Consumer medicine information

Simvastatin Spirit Tablets

Simvastatin

BRAND INFORMATION

Brand name

Simvastatin-Spirit Tablets

Active ingredient

Simvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Simvastatin Spirit Tablets.

What is in this leaflet

This leaflet answers some common questions about SIMVASTATIN-SPIRIT. 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 risks of you taking SIMVASTATIN-SPIRIT against the benefits they expect it will 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-SPIRIT is used for

SIMVASTATIN-SPIRIT helps to lower cholesterol and triglyceride levels.

SIMVASTATIN-SPIRIT 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-SPIRIT may be used in these people, regardless of their cholesterol level to:

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

Cholesterol

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

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

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

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

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

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

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

Triglycerides

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

How SIMVASTATIN-SPIRIT works

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

SIMVASTATIN-SPIRIT does not reduce the cholesterol and triglycerides that come from fat in food. Therefore, when you are taking SIMVASTATIN-SPIRIT, 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.

SIMVASTATIN-SPIRIT is not recommended for use in children, as there have been no studies of its effects in children.

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

SIMVASTATIN-SPIRIT is not addictive.

Before you take SIMVASTATIN-SPIRIT

When you must not take it

Do not take SIMVASTATIN-SPIRIT if:

  • you have an allergy to SIMVASTATIN-SPIRIT, other brands of simvastatin, or any of the ingredients listed at the end of this leaflet
    Symptoms of an allergic reaction may include skin rash, itchiness, shortness of breath, swelling of the tongue or face, or painful joints.
  • you are pregnant or breast-feeding
    Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to the baby.
  • you have liver disease
  • you have had muscle pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.
    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 SIMVASTATIN-SPIRIT, talk to your doctor.

Before you start to take it

Tell your doctor if:

  1. you intend to become pregnant or plan to breast-feed.
    SIMVASTATIN-SPIRIT should not be used during pregnancy or while breastfeeding.
  2. 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.
  3. you are taking niacin or a niacin-containing product, particularly if you are Chinese.
  4. you have ever had liver disease.
    Your doctor will do a blood test to make sure you have no problems with your liver.
  5. you have kidney disease or any other medical problems.
  6. you drink alcohol regularly.
  7. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you take any SIMVASTATIN-SPIRIT.

Taking other medicines

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

Some medicines should not be taken with SIMVASTATIN-SPIRIT as they may increase the risk of muscle side effects with SIMVASTATIN-SPIRIT. It is particularly important to tell your doctor if you are taking:

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

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

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

  • other medicines to lower cholesterol levels, for example, other fibrates, nicotinic acid (also known as niacin)
  • verapamil, diltiazem or amlodipine used to treat high blood pressure, angina or other heart conditions
  • warfarin, or other drugs used to prevent blood clots
  • colchicine, used for gout
  • amiodarone, used to treat irregular heart beat
  • digoxin, used to treat heart failure

Tell your doctor if you are taking nicotinic acid (also known as niacin) or a nicotinic acid containing product and you are Chinese.

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

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

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

How to take SIMVASTATIN-SPIRIT

How much to take

Take SIMVASTATIN-SPIRIT 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.

The recommended starting dose is 10 mg or 20 mg per day, taken in the evening, which may need to be increased up to 80 mg daily to have the best effect.

Because of the increased risk of muscle problems, the 80 mg dose is only for patients at high risk of heart disease problems who have not reached their cholesterol goal on lower doses.

People with CHD or risk factors for CHD are usually started on 40 mg per day, taken in the evening.

Swallow SIMVASTATIN-SPIRIT with a glass of water.

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

They may differ from the information contained in this leaflet.

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

When to take it

Take SIMVASTATIN-SPIRIT once a day in the evening.

The liver produces its greatest amount of cholesterol when the body is at rest and when there is no dietary intake. For most people, this is at night when asleep. Therefore, SIMVASTATIN-SPIRIT 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 SIMVASTATIN-SPIRIT at about the same time each evening.

Taking your tablet(s) at the same time each evening will have the best effect. It will also help you remember when to take the tablets.

How long to take it

SIMVASTATIN-SPIRIT helps lower your cholesterol. It does not cure your condition. Therefore, you must continue to take it as directed by your doctor if you expect to lower your cholesterol and keep it down. You may have to take cholesterol-lowering medicine for the rest of your life. If you stop taking SIMVASTATIN-SPIRIT, your cholesterol levels may rise again.

If you forget to take it

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

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

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

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

If you take too much (overdose)

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

While you are using SIMVASTATIN-SPIRIT

Things you must do

If you become pregnant while you are taking SIMVASTATIN-SPIRIT, stop taking it and contact your doctor immediately.

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

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

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

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

Things you must not do

Do not give SIMVASTATIN-SPIRIT to anyone else, even if they have the same condition as you.

Things to be careful of

Avoid drinking large quantities of alcohol.

Drinking large quantities of alcohol may increase your chance of SIMVASTATIN-SPIRIT causing liver problems.

Grapefruit juice should be avoided while taking SIMVASTATIN-SPIRIT.

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

Be careful driving or operating machinery until you know how SIMVASTATIN-SPIRIT affects you.

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

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

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

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

  • Diet - continue the low fat diet recommended by your doctor, dietician or pharmacist.
  • Weight - your doctor may advise you to lose weight if you are overweight.
  • Exercise - make exercise a part of your routine – walking is good. Ask your doctor for advice before starting exercise.
  • Smoking - your doctor may advise you to stop smoking or at least cut down.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking SIMVASTATIN-SPIRIT.

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

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

Tell your doctor 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-SPIRIT. For the most part, these have been 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-SPIRIT)
  • 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-SPIRIT, 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
  • fever, generally feeling unwell
  • skin rash, itchiness
  • pinkish, itchy swellings on the skin, also called hives or nettlerash
  • painful, swollen joints
  • bruising more easily than normal
  • larger breasts than normal in men

These may be serious side effects of SIMVASTATIN-SPIRIT. Some of these may be symptoms of an allergic reaction to SIMVASTATIN-SPIRIT. You may need urgent medical attention. Serious side effects are rare.

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

  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in swallowing or breathing
  • shortness of breath

These are serious side effects. If you have them, you may have had a serious allergic reaction to SIMVASTATIN-SPIRIT. 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
  • erectile dysfunction
  • breathing problems including persistent cough and/or shortness of breath or fever

These are other side effects that have been reported with simvastatin.

Liver problems can also occur and may be serious. Your doctor will do 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

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using SIMVASTATIN-SPIRIT

Storage

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

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

Keep SIMVASTATIN-SPIRIT in a cool dry place where the temperature stays below 25°C. Do not store it or any other medicine in the bathroom or near a sink.

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

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

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

Disposal

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

Product description

What it looks like

SIMVASTATIN-SPIRIT comes in four types of tablets:

  • SIMVASTATIN-SPIRIT simvastatin 10 mg - pink coloured, shield-shaped tablet with "SV 10" marked on one side
  • SIMVASTATIN-SPIRIT simvastatin 20 mg - tan coloured, shield-shaped tablet with "SV 20" marked on one side
  • SIMVASTATIN-SPIRIT simvastatin 40 mg - pink coloured, shield-shaped tablet with "SV 40" marked on one side.
  • SIMVASTATIN-SPIRIT simvastatin 80 mg - pink coloured, capsule-shaped tablet with "SV 80" marked on one side.

SIMVASTATIN-SPIRIT comes in blister packs containing 30 tablets.

Ingredients

Active ingredient:

  • SIMVASTATIN-SPIRIT 10 mg simvastatin per tablet
  • SIMVASTATIN-SPIRIT 20 mg simvastatin per tablet
  • SIMVASTATIN-SPIRIT 40 mg simvastatin per tablet
  • SIMVASTATIN-SPIRIT 80 mg simvastatin per tablet

Inactive ingredients:

  • butylated hydroxyanisole
  • ascorbic acid
  • citric acid monohydrate
  • cellulose-microcrystalline
  • starch - pregelatinised maize
  • magnesium stearate
  • lactose
  • purified talc
  • Opadry II Pink 40L14842 (10 mg only)
  • Opadry II Flesh Y-22-13577 (20 mg only)
  • Opadry II Pink 32K14834 (40 mg only)
  • Opadry II Pink 40L14278 (80 mg only)

The tablets are gluten free.

Sponsor

SIMVASTATIN-SPIRIT is supplied in Australia by:

Spirit Pharmaceuticals Pty Ltd
117 Harrington Street,
The Rocks, Sydney NSW 2000
Australia
1800 065 772

Australian Register Numbers:
SIMVASTATIN-SPIRIT simvastatin 10 mg Blister pack AUST R 116701
SIMVASTATIN-SPIRIT simvastatin 20 mg Blister pack AUST R 116702
SIMVASTATIN-SPIRIT simvastatin 40 mg Blister pack AUST R 116704
SIMVASTATIN-SPIRIT simvastatin 80 mg Blister pack AUST R 116705

This leaflet was prepared in April 2013.

BRAND INFORMATION

Brand name

Simvastatin-Spirit Tablets

Active ingredient

Simvastatin

Schedule

S4

 

Name of the medicine

Simvastatin.

Excipients

Lactose, microcrystalline cellulose, pregelatinised maize starch, ascorbic acid, monohydrate citric acid, butylated hydroxyanisole, purified talc, magnesium stearate and Opadry II pale yellow Y-22-12720 (5 mg only), Opadry II pink 40L14842 (10 mg only), Opadry II flesh Y-22-13577 (20 mg only), Opadry II pink 32K14834 (40 mg only), Opadry II pink 40L14278 (80 mg only). All tablets are gluten free.

Description

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. MW: 418.57. CAS: 79902-63-9. Simvastatin is a white crystalline powder, practically insoluble in water and freely soluble in chloroform, methanol and ethanol.

Pharmacology

Simvastatin is a lipid lowering agent derived synthetically from a fermentation product of Aspergillus terreus.

Clinical pharmacology.

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 β-hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme which catalyses an early and rate limiting step in the biosynthesis of cholesterol. As a result, in clinical studies 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.

Pharmacokinetics.

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

Absorption & excretion.

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

Metabolism.

The major metabolites of simvastatin present in human plasma are β-hydroxyacid and four additional active metabolites. Simvastatin and other HMG-CoA reductase inhibitors are metabolised by CYP3A4 (see Precautions, Myopathy/ rhabdomyolysis). In dose proportionality studies utilising doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the above pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours postdose.
Although the mechanism is not fully understood, cyclosporin 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.
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 Precautions, Myopathy/ rhabdomyolysis and Interactions with Other Medicines).

Clinical Trials

Simvastatin has 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 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response has been maintained during continuation of therapy. In six controlled clinical studies involving approximately 1700 patients with normal or slightly raised TG (mean 1.9 mmol/L), plasma TG, VLDL-C and Apo B decreased in all studies in a dose dependent manner. In two of these studies in patients with hypercholesterolaemia receiving simvastatin 20 or 40 mg/day for 12 weeks, the following results were observed. (See Table 1.)
In a separate study involving 180 patients with combined hyperlipidaemia, simvastatin 10 mg/day for 17 weeks was also shown to be effective in lowering total-C, LDL-C, VLDL-C, TGs and Apo B. (See Table 2.)
The data from these studies demonstrate that in patients with hypercholesterolaemia and normal or slightly raised TG, simvastatin consistently reduces total-C, LDL-C, TG, VLDL-C and Apo B in a dose dependent manner. The results of 4 separate studies depicting the dose response to simvastatin in patients with primary hypercholesterolaemia are presented in Table 3.
In the upper dose comparative study, one third of patients obtained a reduction in LDL-C of 53% or more at the 80 mg dose. The percent reduction in LDL-C was essentially independent of the baseline level. In contrast, the percent reduction in TG was related to the baseline level of TG. Of the 664 patients randomised to 80 mg, 475 patients with plasma TG ≤ 2.25 mmol/L had a median reduction in TG of 21%, while in 189 patients with hypertriglyceridemia (> 2.25 mmol/L), the median reduction in TG was 36%. In these studies, patients with TG > 4.0 mmol/L were excluded.
In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolaemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. The mean LDL-C reductions for the 40 mg and 80 mg doses were 14% and 25%, respectively. One of the twelve patients in this study had complete absence of LDL receptor function (receptor ‘deficient’). In this patient, LDL-C reduction of 41% occurred with the 80 mg dose. The magnitude of response to therapy with simvastatin was not predictable by the LDL receptor gene defects as patients with some LDL receptor mutations responded differently to the same dose of simvastatin therapy. Five of the twelve patients were also receiving probucol.
The value of drug and/or diet induced reduction in plasma cholesterol is no longer controversial. The benefits of reducing LDL-C on morbidity and mortality due to CHD have been established. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) demonstrated in a seven year, double blind, placebo controlled study that lowering LDL-C with diet and cholestyramine decreased the combined incidence of CHD death plus nonfatal myocardial infarction (MI).
In a randomised, double blind, 3 period crossover study, 130 patients with combined hyperlipidaemia (LDL-C > 3.4 mmol/L and TG: 3.4-7.9 mmol/L) were treated with placebo, simvastatin 40, and 80 mg/day for 6 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 4444 patients with CHD and baseline total-C 5.5-8.0 mmol/L. In this multicentre, randomised, double blind, placebo controlled study, patients with angina or a previous MI were treated with diet and standard care and either with simvastatin 20-40 mg daily (n = 2221) or placebo (n = 2223) for a median duration of 5.4 years. Eighty two percent (82%) of the subjects were male. Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C, and TG of 25%, 35%, and 10% respectively, and a mean increase in HDL-C of 8%. Simvastatin reduced the risk of death by 30%, 95% confidence interval 15-42%, p = 0.0003 (182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD death was reduced by 42%, 95% CI 27-54%, p = 0.00001 (111 vs 189). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital verified and silent nonfatal MI) by 34%, 95% CI 25-41%, p < 0.00001 (431 patients vs 622 patients with one or more events). The risk of having a hospital verified nonfatal MI was reduced by 37%. Simvastatin reduced the risk for undergoing myocardial revascularisation procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%, 95% CI 26-46%, p < 0.00001 (252 patients vs 383 patients).
Furthermore, simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischaemic attacks) by 28%, 95% CI 3-46% (p = 0.033, 75 patients vs 102 patients). There was no statistically significant difference between groups in 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 ≥ 60 years of age was decreased by 27% and in patients < 60 years of age by 37%, 95% CI 12-55% (p < 0.01 in both age groups). The effect of simvastatin on mortality in women could not be adequately assessed, because there were only 53 female deaths. However, simvastatin lessened the risk of having major coronary events by 34%, 95% CI 9-52% (p = 0.012, 60 women vs 91 women with one or more event). In a post hoc analysis in patients with diabetes mellitus and CHD, the risk of major coronary events was reduced by 55%, 95% CI 24-73% (p = 0.002, 24 patients vs 44 patients). Since there were only 39 deaths among diabetic patients (15 among simvastatin treated patients and 24 among placebo treated patients), the effect of 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/d or placebo. Eighty nine percent (89%) of the subjects were male. Angiograms were evaluated at baseline, two and four years. A total of 347 patients had a baseline angiogram and at least one follow-up angiogram. In the patients who received placebo, coronary atherosclerotic lesions worsened in a near linear manner.
In contrast, simvastatin significantly slowed the progression of lesions as measured in the final angiogram by the mean change per patient in minimum (p = 0.005) and mean (p = 0.026) lumen diameters (coprimary endpoints, indicating focal and diffuse disease, respectively), as well as in percent diameter stenosis (p = 0.003). Simvastatin also significantly decreased the proportion of patients with new lesions (13% simvastatin vs 24% placebo, p = 0.009) and with new total occlusions (5% vs 11%, p = 0.04). In interpreting these results, it is important to be aware of the limitations of angiography, which may underestimate the extent and severity of atherosclerosis. In addition, angiography cannot be used to predict the site of future coronary occlusion. Acute ischaemic events tend to occur not at the site of severe stenoses but at lesser stenoses which are lipid rich, soft and more prone to rupture.
In MAAS, 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 40-80 years of age and at high risk of developing a major coronary event based on 3 main categories of past medical history: coronary disease (definite or probable clinical diagnosis of MI, unstable angina, stable angina, PTCA or CABG); occlusive disease of noncoronary arteries (clinical, angiographic or ultrasound diagnosis of carotid artery stenosis (eg. TIA or nondisabling stroke not thought to be haemorrhagic), carotid endarterectomy, leg artery stenosis (eg. intermittent claudication) or surgery); or diabetes mellitus (clinical diagnosis of insulin dependent or maturity onset diabetes). LDL-C levels were assayed using a direct method and collected without regard for meals (results are about 5% lower than fasting sample). At baseline, 3,421 patients (17%) had LDL-C levels below 2.6 mmol/L; 7,068 patients (34%) had levels greater than 2.6 mmol/L and less than 3.4 mmol/L; and 10,047 patients (49%) had levels greater than or equal to 3.4 mmol/L. At baseline, 2030 (19.8%) patients in the simvastatin group and 2042 (19.9%) in the placebo group had total-C less than 5.0 mmol/L; 3942 (38.4%) patients in the simvastatin group and 3941 (38.4%) in the placebo group had levels greater than or equal to 5.0 mmol/L and less than 6.0 mmol/L; and 4297 (41.8%) patients in the simvastatin group and 4284 (41.7%) in the placebo group had levels greater than or equal to 6.0 mmol/L.
The major cardiovascular events prevented were nonfatal 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 4). 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. ASA, beta blockers, ACE inhibitors, or calcium channel blockers), smoking status, alcohol intake, or obesity.

Hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

The results of subgroup analyses from a study including a total of 116 patients with hypertriglyceridaemia (Fredrickson type lV hyperlipidemia) are presented in Table 5. 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 lV patients were: total-C = 6.04 mmol/L; LDL-C = 2.59 mmol/L; HDL-C = 0.91 mmol/L; TG 5.01 mmol/L; VLDL-C = 2.44 mmol/L; non-HDL-C = 5.13 mmol/L. The study demonstrated that simvastatin at doses of 20 to 80 mg/day reduced TG 21 to 33% (placebo: 13%), LDL-C 23 to 35% (placebo: +3%), non-HDL-C 26 to 41% (placebo: 1%), and raised HDL-C by 9 to 11% (placebo: 3%).

Dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).

Table 6 presents the subgroup analysis results of 7 patients with Fredrickson type lll hyperlipidemia (dysbetalipoproteinemia; apo E2/2 and VLDL-C/TG > 0.25) from a 130 patient double blind, placebo controlled, 3 period crossover study. In this study the median baseline values were: total-C = 324 mg/dL (8.39 mmol/L), LDL-C (+IDL) = 121 (3.13), HDL-C = 31 (0.80), TG = 411 (4.67), VLDL-C (+IDL) = 170 (4.40), and non-HDL-C = 291 (7.54). At a dosage of 80 mg/day, simvastatin reduced LDL-C including intermediate density lipoproteins (IDL) by 50% (placebo: 8%) and VLDL-C + IDL by 59% (placebo: 4%).

Indications

Simvastatin is indicated as an adjunct to diet for treatment of hypercholesterolaemia.
Prior to initiating therapy with simvastatin, 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 is indicated in patients at high risk of CHD (with or without hypercholesterolaemia) including patients with diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or with existing CHD to reduce the risk of cardiovascular death, major cardiovascular events including stroke, and hospitalisation due to angina pectoris.
These effects do not replace the need to independently control known causes of cardiovascular mortality and morbidity such as hypertension, diabetes and smoking.

Contraindications

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

Precautions

Myopathy/ rhabdomyolysis.

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
In 4S, there was one case of myopathy among 1399 patients taking simvastatin 20 mg/day and no cases among 822 patients taking 40 mg/day for a median duration of 5.4 years. In two 6 month controlled clinical studies, there was one case of myopathy among 436 patients taking 40 mg and 5 cases among 669 patients taking 80 mg.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/ rhabdomyolysis is dose related for simvastatin.
The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin based therapies with similar LDL-C lowering efficacy. Therefore the 80 mg dose of simvastatin should only be used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. In patients taking simvastatin 80 mg for whom an interacting agent is needed, a lower dose of simvastatin or an alternative statin based regimen with less potential for drug-drug interactions should be used (see Contraindications and Dosage and Administration).
All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms and 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 Adverse 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 simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
80 mg had an approximately 3-fold increased risk of myopathy.
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 (eg. itraconazole, ketoconazole, posaconazole, voriconizole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir or nefazodone) 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 treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment (see Contraindications and Interactions with Other Medicines).

Gemfibrozil, cyclosporin or danazol.

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

Fusidic acid.

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

Other medicines.

Amiodarone.

In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. In the same clinical trial, there were no cases of myopathy reported in patients receiving simvastatin 20 mg and amiodarone (see Table 7). The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone (see Dosage and Administration and Interactions with Other Medicines).

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 7 and Dosage and Administration, Interactions with Other Medicines).

Amlodipine.

In a clinical trial, patients on amlodipine treated concomitantly with simvastatin 80 mg had a slightly increased risk of myopathy. The dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine (see Table 7 and Dosage and Administration and Interactions with Other Medicines).

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.

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.
The incidence of myopathy is higher in Chinese than in non-Chinese patients, and caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) coadministered with lipid modifying doses (≥ 1 g/day) of niacin or niacin containing products. Because the risk of myopathy is dose related, the use of simvastatin 80 mg with lipid modifying doses (≥ 1 g/day) of niacin or niacin containing products is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy with co administration in other Asian patients.
Prescribing recommendations for interacting agents are summarised in Table 7 (further details are provided in the text (see also Interactions with Other Medicines and Clinical pharmacology).

Hepatic effects.

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

Ophthalmic evaluations.

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

Animal studies.

Cataracts have been detected in 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 3-11 times higher than those in humans receiving the maximum daily dose of 80 mg, whereas serum levels at the no effect level in dogs were approximately twofold 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 multicentre 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 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.

Interstitial lung disease.

Cases of interstitial lung disease have been reported with some statins, including simvastatin especially with long term therapy (see Adverse Effects). Presenting symptoms 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.

Effects on fertility, spermatogenesis and testosterone.

In several studies of over 800 men with hypercholesterolaemia treated with simvastatin 20 mg to 80 mg per day for 12 to 48 weeks, basal testosterone levels were mildly decreased during simvastatin therapy, but there were no consistent changes in LH and FSH. In 86 men treated with simvastatin 20 mg to 80 mg per day, there was no impairment of hCG stimulated testosterone secretion.
Testicular degeneration has been seen in two dog safety studies with simvastatin. Special studies designed to further define the nature of these changes have not met with success since the effects are poorly reproducible and unrelated to dose, serum cholesterol levels, or duration of treatment. Simvastatin has been administered for up to two years to dogs at a dose of 50 mg/kg/day without any testicular effects.
Fertility of male and female rats was unaffected at oral doses up to 25 mg/kg/day.

Use in pregnancy.

(Category D)
HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series 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 include limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetal 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 inhibitor is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist.
Atherosclerosis is a chronic process and the discontinuation of lipid lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for foetal development, including synthesis of steroids and cell membranes.
Simvastatin is contraindicated during pregnancy 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 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 foetal 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 foetuses of rats dosed with the active metabolite of simvastatin, L-654,969, at a dose level of 60 mg/kg/day. The no effect dose level of this teratogenic activity has not been established. Other inhibitors of HMG-CoA reductase have also been shown to induce skeletal malformations in rats, and the teratogenic effects may be due to the enzyme inhibitory activity of such drugs. The relevance of these findings to humans is not known.

Use in lactation.

Animal studies have shown that weight gain during lactation is reduced in offspring of rats dosed with simvastatin at dosages of 12.5 to 25 mg/kg/day. There is no information from animal studies on whether simvastatin or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking simvastatin should not breast feed their infants (see Contraindications).

Carcinogenicity in animal studies.

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

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.

Paediatric use.

Studies to show safety and effectiveness in children have not been carried out. Simvastatin is not recommended for paediatric use at this time.

Elderly.

In controlled clinical trials, the efficacy of simvastatin for patients over the age of 65 years, as assessed by reduction in total-C and LDL-C levels, was similar to that seen in the population as a whole. There was no apparent increase in the 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.

Interactions

CYP3A4 interactions.

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

Contraindicated medicines.

Concomitant use of the following medicines is contraindicated.

Potent CYP3A4 inhibitors.

Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Concomitant use with medicines labelled as having a potent inhibitory effect on CYP3A4 (eg. itraconazole, ketoconazole, posaconazole, voriconizole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir or nefazodone) is contraindicated (see Contraindications, Precautions, Myopathy/ rhabdomyolysis and Pharmacology, Pharmacokinetics).

Gemfibrozil, cyclosporine or danazol.

See Contraindications, Precautions, 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 pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins. Where the use of fusidic acid is considered essential, simvastatin should be discontinued throughout the duration of fusidic acid treatment (see Contraindications and Precautions, Myopathy/ rhabdomyolysis).

Other interactions.

Amiodarone.

The risk of myopathy/ rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin [see Dosage and Administration and Precautions, Myopathy/ rhabdomyolysis].

Calcium channel blockers.

The risk of myopathy/ rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine (see Dosage and Administration and Precautions, 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.

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 Precautions, 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.

Other fibrates.

The risk of myopathy is increased by gemfibrozil (see 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 Contraindications and Precautions, 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 during simvastatin therapy, grapefruit juice should be avoided during simvastatin therapy (see Precautions, 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.

Propanolol.

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 (NSAIDS) without evidence of clinically significant adverse interactions.

Adverse 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 percent 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 are considered to be definitely, probably or possibly due to simvastatin may be grouped as follows. (See Table 8.)
Myopathy has been reported rarely.
In HPS (see Clinical Trials) involving 20,536 patients treated with 40 mg/day of simvastatin (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 Precautions, Myopathy/ rhabdomyolysis). Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21% of patients treated with simvastatin compared with 0.09% of patients treated with placebo.
In 4S (see Clinical Trials) involving 4444 patients treated with 20-40 mg/day of simvastatin (n = 2221) or placebo (n = 2223), the safety and tolerability profiles were comparable between treatment groups over the median 5.4 years of the study.
The following additional adverse effects were reported either in uncontrolled clinical trials or in marketed use: pruritus, alopecia, dizziness, muscle cramps, myalgia, depression, pancreatitis, paraesthesia, peripheral neuropathy, vomiting, gynaecomastia, anaemia, memory impairment, insomnia, erectile dysfunction and interstitial lung disease.
There have been very rare reports of immune mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see Precautions, Myopathy/ rhabdomyolysis).
Rhabdomyolysis and hepatitis/ jaundice occurred rarely and hepatic failure occurred very rarely. An apparent hypersensitivity syndrome that included some of the following features has been reported rarely: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.
There have been rare postmarketing reports of cognitive impairment (e.g memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

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 Precautions, Hepatic effects).

Adverse effects, causal relationship unknown.

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

Dosage and Administration

The dosage range for simvastatin is 10-80 mg/day, given as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80 mg dose of simvastatin should be used only for those patients who have not achieved their LDL-C goal utilizing the 40 mg dose (see Precautions, Myopathy/ rhabdomyolysis).

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

Concomitant therapy.

Simvastatin is effective alone or in combination with bile acid sequestrants.
In patients taking fibrates other than gemfibrozil (see Contraindications) or fenofibrate, the dose of simvastatin should not exceed 10 mg/day.
In patients taking amiodarone, verapamil or diltiazem concomitantly with simvastatin, the dose of simvastatin should not exceed 20 mg/day.
In patients taking amlodipine concomitantly with simvastatin, the dose of simvastatin should not exceed 40 mg/day (see Contraindications, Precautions, Myopathy/ rhabdomyolysis, and Interactions with Other Medicines).
In patients taking niacin (nicotinic acid) ≥ 1 g/day , the dose of simvastatin should not exceed 40 mg/day (see Precautions).

Dosage in renal insufficiency.

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

Overdosage

A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. General measures should be adopted, and liver function should be monitored.
Contact the Poisons Information Centre on 13 11 26 for advice on management of overdose.

Presentation

Tablets (marked on one side), 5 mg* (cream, shield shaped, marked SV 5), 10 mg (pink, shield shaped, marked SV 10), 20 mg (tan, shield shaped, marked SV 20), 40 mg (pink, shield shaped, marked SV 40), 80 mg (pink, capsule shaped, marked SV 80): 30's (blister pack), 30's*, 90's* (60 mL bottle), 300's* (300 mL bottle).
*Not currently marketed in Australia.

Storage

Store below 25°C. Avoid transient temperatures above 50°C. Protect from light and moisture.

Poison Schedule

S4.