exceed 20 mg/day.
In patients taking amlodipine concomitantly with Lipex, the dose of Lipex should not exceed 40 mg/day (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients taking niacin (nicotinic acid) ≥ 1 g/day, the dose of Lipex should not exceed 40 mg/day (see Section 4.4 Special Warnings and Precautions for Use).
In patients taking lomitapide concomitantly with Zocor, the dose of Zocor should not exceed 40 mg/day (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Renal impairment.

Lipex does not undergo significant renal excretion.
However, because no data is available in patients with impaired renal function, caution should be used in these patients.
In patients with severe renal insufficiency (creatinine clearance < 30 mL/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Dosage in paediatric patients (10-17 years of age) with heterozygous familial hypercholesterolaemia.

The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualised according to the recommended goal of therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.3 Contraindications

Hypersensitivity to any component of this preparation.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and nursing (also see Section 4.4 Special Warnings and Precautions for Use). Women of child bearing potential unless on an effective contraceptive and highly unlikely to conceive.
Myopathy secondary to other lipid lowering agents.
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and drugs containing cobicistat (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of gemfibrozil, ciclosporin, or danazol (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant use with fusidic acid (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Myopathy/rhabdomyolysis.

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10 x the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma (i.e. elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
In 4S, there was one case of myopathy among 1399 patients taking simvastatin 20 mg/day and no cases among 822 patients taking 40 mg/day for a median duration of 5.4 years. In two 6 month controlled clinical studies, there was one case of myopathy among 436 patients taking 40 mg and 5 cases among 669 patients taking 80 mg.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a major, large, long-term clinical trial (SEARCH) in which patients with a history of myocardial infarction were treated with Lipex 80 mg/day (mean follow up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. This includes rhabdomyolysis for which the incidence was 0.1 to 0.2%, all allocated to Lipex 80 mg/day. There is no universally accepted definition of rhabdomyolysis. In SEARCH, rhabdomyolysis was defined as a subset of myopathy with CK > 40 x ULN plus evidence of end organ damage (e.g. elevated creatinine, dark urine). Approximately half of all the myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.
The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C lowering efficacy. Therefore the 80 mg dose of simvastatin should only be used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking simvastatin 80 mg for whom an interacting agent is needed, a lower dose of simvastatin or an alternative statin-based regimen with less potential for drug-drug interactions should be used (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).
All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level > 10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved (see Section 4.8 Adverse Effects (Undesirable Effects)). Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased. Periodic CK determinations are recommended for patients titrating to the 80 mg dose. There is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
An increased risk of myopathy in Chinese subjects has been identified. In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n = 4 of 7367) compared with 0.24% for Chinese patients (n = 13 of 5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing simvastatin to Asian patients and the lowest dose necessary should be employed.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin with the following medicines:

Contraindicated medicines.

Potent inhibitors of CYP3A4.

Concomitant use with medicines labelled as having a potent inhibitory effect on CYP3A4 at therapeutic doses (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone or drugs containing cobicistat) is contraindicated. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy. If short-term treatment with potent CYP3A4 inhibitors is unavoidable, therapy with simvastatin should be suspended during the course of treatment (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gemfibrozil, ciclosporin or danazol.

Concomitant use of these drugs with simvastatin is contraindicated (see Section 4.3 Contraindications).

Fusidic acid.

Patients on fusidic acid treated concomitantly with simvastatin may have an increased risk of myopathy/rhabdomyolysis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Fusidic acid must not be co-administered with statins (see Section 4.3 Contraindications). In patients where the use of systemic fusidic acid is considered essential, Lipex should be discontinued throughout the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Lipex therapy may be reintroduced seven days after the last dose of fusidic acid.

Other medicines.

Amiodarone. In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. In the same clinical trial, there were no cases of myopathy reported in patients receiving simvastatin 20 mg and amiodarone (see Table 1). The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Calcium channel blockers.

Verapamil and diltiazem.

The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil or diltiazem (see Table 1; see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Amlodipine.

In a clinical trial, patients on amlodipine treated concomitantly with simvastatin 80 mg had a slightly increased risk of myopathy. The dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine (see Table 1; see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Lomitapide. The dose of simvastatin should not exceed 40 mg daily in patients with homozygous familial hypercholesterolemia (HoFH) receiving concomitant medication with lomitapide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Moderate inhibitors of CYP3A4. Patients taking other medicines labelled as having a moderate inhibitor effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy. When co-administering simvastatin with a moderate inhibitor of CYP3A4, a dose adjustment of simvastatin may be necessary.
Other fibrates. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with other fibrates (except fenofibrate). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone. Addition of fibrates to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. Combinations of fibrates with simvastatin have been used without myopathy in small, short-term clinical studies with careful monitoring.
Inhibitors of breast cancer resistance protein (BCRP). Concomitant administration of products that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore, a dose adjustment of simvastatin may be necessary. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Niacin (≥ 1 g/day). The dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with niacin (nicotinic acid) ≥ 1 g/day. Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid-modifying doses (≥ 1 g/day) of niacin. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥ 1 g/day) of niacin. Therefore, the benefit of the combined use of simvastatin with niacin should be carefully weighed against the potential risks of the combination. In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with extended-release niacin/laropiprant 2 g/40 mg. In comparison, in European/Non-Chinese patients the incidence of myopathy was approximately 0.05% for patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 0.09% for patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with extended-release niacin/laropiprant 2 g/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in European/Non-Chinese patients, coadministration of simvastatin with lipid-modifying doses (≥ 1 g/day) of niacin is not recommended in Asian patients.
Daptomycin. Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA reductase inhibitors coadministered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to suspending Lipex temporarily in patients taking daptomycin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other drug interactions).
Prescribing recommendations for interacting agents are summarised in Table 1 (further details are provided in the text (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1 Pharmacodynamic Properties, Mechanism of action)).

Myasthenia gravis/ocular myasthenia.

In few cases, statins have been reported to induce new onset or aggravate pre-existing myasthenia gravis or ocular myasthenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Lipex should be discontinued in case of these conditions occur. There have been reports of recurrences of these conditions when the same or a different statin was re-administered.

Hepatic effects.

In clinical studies persistent increases (to more than 3 x ULN) in serum transaminases have occurred in 1% of adult patients who received simvastatin. When the drug was interrupted or discontinued in these patients, transaminases usually fell slowly to pre-treatment concentration. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. Some of these patients had abnormal liver function tests (LFTs) prior to therapy with simvastatin and/or consumed substantial quantities of alcohol.
In 4S (see Section 5.1 Pharmacodynamic Properties, Clinical trials), the number of patients with more than one ALT elevation to > 3 x ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs 12 [0.6%]). The incidence of ALT elevations in simvastatin subjects was greater than the incidence of AST elevations and the number of subjects with at least one elevation of ALT greater than 3 x ULN was 46 (2.2%) in the simvastatin group and 32 (1.4%) in the placebo group, the difference not being statistically significant. The frequency of single elevations of ALT to 3 x ULN was significantly higher in the simvastatin group in the first year of the study (20 vs 8, p=0.023), but not thereafter. Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1986 simvastatin treated patients in 4S with normal LFTs at baseline, only 8 (0.4%) developed consecutive LFT elevations to > 3 x ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1105 patients, the 6 month incidence of persistent hepatic transaminase elevations considered drug related was 0.7% and 1.8% at the 40 and 80 mg dose respectively.
In HPS (see Section 5.1 Pharmacodynamic Properties, Clinical trials), in which 20,536 patients were randomised to receive Lipex 40 mg/day or placebo, the incidences of elevated transaminases (> 3 x ULN confirmed by repeat test) were 0.21% (n=21) for patients treated with Lipex and 0.09% (n=9) for patients treated with placebo.
Liver function tests should be performed before the initiation of treatment and thereafter when clinically indicated. Patients titrated to the 80 mg dose should receive an additional test at 3 months. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with Lipex, promptly interrupt therapy. If an alternate aetiology is not found do not restart Lipex.
Patients who develop increased transaminase levels should have the finding confirmed and be followed thereafter with frequent liver tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 x ULN persist, withdrawal of simvastatin therapy is recommended. Liver biopsy should be considered if elevations persist despite discontinuation of the drug. Unconfirmed reports of "drug-induced hepatitis" have been reported with simvastatin.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.
As with other lipid-lowering agents, moderate (less than 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes were not specific to Lipex and were also observed with comparative lipid-lowering agents. They generally appeared within the first 3 months after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Immune mediated necrotizing myopathy.

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

Interstitial lung disease.

Cases of interstitial lung disease have been reported with some statins, including simvastatin especially with long term therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Ophthalmic evaluations.

Current long-term data from clinical studies, e.g. 4S, do not indicate an adverse effect of simvastatin on the human lens. However, the very long-term effects are not yet established and therefore periodic ophthalmic examinations are recommended after five years of treatment, taking into consideration that in the absence of any drug therapy, an increase in the prevalence of lens opacities with time is expected as a result of aging.

Animal studies.

Cataracts have been detected in 2 year studies in rats and dogs at dose levels greater than 25 and 10 mg/kg/day, respectively, although at a very low incidence. While there is no clear correlation between the magnitude of serum lipid-lowering and the development of cataracts, a consistent relationship has been observed between high serum levels of drug and cataract development with simvastatin and related HMG-CoA reductase inhibitors.
Serum levels (expressed as total inhibitors) in rats at the no-effect dose level were 3-11 times higher than those in humans receiving the maximum daily dose of 80 mg, whereas serum levels at the no-effect level in dogs were approximately two-fold higher than those in humans receiving the maximum daily dose of 80 mg.

Thyroid function.

The concentration of serum thyroxin has been measured at baseline and at the end of simvastatin treatment in 785 patients enrolled in multicentre studies. The results of this analysis indicate that simvastatin has little, if any, effect upon thyroxin activity.
In one study involving 183 patients treated with simvastatin, four patients had TSH levels within the normal range before commencing simvastatin, but had an elevated TSH after two years of simvastatin therapy.

Transient hypotension.

Three cases of symptomatic hypotension in the first few days following the start of simvastatin therapy have been reported. Two of the patients were on antihypertensive medication. The hypotension resolved with continued therapy with simvastatin.

Neurological effects.

The neurological adverse effects reported to date include cases of peripheral neuropathy and paraesthesia possibly due to simvastatin.

Use in the elderly.

In controlled clinical trials, the efficacy of simvastatin for patients over the age of 65 years, as assessed by reduction in total-C and LDL-C levels, was similar to that seen in the population as a whole. There was no apparent increase in the overall frequency of clinical or laboratory adverse findings.
However, in a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥ 65 years of age had an increased risk of myopathy compared to patients < 65 years of age.

Paediatric use.

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.
The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
The safety and efficacy of simvastatin in children and adolescents with non-familial hypercholesterolaemia, those aged less than 10 years or premenarchal girls have not been studied.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory test findings.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Multiple mechanisms may contribute to potential interactions with HMG-CoA reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.

CYP3A4 interactions.

Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolised by CYP3A4.

Contraindicated medicines.

Concomitant use of the following medicines is contraindicated.

Potent CYP3A4 inhibitors.

Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin.
Concomitant use with medicines labelled as having a potent inhibitory effect on CYP3A4 (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) is contraindicated. (See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 5.2 Pharmacokinetic Properties.)

Gemfibrozil, ciclosporin or danazol.

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

Fusidic acid.

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

Other drug interactions.

Amiodarone.

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

Calcium channel blockers.

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

Lomitapide.

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

Moderate inhibitors of CYP3A4.

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Inhibitors of the transport protein OATP1B1.

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Inhibitors of breast cancer resistance protein (BCRP).

Simvastatin is a substrate of the efflux transporter BCRP. Concomitant administration of products that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy. When co-administering simvastatin with an inhibitor of BCRP, a dose adjustment of simvastatin may be necessary (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Niacin (nicotinic acid) (≥ 1 g/day).

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day) of niacin (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Colchicine.

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

Daptomycin.

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

Other fibrates.

The risk of myopathy is increased by gemfibrozil (see Section 4.3 Contraindications) and other fibrates (except fenofibrate); these lipid-lowering drugs can cause myopathy when given alone. When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. (See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis.)

Grapefruit juice.

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

Coumarin derivatives.

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of warfarin. The prothrombin time, reported as International Normalised Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Propranolol.

In normal volunteers, concomitant administration of single doses of Lipex with propranolol produced no clinically significant pharmacokinetic or pharmacodynamic interaction.

Antipyrine.

Lipex had no effect on the pharmacokinetics of antipyrine. However, since Lipex is metabolised by the CYP3A4, this does not preclude an interaction with other drugs metabolised by the same isoform.

Digoxin.

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

Ticagrelor.

Co-administration of ticagrelor with simvastatin increased the simvastatin C_max by 81% and AUC by 56% and increased simvastatin acid C_max by 64% and AUC by 52% with some individual increases equal to 2 to 3-fold. There was no effect of simvastatin on ticagrelor plasma levels. There is the potential for an increase in simvastatin-related adverse reactions such as myopathy and rhabdomyolysis with co-administration; no cases of rhabdomyolysis were reported when ticagrelor was co-administered with simvastatin 40 mg daily or lower. Therefore, concomitant use of ticagrelor with doses of simvastatin greater than 40 mg daily is not recommended.

Other concomitant therapy.

In clinical studies, Lipex was used concomitantly with beta-blockers, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In several studies of over 800 men with hypercholesterolaemia treated with simvastatin 20 mg to 80 mg per day for 12 to 48 weeks, basal testosterone levels were mildly decreased during simvastatin therapy, but there were no consistent changes in LH and FSH. In 86 men treated with simvastatin 20 mg to 80 mg per day, there was no impairment of hCG-stimulated testosterone secretion.
Testicular degeneration has been seen in two dog safety studies with simvastatin. Special studies designed to further define the nature of these changes have not met with success since the effects are poorly reproducible and unrelated to dose, serum cholesterol levels, or duration of treatment. Simvastatin has been administered for up to two years to dogs at a dose of 50 mg/kg/day without any testicular effects.
Fertility of male and female rats was unaffected at oral doses up to 25 mg/kg/day.
(Category D)
Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
HMG-CoA reductase inhibitors, including Lipex, are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 134 cases where pregnant women took an HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy serious foetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetus occurring after a pregnant woman is exposed to a HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in women exposed to HMG-CoA reductase inhibitors is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist.
Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for foetal development, including synthesis of steroids and cell membranes.
Because of the ability of inhibitors of HMG-CoA reductase such as Lipex to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, Lipex is contraindicated during pregnancy. Lipex should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, Lipex should be discontinued and the patient informed of the potential hazard to the foetus.
Animal studies showed increased incidences of foetal resorption at dosages 50 mg/kg/day in rats and 15 mg/kg/day in rabbits. In another study, an increased incidence of skeletal malformations was observed in foetuses of rats dosed with the active metabolite of simvastatin, L-654,969, at a dose level of 60 mg/kg/day. The no-effect dose level of this teratogenic activity has not been established. Other inhibitors of HMG-CoA reductase have also been shown to induce skeletal malformations in rats, and the teratogenic effects may be due to the enzyme inhibitory activity of such drugs. The relevance of these findings to humans is not known.
Animal studies have shown that weight gain during lactation is reduced in offspring of rats dosed with simvastatin at dosages of 12.5 to 25 mg/kg/day. There is no information from animal studies on whether simvastatin or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking Lipex should not breastfeed their infants (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Lipex has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Adverse Effects (Undesirable Effects)

Lipex is generally well tolerated; for the most part adverse effects have been mild and transient in nature. In controlled clinical studies less than 2 percent of patients were discontinued due to adverse effects attributable to Lipex.
The clinical adverse events occurring at an incidence of greater than 0.5% in controlled clinical trials and are considered to be definitely, probably or possibly due to simvastatin may be grouped as shown in Table 2.
Myopathy has been reported rarely.
In HPS (see Section 5.1 Pharmacodynamic Properties, Clinical trials) involving 20,536 patients treated with 40 mg/day of Lipex (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with Lipex and patients treated with placebo over the mean 5.3 years of the study. In this trial, only serious adverse effects and discontinuations due to any adverse effects were recorded. Discontinuation rates due to side effects were comparable (4.2% in patients treated with Lipex compared with 4.3% in patients treated with placebo). The incidence of myopathy was 0.07% in patients treated with Lipex compared with 0.03% in patients treated with placebo. This includes rhabdomyolysis for which incidences were 0.04% in patients treated with Lipex compared with 0.01% in patients treated with placebo. Some of these patients were taking Lipex concomitantly with medications which are known to increase the risk of myopathy (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis). Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21% of patients treated with Lipex compared with 0.09% of patients treated with placebo.
In 4S (see Section 5.1 Pharmacodynamic Properties, Clinical trials) involving 4444 patients treated with 20-40 mg/day of Lipex (n=2221) or placebo (n=2223), the safety and tolerability profiles were comparable between treatment groups over the median 5.4 years of the study.
The following rare (≥ 1/10,000, ˂ 1/1000) or very rare (˂ 1/10,000) adverse experiences were reported in patients taking simvastatin.

Eye disorders.

Rare: vision blurred, visual impairment.

Skin and subcutaneous tissue disorders.

Very rare: lichenoid drug eruptions.

Musculoskeletal and connective tissue disorders.

Very rare: muscle rupture.

Reproductive system and breast disorders.

Very rare: gynaecomastia.
The following additional adverse effects were reported either in uncontrolled clinical trials or in marketed use: pruritus, alopecia, dizziness, muscle cramps, myalgia, depression, pancreatitis, paraesthesia, peripheral neuropathy, insomnia, vomiting, anaemia, erectile dysfunction, and interstitial lung disease.
There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).
Rhabdomyolysis and hepatitis/jaundice occurred rarely and fatal and non-fatal hepatic failure occurred very rarely. An apparent hypersensitivity syndrome that included some of the following features has been reported rarely: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.
There have been rare postmarketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Myasthenia gravis or ocular myasthenia associated with statin use has been reported (see Section 4.4 Special Warnings and Precautions for Use, Myasthenia gravis/ocular myasthenia).

Laboratory test findings.

Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum CK levels derived from skeletal muscle have been reported (see Section 4.4 Special Warnings and Precautions for Use, Hepatic effects).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Lipex.

Paediatric patients (ages 10-17 years).

In a study involving paediatric patients 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with Lipex was generally similar to that of the group treated with placebo (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Adverse effects - causal relationship unknown.

The following adverse effects have been reported; however, a causal relationship to therapy with Lipex has not been established: erythema multiforme including Stevens-Johnson syndrome, leucopoenia, impotence, proteinuria, and purpura.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. General measures should be adopted, and liver function should be monitored.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The involvement of low-density lipoprotein-cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have established that high LDL-C and low high-density lipoprotein-cholesterol (HDL-C) are both risk factors for coronary heart disease (CHD).
After oral ingestion, Lipex, which is an inactive lactone, is hydrolysed to the corresponding β-hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme which catalyses an early and rate-limiting step in the biosynthesis of cholesterol. As a result, in clinical studies Lipex reduced total plasma cholesterol (total-C), LDL-C and very low-density lipoprotein-cholesterol (VLDL-C) concentrations. In addition, Lipex increases HDL-C and reduces plasma triglycerides (TG).
Lipex has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from VLDL and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Lipex may involve both reduction of VLDL-C concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B (Apo B) also falls substantially during treatment with Lipex. Since each LDL particle contains one molecule of Apo B, and since little Apo B is found in other lipoproteins, this strongly suggests that Lipex does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. As a result of these changes the ratios of total-C to HDL-C and LDL-C to HDL-C are reduced.
Even though Lipex is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyses the conversion of HMG-CoA to mevalonate is not completely blocked at therapeutic doses, therefore it allows the necessary amounts of mevalonate to be available for biological functions. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with Lipex would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolised readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.

Clinical trials.

Lipex has been studied in the treatment of primary hypercholesterolaemia where diet alone has been insufficient. Lipex was highly effective in reducing total-C and LDL-C in heterozygous familial (Fredrickson type IIa) and non-familial forms of hypercholesterolaemia, and in mixed hyperlipidaemia (Fredrickson type IIb) when elevated cholesterol was a cause of concern. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response has been maintained during continuation of therapy. In six controlled clinical studies involving approximately 1700 patients with normal or slightly raised TG (mean 1.9 mmol/L), plasma TG, VLDL-C and Apo B decreased in all studies in a dose-dependent manner. In two of these studies in patients with hypercholesterolaemia receiving Lipex 20 or 40 mg/day for 12 weeks, the following results were observed (see Table 3).

In a separate study involving 180 patients with combined hyperlipidaemia, Lipex 10 mg/day for 17 weeks was also shown to be effective in lowering total-C, LDL-C, VLDL-C, TGs and Apo B (see Table 4).

The data from these studies demonstrate that in patients with hypercholesterolaemia and normal or slightly raised TG, Lipex consistently reduces total-C, LDL-C, TG, VLDL-C and Apo B in a dose dependent manner. The results of 4 separate studies depicting the dose response to simvastatin in patients with primary hypercholesterolaemia are presented in Table 5.

In the upper dose comparative study, one-third of patients obtained a reduction in LDL-C of 53% or more at the 80 mg dose. The percent reduction in LDL-C was essentially independent of the baseline level. In contrast, the percent reduction in TG was related to the baseline level of TG. Of the 664 patients randomised to 80 mg, 475 patients with plasma TG ≤ 2.25 mmol/L had a median reduction in TG of 21%, while in 189 patients with hypertriglyceridaemia (> 2.25 mmol/L), the median reduction in TG was 36%. In these studies, patients with TG > 4.0 mmol/L were excluded.
In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolaemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. The mean LDL-C reductions for the 40 mg and 80 mg doses were 14% and 25%, respectively. One of the twelve patients in this study had complete absence of LDL receptor function (receptor 'deficient'). In this patient, LDL-C reduction of 41% occurred with the 80 mg dose. The magnitude of response to therapy with simvastatin was not predictable by the LDL-receptor gene defects as patients with some LDL-receptor mutations responded differently to the same dose of simvastatin therapy. Five of the twelve patients were also receiving probucol.
The value of drug- and/or diet-induced reduction in plasma cholesterol is no longer controversial. The benefits of reducing LDL-C on morbidity and mortality due to CHD have been established. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) demonstrated in a seven-year, double-blind, placebo-controlled study that lowering LDL-C with diet and colestyramine decreased the combined incidence of CHD death plus non-fatal myocardial infarction (MI).
In a randomised, double-blind, 3-period crossover study, 130 patients with combined hyperlipidaemia (LDL-C > 3.4 mmol/L and TG 3.4 - 7.9 mmol/L) were treated with placebo, Lipex 40, and 80 mg/day for 6 weeks. In a dose-dependent manner Lipex 40 and 80 mg/day, respectively, decreased mean LDL-C by 29 and 36% (placebo: 2%) and median TG levels by 28 and 33% (placebo: 4%), and increased mean HDL-C by 13 and 16% (placebo: 3%) and apolipoprotein A-1 by 8 and 11% (placebo: 4%).
In the Scandinavian Simvastatin Survival Study (4S), Lipex reduced the risk of death, coronary death, non-fatal MI and undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty) in patients with CHD and hypercholesterolaemia.
In 4S, the effect of therapy with Lipex on total mortality was assessed in 4444 patients with CHD and baseline total-C 5.5-8.0 mmol/L. In this multicentre, randomised, double-blind, placebo-controlled study, patients with angina or a previous MI were treated with diet and standard care and either with Lipex 20-40 mg daily (n = 2221) or placebo (n = 2223) for a median duration of 5.4 years. Eighty-two percent (82%) of the subjects were male. Over the course of the study, treatment with Lipex led to mean reductions in total-C, LDL-C, and TG of 25%, 35%, and 10% respectively, and a mean increase in HDL-C of 8%. Lipex reduced the risk of death by 30% (95% confidence interval 15-42%; p=0.0003 (182 deaths in the Lipex group vs 256 deaths in the placebo group)). The risk of CHD death was reduced by 42% (95% CI 27-54%; p = 0.00001 (111 vs 189)). Lipex also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent non-fatal MI) by 34% (95% CI 25-41%; p < 0.00001 (431 patients vs 622 patients with one or more events)). The risk of having a hospital verified nonfatal MI was reduced by 37%. Lipex reduced the risk for undergoing myocardial revascularisation procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (95% CI 26-46%; p < 0.00001 (252 patients vs 383 patients)).
Furthermore, Lipex significantly reduced the risk of fatal plus non-fatal cerebrovascular events (stroke and transient ischaemic attacks) by 28% (95% CI 3-46% (p=0.033, 75 patients vs 102 patients)). There was no statistically significant difference between groups in non-cardiovascular mortality. Lipex reduced the risk of major coronary events to a similar extent across the range of baseline total-C and LDL-C levels.
The risk of death in patients ≥ 60 years of age was decreased by 27% and in patients < 60 years of age by 37% (95% CI 12-55%; p < 0.01 in both age groups). Because there were only 53 female deaths, the effect of Lipex on mortality in women could not be adequately assessed. However, Lipex lessened the risk of having major coronary events by 34% (95% CI 9-52%; p = 0.012 (60 women vs 91 women with one or more event)). In a post hoc analysis in patients with diabetes mellitus and CHD, the risk of major coronary events was reduced by 55% (95% CI 24-73%; p = 0.002 (24 patients vs 44 patients)). Since there were only 39 deaths among diabetic patients (15 among simvastatin-treated patients and 24 among placebo treated patients), the effect of Lipex on mortality in diabetic patients could not be adequately assessed. It should be noted that 4S excluded patients with triglycerides > 2.5 mmol/L or with severe cardiac or renal disease.
In the Multicenter Anti-Atheroma Study (MAAS), the effect of therapy with simvastatin on coronary atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolaemic men and women with coronary heart disease. In this randomised, double-blind, controlled clinical trial, 404 patients with total-C values of 5.5 to 8.0 mmol/L and a mean baseline LDL-C value of 4.4 mmol/L were treated with conventional measures and with simvastatin 20 mg/d or placebo. Eighty-nine percent (89%) of the subjects were male. Angiograms were evaluated at baseline, two and four years. A total of 347 patients had a baseline angiogram and at least one follow-up angiogram. In the patients who received placebo, coronary atherosclerotic lesions worsened in a near-linear manner.
In contrast, simvastatin significantly slowed the progression of lesions as measured in the final angiogram by the mean change per patient in minimum (p=0.005) and mean (p=0.026) lumen diameters (co-primary endpoints, indicating focal and diffuse disease, respectively), as well as in percent diameter stenosis (p=0.003). Simvastatin also significantly decreased the proportion of patients with new lesions (13% simvastatin vs 24% placebo, p=0.009) and with new total occlusions (5% vs 11%, p=0.04). In interpreting these results, it is important to be aware of the limitations of angiography, which may underestimate the extent and severity of atherosclerosis. In addition, angiography cannot be used to predict the site of future coronary occlusion. Acute ischaemic events tend to occur not at the site of severe stenoses but at lesser stenoses which are lipid-rich, soft and more prone to rupture.
In MAAS, Lipex slowed the progression of coronary atherosclerosis and reduced the development of both new lesions and new total occlusions, whereas coronary atherosclerotic lesions steadily worsened over four years in patients receiving standard care.

High risk of coronary heart disease (CHD) or existing coronary heart disease.

The Heart Protection Study (HPS) was a large, multicenter, randomised, placebo-controlled, double-blind study with a mean duration of 5.3 years conducted in 20,536 patients (10,269 on Lipex 40 mg and 10,267 on placebo). Patients were 40-80 years of age and at high risk of developing a major coronary event based on 3 main categories of past medical history: coronary disease (definite or probable clinical diagnosis of MI, unstable angina, stable angina, PTCA or CABG); occlusive disease of non-coronary arteries (clinical, angiographic or ultrasound diagnosis of carotid artery stenosis (e.g. TIA or non-disabling stroke not thought to be haemorrhagic), carotid endarterectomy, leg artery stenosis (e.g. intermittent claudication) or surgery); or diabetes mellitus (clinical diagnosis of insulin-dependent or maturity-onset diabetes). LDL-C levels were assayed using a direct method and collected without regard for meals (results are about 5% lower than fasting sample). At baseline, 3,421 patients (17%) had LDL-C levels below 2.6 mmol/L; 7,068 patients (34%) had levels greater than 2.6 mmol/L and less than 3.4 mmol/L; and 10,047 patients (49%) had levels greater than or equal to 3.4 mmol/L. At baseline, 2030 (19.8%) patients in the simvastatin group and 2042 (19.9%) in the placebo group had total-C less than 5.0 mmol/L; 3942 (38.4%) patients in the simvastatin group and 3941 (38.4%) in the placebo group had levels greater than or equal to 5.0 mmol/L and less than 6.0 mmol/L; and 4297 (41.8%) patients in the simvastatin group and 4284 (41.7%) in the placebo group had levels greater than or equal to 6.0 mmol/L.
The major cardiovascular events prevented were non-fatal myocardial infarction, CHD death, stroke and revascularisation procedures. The HPS results showed that Lipex 40 mg/day significantly reduced total and CHD mortality (with no evidence of any increase in non-CHD mortality); major coronary events (a composite endpoint comprised of nonfatal MI or CHD deaths); stroke; coronary revascularisation procedures; hospitalisation for angina; and major vascular events, a composite endpoint which was comprised of major coronary events, stroke, or revascularisation procedures (see Table 6). Risk reductions of approximately one-quarter were observed for major vascular events, major coronary events, and stroke. These risk reductions are underestimates due to the fact that 33% of the patients in the intention-to-treat analysis did not comply with the study protocol (i.e. patients allocated placebo took a statin, or patients allocated Lipex did not take the study drug). Thus, by five years, Lipex taken consistently would be expected to reduce the risk of these events by about one-third.

The effects of Lipex on major vascular events and major coronary events were similar in all subgroups of patients (see Figure 1).

The risk reductions produced by Lipex in both major coronary events and major vascular events were evident and consistent across all baseline characteristics shown in Figure 1. In addition, these risk reductions were evident and consistent regardless of prior treated hypertension, creatinine levels up to the entry limit of 2.3 mg/dL, apolipoprotein A-I and B levels, baseline concomitant cardiovascular medications (i.e. ASA, beta-blockers, ACE inhibitors, or calcium channel blockers), smoking status, alcohol intake, or obesity.

Hypertriglyceridaemia (Fredrickson type IV hyperlipidaemia).

The results of subgroup analyses from a study including a total of 116 patients with hypertriglyceridaemia (Fredrickson type IV hyperlipidaemia) are presented in Table 7. This study was a double blind, placebo controlled, parallel study, comparing Lipex 20, 40, and 80 mg/day with placebo. Each treatment group included approximately 30 patients. The respective baseline values for the type IV patients were: total-C = 6.04 mmol/L; LDL-C = 2.59 mmol/L; HDL-C = 0.91 mmol/L; TG 5.01 mmol/L; VLDL-C = 2.44 mmol/L; non-HDL-C = 5.13 mmol/L. The study demonstrated that Lipex at doses of 20 to 80 mg/day reduced TG 21 to 33% (placebo: 13%), LDL-C 23 to 35% (placebo: +3%), non-HDL-C 26 to 41% (placebo: 1%), and raised HDL-C by 9 to 11% (placebo: 3%).

Dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia).

Table 8 presents the subgroup analysis results of 7 patients with Fredrickson type III hyperlipidaemia (dysbetalipoproteinaemia; apo E2/2 and VLDL-C/TG > 0.25) from a 130-patient double-blind, placebo-controlled, 3-period crossover study. In this study the median baseline values were: total-C = 324 mg/dL (8.39 mmol/L), LDL-C (+ IDL) = 121 (3.13), HDL-C = 31 (0.80), TG = 411 (4.67), VLDL-C (+ IDL) = 170 (4.40), and non-HDL-C = 291 (7.54). At a dosage of 80 mg/day, Lipex reduced LDL-C including intermediate-density lipoproteins (IDL) by 50% (placebo: 8%) and VLDL-C + IDL by 59% (placebo: 4%).

Clinical studies in paediatric patients (10-17 years of age).

In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (HeFH) were randomised to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 4.1 and 10.4 mmol/L and at least one parent with an LDL-C level > 4.9 mmol/L. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.
Lipex significantly decreased plasma levels of total-C, LDL-C, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.
Table 9 shows results after 24 weeks of treatment - the mean achieved LDL-C value was 3.2 mmol/L (range: 1.6-7.5 mmol/L) in the Lipex 40 mg group compared to 5.4 mmol/L (range: 3.3-8.7 mmol/L) in the placebo group.

Simvastatin compared with placebo showed -31.8% vs +1.3% change in LDL level after 8 weeks on 10 mg and -36.4% vs -2.9% after 8 weeks on 20 mg.
The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
The safety and efficacy of simvastatin in children and adolescents with non-familial hypercholesterolaemia, those aged less than 10 years or pre-menarchal girls have not been studied.

5.2 Pharmacokinetic Properties

The inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors). Both are measured in plasma following administration of simvastatin.

Absorption.

In a disposition study with ¹⁴C-labelled simvastatin, 100 mg (20 microCi) of drug was administered as capsules (5 x 20 mg), and blood, urine, and faeces collected. Thirteen percent of the radioactivity was recovered in the urine and 60 percent in faeces. The latter represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Less than 0.5 percent of the dose was recovered in urine as HMG-CoA reductase inhibitors. In plasma, the inhibitors account for 14 percent and 28 percent (active and total inhibitors) of the AUC of total radioactivity, indicating that the majority of chemical species present were inactive or weak inhibitors.
Both simvastatin and β-hydroxyacid are bound to human plasma proteins (95%). The availability of β-hydroxyacid to the systemic circulation following an oral dose of simvastatin was estimated using an I.V. reference dose of β-hydroxyacid; the value was found to be less than 5 percent of the dose.
By analogy to a dog model, simvastatin is well absorbed and undergoes extensive first-pass extraction in the liver, the primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the general circulation is low.

Metabolism.

The major metabolites of simvastatin present in human plasma are β-hydroxyacid and four additional active metabolites. Simvastatin and other HMG-CoA reductase inhibitors are metabolised by CYP 3A4 (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis). In dose-proportionality studies utilising doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the above pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours post dose.
Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.
The pharmacokinetic effects of calcium channel blockers on simvastatin and HMG-CoA reductase inhibitors are summarised in Table 10. The data show increases in simvastatin acid exposure (AUC) with calcium channel blockers (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

A single dose of 2 g niacin extended-release co-administered with 20 mg simvastatin increased the AUC and C_max of simvastatin acid by approximately 60% and 84%, respectively, compared to administration of 20 mg simvastatin alone. In this study, the effect of simvastatin on niacin pharmacokinetics was not measured.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Genotoxicity.

Genetic toxicology studies of simvastatin showed no evidence of mutagenic activity in bacteria or in mammalian cells in vitro, or of clastogenic activity in vitro or in mice in vivo. In vitro and in vivo assays showed that simvastatin does not cause DNA damage in rat hepatocytes.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet for oral administration contains the following non-medicinal ingredients: butylated hydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, pregelatinised maize starch, magnesium stearate, lactose monohydrate, hypromellose, hyprolose, titanium dioxide, purified talc. Each tablet may also contain one or both of the following: iron oxide yellow and iron oxide red.

6.2 Incompatibilities

Not applicable.

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. Avoid transient temperatures above 50°C.

6.5 Nature and Contents of Container

Lipex is supplied in PVC/PE/PVDC/Aluminium blister packs of 30 tablets.

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

Lipex (simvastatin) is a lipid-lowering agent derived synthetically from a fermentation product of Aspergillus terreus.
Simvastatin is described chemically as [1S-[1α, 3α, 7β, 8β (2S*,4S*),8aβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1-naphthalenyl 2,2-dimethylbutanoate.
Its empirical formula is C₂₅H₃₈O₅ and its molecular weight is 418.57.

Chemical structure.

Its structural formula is:

CAS number.

The CAS Registry Number is - CAS-79902-63-9.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

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