Consumer medicine information

Simvastatin Sandoz

Simvastatin

BRAND INFORMATION

Brand name

Simvastatin Sandoz

Active ingredient

Simvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Simvastatin Sandoz.

What is in this leaflet

This leaflet answers some common questions about Simvastatin Sandoz. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risk of you taking this medicine against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Simvastatin Sandoz is used for

Simvastatin Sandoz helps to lower cholesterol and triglyceride levels.

Simvastatin Sandoz is used 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.

Simvastatin Sandoz 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, such as 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 patients with CHD, Simvastatin Sandoz may slow down the hardening of blood vessels and reduces the risk of developing new plaques.

There are different types of cholesterol, called LDL and HDL. 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 a source of energy for the body. However, as with cholesterol, too much triglycerides can be a problem.

How Simvastatin Sandoz works

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

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

Therefore, when you are taking Simvastatin Sandoz, 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 Simvastatin Sandoz). Simvastatin Sandoz has not been studied in children under the age of 10 years. For more information, talk to your doctor.

Ask your doctor if you have any questions about why this medicine was prescribed for you. Your doctor may have prescribed it for another reason.

Simvastatin Sandoz is not addictive.

Before you take Simvastatin Sandoz

When you must not take it

Do not take this medicine if:

  • you have an allergy to Simvastatin Sandoz or other brands of simvastatin or to any of the active ingredient listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, skin rash, itchiness or painful joints.

Do not take this medicine if you have or have had any of the following medical conditions:

  • liver disease
  • muscle pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides.

Do not take this medicine if you are pregnant or breastfeeding. Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to the baby.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal. If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if:

  • you intend to become pregnant or plan to breast feed. Simvastatin Sandoz should not be used during pregnancy or while breast-feeding.
  • 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.
  • you are Asian.
  • you ever had liver disease. Your doctor will do a blood test to make sure you have no problems with your liver.
  • you have kidney problems or any other medical problems
  • you drink alcohol regularly
  • you have allergies to any other medicines, or any other substances, such as foods, preservatives or dyes.

Simvastatin Sandoz contains lactose. If you have been told by your doctor that you have intolerance to some sugars, tell your doctor before taking it.

If you have not told your doctor about any of the above, tell them before you start taking Simvastatin Sandoz.

Taking other medicines

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

Some medicines should not be taken with Simvastatin Sandoz as they may increase the risk of muscle side effects with Simvastatin Sandoz. 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, used to treat HIV infection, including indinavir, nelfinavir, ritonavir and saquinavir
  • 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, fluconazole, posaconazole and voriconazole, used to treat certain fungal infections.

If you are taking any of the medicines listed above, your doctor may suggest stopping Simvastatin Sandoz temporarily or permanently.

Some medicines and Simvastatin Sandoz interfere with each other. Because taking Simvastatin Sandoz 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 used to lower cholesterol levels, e.g. other fibrates (such as gemfibrozil) or nicotinic acid (also known as niacin)
  • warfarin, or other drugs used to prevent blood clots
  • colchicine, used to treat 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 heartbeat.
  • 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 Simvastatin Sandoz, or may affect how well it works or may increase the risk of side effects with Simvastatin Sandoz. You may need to take different amounts of your medicine, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

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

How to take Simvastatin Sandoz

How much to take

Take Simvastatin Sandoz 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 10 mg or 20 mg per day, taken in the evening. To have the best effect, this 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 the lower doses.

For people with CHD or risk factors for CHD, the usual starting dose is 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.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

How to take it

Swallow the tablets with a full glass of water.

If you need to break Simvastatin Sandoz, hold the tablet with both hands and snap along the break line.

When to take Simvastatin Sandoz

Take your medicine 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 they are asleep. Therefore, Simvastatin Sandoz 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 your medicine at about the same time each day. Taking it at the same time each evening will have the best effect. It will also help you remember when to take the tablets.

How long to take Simvastatin Sandoz

Your doctor will determine how long you have to take Simvastatin Sandoz.

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to lower your cholesterol levels, but 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 medicines for the rest of your life. If you stop taking this medicine, your cholesterol levels may rise again.

If you forget to take it

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

Do not take a double dose to make up for the dose you missed. This may increase the chance of getting an unwanted side effect.

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at your nearest hospital, if you think you or anyone else has taken too much Simvastatin Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Simvastatin Sandoz

Things you must do

If you become pregnant while taking Simvastatin Sandoz, stop taking it and contact your doctor immediately.

Have your blood fats checked when your doctor says so, to make sure this medicine is working.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Simvastatin Sandoz.

If you are about to have elective surgery, tell your doctor that you are taking Simvastatin Sandoz. Your doctor may suggest stopping the tablets a few days before surgery.

Things you must not do

Do not stop taking Simvastatin Sandoz without your doctor's permission.

Do not take Simvastatin Sandoz to treat any other complaint unless your doctor tells you to.

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

Things to be careful of

Be careful driving or operating machinery until you know how Simvastatin Sandoz affects you. Simvastatin Sandoz generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, Simvastatin Sandoz may cause dizziness in some people. Make sure you know how you react to Simvastatin Sandoz before you drive a car or operate machinery.

Avoid drinking large quantities of alcohol. Drinking large quantities of alcohol may increase your chance of Simvastatin Sandoz causing liver problems.

Grapefruit juice should be avoided while taking Simvastatin Sandoz. Grapefruit juice contains one or more components that alter the metabolism of some medicines, including Simvastatin Sandoz.

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, a 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 will advise you to stop smoking or at least cut down.

Side effects

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

Simvastatin Sandoz helps most people with high cholesterol, but it may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

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

These are the more common side effects of Simvastatin Sandoz. For the most part, these are mild and short-lived.

Tell your doctor immediately if you notice any of the following:

  • aching muscles, muscle tenderness or weakness, not caused by exercise (in very rare cases this may not go away after stopping Simvastatin Sandoz)
  • brown/black coloured urine.

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 Simvastatin Sandoz, particularly the 80 mg dose
  • older patients (65 years of age and older)
  • female patients
  • patients with abnormal kidney function
  • patients with thyroid problems.

Tell your doctor immediately if you notice any of the following:

  • tingling in the hands or feet
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • larger breasts than normal in men
  • bruising more easily than normal
  • skin rash, itchiness
  • fever, generally feeling unwell
  • pinkish, itchy swellings on the skin, also called hives or nettle rash
  • painful, swollen joints.

These may be serious side effects of Simvastatin Sandoz. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop taking Simvastatin Sandoz and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • swelling of the limbs, face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • shortness of breath
  • itchy rash or hives.

These are serious side effects. You may need urgent medical attention or hospitalisation. Serious side effects are rare.

Also, tell your doctor if you notice:

  • hair loss
  • muscle cramps
  • trouble sleeping
  • poor memory, memory loss, confusion
  • feelings of depression
  • blurred vision and impaired vision
  • erectile dysfunction
  • breathing problems including persistent cough and/or shortness of breath or fever.
  • gynaecomastia (breast enlargement in men) (very rare)
  • muscle rupture (very rare)
  • rash that occur on the skin or sores in the mouth (lichenoid drug eruptions) (very rare)

These are other side effects that have been reported with Simvastatin Sandoz.

Liver problems can also occur and may be serious. Your doctor will do regular blood tests to check your liver.

Tell your doctor immediately if you have the following symptoms of liver problems:

  • feel tired or weak
  • loss of appetite
  • upper belly pain
  • dark urine
  • yellowing of your skin or the whites of your eyes.

Tell your doctor or pharmacist if you notice any other effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Other side effects not listed above may also occur in some people.

After taking Simvastatin Sandoz

Storage

Keep your medicine in the original container.

If you take it out of its container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C. Protect from light.

Do not store Simvastatin Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Simvastatin Sandoz 5 mg: yellow, oval, scored, convex, film-coated tablets, coded 'SIM 5' on one side.

Simvastatin Sandoz 10 mg - pale pink, oval, scored, convex, film-coated tablets, coded 'SIM 10' on one side.

Simvastatin Sandoz 20 mg - orange, oval, scored, convex, film-coated tablets, coded 'SIM 20' on one side.

Simvastatin Sandoz 40 mg - pink, oval, scored, convex, film-coated tablets, coded 'SIM 40' on one side.

Simvastatin Sandoz 80 mg - light green, oval, scored, convex, film-coated tablets, coded 'SIM 80' on one side.

They are available in blisters of 30 tablets.

Ingredients

Active ingredients:

Simvastatin Sandoz 5 mg - 5 mg simvastatin

Simvastatin Sandoz 10 mg - 10 mg simvastatin

Simvastatin Sandoz 20 mg - 20 mg simvastatin

Simvastatin Sandoz 40 mg - 40 mg simvastatin

Simvastatin Sandoz 80 mg - 80 mg simvastatin

Inactive ingredients:

  • pregelatinised maize starch
  • lactose monohydrate
  • microcrystalline cellulose
  • butylated hydroxyanisole
  • ascorbic acid
  • citric acid monohydrate
  • magnesium stearate
  • hypromellose
  • purified talc
  • titanium dioxide
  • iron oxide yellow (Simvastatin Sandoz 5 mg, 10 mg and 20 mg only)
  • iron oxide red (Simvastatin Sandoz 10 mg, 20 mg and 40 mg only)
  • indigo carmine aluminium lake (Simvastatin Sandoz 80 mg only)
  • quinoline yellow aluminium lake (Simvastatin Sandoz 80 mg only).

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Novartis New Zealand Limited
PO Box 99102
Newmarket, Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was revised in April 2021.

Australian Register Numbers

Simvastatin Sandoz 5 mg film-coated tablets: AUST R 114796 (blisters)

Simvastatin Sandoz 10 mg film-coated tablets: AUST R 114797 (blisters)

Simvastatin Sandoz 20 mg film-coated tablets: AUST R 114798 (blisters)

Simvastatin Sandoz 40 mg film-coated tablets: AUST R 114800 (blisters)

Simvastatin Sandoz 80 mg film-coated tablets: AUST R 98624 (blisters)

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Simvastatin Sandoz

Active ingredient

Simvastatin

Schedule

S4

 

1 Name of Medicine

Simvastatin.

2 Qualitative and Quantitative Composition

Each Simvastatin Sandoz 5 mg film coated tablet contains 5 mg simvastatin.
Each Simvastatin Sandoz 10 mg film coated tablet contains 10 mg simvastatin.
Each Simvastatin Sandoz 20 mg film coated tablet contains 20 mg simvastatin.
Each Simvastatin Sandoz 40 mg film coated tablet contains 40 mg simvastatin.
Each Simvastatin Sandoz 80 mg film coated tablet contains 80 mg simvastatin.

Excipient with known effect.

Sugars as lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Simvastatin Sandoz 5 mg film-coated tablets are yellow coated, oval, scored, convex tablets, coded 'SIM 5' on one side.
Simvastatin Sandoz 10 mg film-coated tablets are pale pink coated, oval, scored, convex tablets, coded 'SIM 10' on one side.
Simvastatin Sandoz 20 mg film-coated tablets are orange coated, oval, scored, convex tablets, coded 'SIM 20' on one side.
Simvastatin Sandoz 40 mg film-coated tablets are pink coated, oval, scored, convex tablets, coded 'SIM 40' on one side.
Simvastatin Sandoz 80 mg film-coated tablets are light green coated, oval, scored, convex tablets, coded 'SIM 80' on one side.
Not all strengths may be available in Australia.

4 Clinical Particulars

4.1 Therapeutic Indications

Adjunct to diet for treatment of hypercholesterolaemia.
Prior to initiating therapy with Simvastatin Sandoz, 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.
Simvastatin Sandoz is indicated in patients at high risk of coronary heart disease (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.
Simvastatin Sandoz 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 Simvastatin Sandoz, 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

Dosage.

The dosage range for simvastatin is 10 to 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 four weeks, to a maximum of 80 mg/day given as a single dose in the evening. 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 (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis).

Adults.

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

The usual starting dose of simvastatin 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 Simvastatin Sandoz and should continue on this diet during treatment with Simvastatin Sandoz.
The recommended starting dose is 10 to 20 mg/day given in the evening. Therapy should be individualised according to the patient's response.

Dosage adjustment.

Concomitant therapy.

Simvastatin 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 Simvastatin Sandoz should not exceed 10 mg/day.
In patients taking amiodarone, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with simvastatin, the dose of simvastatin should not exceed 20 mg/day (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients taking amlodipine concomitantly with simvastatin, the dose of simvastatin should not exceed 40 mg/day.
In patients taking niacin (nicotinic acid) ≥ 1 g/day, the dose of simvastatin should not exceed 40 mg/day (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In patients taking lomitapide concomitantly with simvastatin, the dose of simvastatin should not exceed 40 mg/day (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Paediatric use.

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).

Renal impairment.

Simvastatin 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/minute), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

4.3 Contraindications

Hypersensitivity to any component of this preparation.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and lactation (see Section 4.4 Special Warnings and Precautions for Use). Women of childbearing 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 and other inhibitors of HMG-CoA reductase occasionally cause 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 1,399 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 six month controlled clinical studies, there was one case of myopathy among 436 patients taking 40 mg and five 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 simvastatin 80 mg/day (mean follow up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. This includes rhabdomyolysis for which the incidence was 0.1-0.2%, all allocated to simvastatin 80 mg/day. There is no universally accepted definition of rhabdomyolysis. In SEARCH, rhabdomyolysis was defined as a subset of myopathy with CK > 40 x ULN plus evidence of end organ damage (e.g. elevated creatinine, dark urine). Approximately half of all the myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.
The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-base therapies with similar LDL-C lowering efficacy. Therefore the 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 4.2 Dose and Method of Administration; Section 4.3 Contraindications).
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 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, cyclosporin 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 coadministered with statins (see Section 4.3 Contraindications). In patients where the use of systemic fusidic acid is considered essential, statin treatment 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. Simvastatin therapy may be re-introduced 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 patient 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 and see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration of verapamil increased the incidence of myopathy to 0.7% (with simvastatin 40 mg) or 1% (with simvastatin 80 mg).
Coadministration of diltiazem and simvastatin 80 mg led to a mean 70% increase in systemic exposure to simvastatin derived HMG-CoA reductase inhibitory activity, with individual increases ranging up to 200%. In a clinical trial, patients on diltiazem treated concomitantly with simvastatin 80 mg had an approximately 3-fold increased risk of myopathy.

Amlodipine.

In a clinical trial, patients on amlodipine treated concomitantly with simvastatin 80 mg had a slightly increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. The dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine (see Table 1 and 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 coadministering 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 coadministered 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 used 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.

Acipimox.

Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.

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 simvastatin temporarily in patients taking daptomycin (see Section 4.5 Interactions with Other Medicines and Other Forms of 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 Pharmacological Properties).

Diabetes mellitus.

Some evidence suggests that statins as a class raise blood glucose and in some patients at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be the reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI ≥ 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

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 characterised by persistent proximal muscle weakness and elevated serum creatinine kinase, which persists despite discontinuation of statin treatment.

Interstitial lung disease.

Cases of interstitial lung disease have been reported with some statins, including simvastatin especially with long-term therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Presenting features can include dyspnoea, nonproductive 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.

Reduced function of transport proteins.

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (e.g. cyclosporin) or in patients who are carriers of the SLCO1B1 c.521T > C genotype.
Patients carrying the SLCO1B1 gene allele (c.521T > C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin and increased risk of myopathy. Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

Ophthalmological evaluations.

Current long-term data from clinical trials, 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 ophthalmological 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 ageing.

Animal studies.

Cataracts have been detected in two 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 three to eleven 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 thyroxine has been measured at baseline and at the end of simvastatin treatment in 785 patients enrolled in multicenter studies. The results of this analysis indicate that simvastatin has little, if any, effect upon thyroxine activity.
In one study involving 183 patients treated with simvastatin, four patients had thyroid stimulating hormone (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 hepatic impairment.

In clinical studies, persistent increases (to more than three times the 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 concentrations. 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 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 of greater than three times the ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 (0.7%) versus 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 three times the 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 three times the ULN was significantly higher in the simvastatin group in the first year of the study (20 versus 8, p = 0.023), but not thereafter. Elevated transaminases resulted in the discontinuation of eight patients from therapy in the simvastatin group (n = 2,221) and five in the placebo group (n = 2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests at baseline, only eight (0.4%) developed consecutive liver function test elevations to greater than three times the 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 simvastatin 20 mg; 37% were titrated to 40 mg.
In two controlled clinical studies in 1,105 patients, the six 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 simvastatin 40 mg/day or placebo, the incidences of elevated transaminases (greater than three times the ULN confirmed by repeat test) were 0.21% (n = 21) for patients treated with simvastatin 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 three 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 nonfatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with simvastatin, promptly interrupt therapy. If an alternate aetiology is not found do not restart simvastatin.
Patients who develop increased transaminase levels should have the finding confirmed and be followed up thereafter with frequent liver function tests until any abnormality(ies) return to normal. Should an increase in AST or ALT of three times the 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 three times the ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes were not specific to simvastatin and were also observed with comparable lipid lowering agents. They generally appeared within the first three months after initiation of therapy with simvastatin, were often transient and were not accompanied by any symptoms, and interruption of treatment was not required.

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 cholesterol and low density lipoprotein cholesterol levels, was similar to that seen in the population as a whole. There was no apparent increase in the 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 4.4 Special Warnings and Precautions for Use; 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 pre-menarchal girls have not been studied.

Effects on laboratory tests.

Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and gamma-glutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum creatine kinase (CK) levels, derived from skeletal muscle, have been reported (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Increases in HBA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

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 (listed below) 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).
Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite).

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. Coadministration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetics, or both) is yet unknown.
Although interaction studies with statins and fusidic acid have not been conducted, there have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, statin treatment should be discontinued throughout the duration of the 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).

Fluconazole.

Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported.

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 simvastatin with propranolol produced no clinically significant pharmacokinetic or pharmacodynamic interaction.

Antipyrine.

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

Digoxin.

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

Other concomitant therapy.

In clinical studies, simvastatin was used concomitantly with beta-blockers, diuretics and nonsteroidal anti-inflammatory drugs 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 to 80 mg/day for 12 to 48 weeks, basal testosterone levels were mildly decreased during simvastatin therapy, but there were no consistent changes in luteinising hormone and follicle stimulating hormone. In 86 men treated with simvastatin 20 to 80 mg/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)
HMG-CoA reductase inhibitors, including simvastatin, are contraindicated during pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
Atherosclerosis is a chronic process and the discontinuation of lipid lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes.
In two series of 178 and 134 cases where pregnant women took a 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.
Because of the ability of inhibitors of HMG-CoA reductase such as simvastatin, to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, simvastatin is contraindicated during pregnancy. Simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, simvastatin should be discontinued and the patient informed of the potential hazard to the foetus.
Animal studies showed increased incidences of fetal resorption at dosages of 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 fetuses 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 the offspring of rats dosed with simvastatin at dosages of 12.5 to 25 mg/kg/day. There is no information from animal studies on whether simvastatin or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin Sandoz should not breastfeed their infants (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Simvastatin 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)

Simvastatin is generally well tolerated; for the most part adverse effects have been mild and transient in nature. In controlled clinical studies less than 2% of patients were discontinued due to adverse effects attributable to simvastatin.
The clinical adverse events occurring at an incidence of greater than 0.5% in controlled clinical trials and considered to be definitely, probably or possibly due to simvastatin may be grouped as shown in Table 2.
Myopathy has been reported rarely.
In the Heart Protection Study (HPS) (see Section 5.1 Pharmacodynamic Properties, Clinical trials) involving 20,536 patients treated with simvastatin 40 mg/day (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with simvastatin 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 simvastatin compared with 4.3% in patients treated with placebo). The incidence of myopathy was 0.07% in patients treated with simvastatin compared with 0.03% in patients treated with placebo. This includes rhabdomyolysis for which incidences were 0.04% in patients treated with simvastatin compared with 0.01% in patients treated with placebo. Some of these patients were taking simvastatin 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 (greater than three times the ULN confirmed by repeat test) occurred in 0.21% of patients treated with simvastatin compared with 0.09% of patients treated with placebo.
In the Scandinavian Simvastatin Survival Study (4S) (see Section 5.1 Pharmacodynamic Properties, Clinical trials) involving 4,444 patients treated with simvastatin tablets 20 to 40 mg/day (n = 2,221) or placebo (n = 2,223), 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: nightmare, memory loss, sexual dysfunction occurred uncommonly. Pruritus, alopecia, dizziness, muscle cramps, myalgia, depression, pancreatitis, paraesthesia, peripheral neuropathy, peripheral polyneuropathy, memory impairment, insomnia, vomiting, gynaecomastia, anaemia, erectile dysfunction, interstitial lung disease and hepatic failure occurred very rarely.
There have been very rare reports of immune mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterised by: persistent 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 with or without acute renal failure, hepatitis/ jaundice, myositis and polymyositis occurred rarely. 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, increased erythrocyte sedimentation rate (ESR), 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).

Diabetes mellitus.

Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m2, raised triglycerides, history of hypertension (see Section 4.4 Special Warnings and Precautions for Use).

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, Use in hepatic impairment).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

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 simvastatin 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 simvastatin has not been established: depression, erythema multiform including Stevens-Johnson syndrome, leucopenia, 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

Symptoms.

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

Treatment.

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, simvastatin, which is an inactive lactone, is hydrolysed to the corresponding beta-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 simvastatin reduced total plasma cholesterol (total-C), LDL-C and very low density lipoprotein cholesterol (VLDL-C) concentrations. In addition, simvastatin increases HDL-C and reduces plasma triglycerides (TG).
Simvastatin 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 simvastatin 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 simvastatin. Since each LDL particle contains one molecule of Apo B, and since little Apo B is found in other lipoproteins, this strongly suggests that simvastatin 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 simvastatin 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 simvastatin 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.

Simvastatin tablets have been studied in the treatment of primary hypercholesterolaemia where diet alone has been insufficient. Simvastatin was highly effective in reducing total-C and LDL-C in heterozygous familial (Fredrickson type IIa) and nonfamilial forms of hypercholesterolaemia and in mixed hyperlipidaemia (Fredrickson type IIb) when elevated cholesterol was a cause of concern. A marked response was seen within two weeks and the maximum therapeutic response occurred within four to six weeks. The response has been maintained during continuation of therapy. In six controlled clinical studies involving approximately 1,700 patients with normal or slightly raised TGs (mean 1.9 mmol/L), plasma TGs, VLDL-C and Apo B decreased in all studies in a dose dependent manner. In two of these studies in patients with hypercholesterolaemia receiving simvastatin tablets 20 or 40 mg daily for twelve weeks, the results reported in Table 3 were observed.
In a separate study involving 180 patients with combined hyperlipidaemia, simvastatin tablets 10 mg daily 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 TGs, simvastatin consistently reduce total-C, LDL-C, TGs, VLDL-C and Apo B in a dose dependent manner.
The results of four 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 less than or equal to 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, twelve patients 15 to 39 years of age with homozygous familial hypercholesterolaemia received simvastatin 40 mg/day in a single dose or in three divided doses, or 80 mg/day in three 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 coronary heart disease (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 cholestyramine decreased the combined incidence of CHD death plus nonfatal myocardial infarction (MI).
In a randomised, double blind, three period crossover study, 130 patients with combined hyperlipidaemia (LDL-C > 3.4 mmol/L and TG 3.4 to 7.9 mmol/L) were treated with placebo, simvastatin 40 and 80 mg/day for six weeks. In a dose dependent manner simvastatin 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), simvastatin reduced the risk of death, coronary death, nonfatal 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 simvastatin on total mortality was assessed in 4,444 patients with CHD and a baseline total cholesterol of 5.5 to 8.0 mmol/L. In this multicenter, randomised, double blind, placebo controlled study, patients with angina or a previous MI were treated with diet and standard care and either with simvastatin 20 to 40 mg daily (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. 82% of the subjects were male. Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TGs of 25, 35 and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin reduced the risk of death by 30% (95% confidence interval 15 to 42%; p = 0.0003 (182 deaths in the simvastatin group versus 256 deaths in the placebo group)). The risk of CHD death was reduced by 42% [95% confidence interval 27 to 54%; p = 0.00001 (111 versus 189)). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital verified and silent nonfatal MI) by 34% (95% confidence interval 25-41%; p < 0.00001 (431 patients versus 622 patients with one or more events)]. The risk of having a hospital verified nonfatal MI was reduced by 37%. Simvastatin reduced the risk for undergoing myocardial revascularisation procedures [coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (95% confidence interval 26 to 46%; p < 0.00001 (252 patients versus 383 patients)].
Furthermore, simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischaemic attacks) by 28%, (95% confidence interval 3 to 46% (p = 0.033, 75 patients versus 102 patients)). There was no statistically significant difference between groups in noncardiovascular mortality. Simvastatin 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 greater than or equal to 60 years of age was decreased by 27% and in patients < 60 years of age by 37% (95% confidence interval 12 to 55%; p < 0.01 in both age groups). Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin lessened the risk of having major coronary events by 34% (95% confidence interval 9 to 52%; p = 0.012 (60 versus 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% confidence interval 24 to 73%; p = 0.002 (24 patients versus 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 simvastatin 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/day or placebo. 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 versus 24% placebo, p = 0.009) and with new total occlusions (5 versus 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, simvastatin 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 simvastatin 40 mg and 10,267 on placebo). Patients were 40 to 80 years of age and at high risk of developing a major coronary event based on three main categories of past medical history:
1. Coronary disease [definite or probable clinical diagnosis of myocardial infarction (MI), unstable angina, stable angina, percutaneous transluminal coronary arterioplasty (PTCA) or coronary artery bypass graft (CABG)].
2. Occlusive disease of non-coronary arteries (clinical, angiographic or ultrasound diagnosis of carotid artery stenosis (e.g. transient ischaemic attack (TIA) or nondisabling stroke not thought to be haemorrhagic), carotid endarterectomy, leg artery stenosis (e.g. intermittent claudication) or surgery.
3. 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/mL 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, 2,030 (19.8%) patients in the simvastatin group and 2,042 (19.9%) in the placebo group had total-C less than 5.0 mmol/L; 3,942 (38.4%) patients in the simvastatin group and 3,941 (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 4,297 (41.8%) patients in the simvastatin group and 4,284 (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 simvastatin 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 simvastatin did not take the study drug). Thus, by five years, simvastatin taken consistently would be expected to reduce the risk of these events by about one-third.
The effects of simvastatin on major vascular events and major coronary events were similar in all subgroups of patients (see Figure 1).
The risk reductions produced by simvastatin 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. aspirin, beta-blockers, angiotensin converting enzyme (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 simvastatin 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; TGs 5.01 mmol/L; VLDL-C=2.44 mmol/L; nonHDL-C=5.13 mmol/L. The study demonstrated that simvastatin at doses of 20 to 80 mg/day reduced TGs 21 to 33% (placebo 13%), LDL-C 23 to 35% (placebo +3%), nonHDL-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 seven patients with Fredrickson type III hyperlipidaemia (dysbetalipoproteinaemia; Apo E2/2 and VLDL-C/TG > 0.25) from a 130 patient double blind, placebo controlled, three period crossover study. In this study the median baseline values were: total-C=324 mg/dL (8.39 mmol/L), LDL-C (+ intermediate density lipoproteins (IDL))=121 mg/dL (3.13 mmol/L), HDL-C=31 mg/dL (0.80 mmol/L), TG=411 mg/dL (4.67 mmol/L), VLDL-C (+ intermediate density lipoproteins (IDL))=170 mg/dL (4.40 mmol/L), and nonHDL-C=291 mg/dL (7.54 mmol/L). At a dosage of 80 mg/day, simvastatin 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.
Simvastatin 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 simvastatin 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 beta-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. 13% of the radioactivity was recovered in the urine and 60% in faeces. The latter represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Less than 0.5% of the dose was recovered in urine as HMG-CoA reductase inhibitors. In plasma, the inhibitors account for 14 and 28% (active and total inhibitors) of the area under the curve (AUC) of total radioactivity, indicating that the majority of chemical species present were inactive or weak inhibitors.
The availability of beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was estimated using an intravenous reference dose of beta-hydroxyacid; the value was found to be less than 5% of the dose.

Distribution.

Both simvastatin and beta-hydroxyacid are bound to human plasma proteins (95%).

Metabolism.

The major metabolites of simvastatin present in human plasma are beta-hydroxyacid and four additional active metabolites. Simvastatin and other HMG-CoA reductase inhibitors are metabolised by CYP3A4 (see Section 4.4 Special Warnings and Precautions for Use, Myopathy/rhabdomyolysis). In dose proportionality studies utilising doses of simvastatin 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 coadministered with 20 mg simvastatin increased the AUC and Cmax 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).

Excretion.

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.

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 area under the curve (AUC) for enzyme inhibitory activity, were three to eleven 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 doses greater than 5 mg/kg/day and in males at doses greater than 25 mg/kg/day. These thyroid tumours were associated with focal cystic follicular hyperplasia, and may be a secondary effect reflective of a simvastatin mediated enhancement of thyroid hormone clearance by the liver.

6 Pharmaceutical Particulars

6.1 List of Excipients

Simvastatin Sandoz also contains pregelatinised maize starch, lactose monohydrate, microcrystalline cellulose, butylated hydroxyanisole, ascorbic acid, citric acid monohydrate, magnesium stearate, hypromellose, purified talc, titanium dioxide, iron oxide yellow (Simvastatin Sandoz 5 mg, 10 mg and 20 mg only), iron oxide red (Simvastatin Sandoz 10 mg, 20 mg and 40 mg only), indigo carmine aluminium lake (Simvastatin Sandoz 80 mg only) and quinoline yellow aluminium lake (Simvastatin Sandoz 80 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.
Protect from light.

6.5 Nature and Contents of Container

Simvastatin Sandoz film-coated tablets are available in HDPE bottles and PVC/Al blister packs of 30 tablets.
Not all presentations may be available in Australia.

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

Simvastatin is a white or almost white, crystalline powder, practically insoluble in water, very soluble in methylene chloride, freely soluble in alcohol.

Chemical structure.


Chemical name: [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.
Molecular formula: C25H38O5.
Molecular weight: 418.6.

CAS number.

79902-63-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes