Consumer medicine information

APO-Rosuvastatin

Rosuvastatin

BRAND INFORMATION

Brand name

APO-Rosuvastatin

Active ingredient

Rosuvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Rosuvastatin.

What is in this leaflet

Read this leaflet carefully before taking your medicine. This leaflet answers some common questions about rosuvastatin. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Rosuvastatin. It contains the active ingredient rosuvastatin (as rosuvastatin calcium).

This medicine is used to lower high cholesterol levels.

Even though you may have normal cholesterol, this medicine can also be used to reduce the risk of you having a stroke or heart attack if you are a man 50 or more years old or a woman 60 or more years old and have at least 2 risk factors for having a heart attack or stroke. Risk factors include: high blood pressure, low levels of good cholesterol (HDL), smoking or a family history of premature coronary heart disease. Your doctor may also do a blood test to measure a substance called C Reactive Protein to help decide if you should be given this medicine for this use.

Cholesterol and triglycerides

Everyone has cholesterol and triglycerides in their blood. They are fatty substances needed by the body for many things.

Triglycerides are an energy source for the body. Cholesterol is used for such things as building cells, making bile acids (which help to digest foods) and making some hormones.

There are different types of cholesterol. Too much of the "bad" cholesterol (LDL) can block the blood vessel that supply your heart and brain with blood, and can cause heart attack, angina and stroke. The "good" cholesterol (HDL) helps to remove the bad cholesterol from the blood vessels. High levels of triglycerides can be associated with a low level of "good" cholesterol and may increase the risk of heart disease.

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

This medicine is available only with a doctor's prescription.

How it works

Rosuvastatin belongs to a group of medicines known as HMG-CoA reductase inhibitors (also known as 'statins'). It lowers the "bad" cholesterol and raises the "good" cholesterol when exercise and changes to diet are not enough on their own.

Cholesterol is present in many foods and is also made by your body. Rosuvastatin does not reduce the cholesterol that comes from fat in food. Because of this, when you are taking rosuvastatin, you need to follow a low-fat diet, control your weight and exercise regularly.

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

Your doctor will have explained why you are being treated with rosuvastatin and told you what dose to take. Your doctor may need to check your cholesterol levels before prescribing rosuvastatin or changing your dose.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have active liver disease. If tests show you have elevated levels of liver enzymes, this may indicate that you have a problem with your liver.
  • You have been prescribed any medicine containing fusidic acid.
  • You are pregnant, you intend to become pregnant or you are not taking an effective method of contraception.
    Rosuvastatin may affect your developing baby if you take it during pregnancy. Ask your doctor about effective methods of contraception. If you become pregnant, stop taking this medicine as soon as you find out and see your doctor immediately.
  • You are breastfeeding.
    Rosuvastatin may pass into human breast milk.
  • You are hypersensitive to, or have had an allergic reaction to, rosuvastatin or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.

The packaging is torn, shows signs of tampering or it does not look quite right. You must not use APO-Rosuvastatin 40 mg if you have:

  • low thyroid hormone levels (hypothyroidism)
  • personal or family history of hereditary muscular disorders
  • history of muscular problems from using other lipid-lowering agents
  • history of heavy alcohol use
  • Asian heritage
  • been prescribed another class of lipid-lowering agent called a fibrate
  • severe kidney impairment
  • situations that may increase rosuvastatin blood levels (ask your doctor).

Before you start to take it

Before you start taking this, tell your doctor if:

  1. You have allergies to:
  • any other statins such as simvastatin, pravastatin, atorvastatin, fluvastatin
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • liver problems
  • kidney problems
  • low thyroid hormone levels (hypothyroidism)
  • personal or family history of muscle disorders
  • history of muscle problems from using other lipid-lowering agents
  • unexplained aches or pains in your muscles.
  1. You regularly drink large amounts of alcohol. Excessive alcohol consumption may not be safe in patients taking this medicine.
  2. You are currently pregnant, you plan to become pregnant or you are not taking an effective method of contraception. Do not take this medicine whilst pregnant.
  3. You are currently breastfeeding or you plan to breast-feed. Do not take this medicine whilst breastfeeding.
  4. You are planning to have surgery or an anaesthetic.
  5. You are currently receiving or are planning to receive dental treatment.
  6. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with rosuvastatin. These include:

  • cyclosporins (may be used after organ transplant)
  • antacids (medicines used to treat heartburn and indigestion). This medicine can be taken 2 hours before or 2 hours after taking an antacid
  • warfarin (used to stop blood clots)
  • clopidogrel (used to prevent blood clots)
  • gemfibrozil (used to lower blood lipids)
  • fusidic acid used to treat some infections, you must not take this medicine with fusidic acid
  • various protease inhibitors used in combination with ritonavir to treat HIV infection.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with rosuvastatin.

Your doctor can tell you what to do if you are taking any of these medicines. These medicines may affect the way rosuvastatin works.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition, your ethnicity and whether you are taking any other medicines.

If you have high cholesterol, your doctor will probably start you on 5 mg or 10 mg tablet taken once daily. Your doctor will then monitor your cholesterol and triglyceride levels during your treatment and, if needed, may increase your rosuvastatin dose to 20 mg once daily. For most patients, a maximum 20 mg rosuvastatin daily dose is sufficient to treat their condition.

A small number of patients may need to further increase their rosuvastatin dose to 40 mg once daily, for example, patients whose high cholesterol is hereditary.

If your cholesterol is not high but you have risks for having a heart attack or stroke, your doctor may start you on 20 mg.

Your doctor will advise you on the dose that's right for your condition. The daily dose of rosuvastatin must not exceed 40 mg.

DO NOT INCREASE OR ADJUST YOUR ROSUVASTATIN DOSE YOURSELF.

How to take it

Tablets must not be broken or crushed and must be swallowed whole with a glass of water.

When to take it

Take this medicine once a day, at about the same time each day.

Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

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

This medicine helps lower your blood cholesterol and triglycerides. It does not cure your condition. If you stop taking this medicine, your cholesterol and triglyceride levels may rise again.

You may have to take cholesterol-lowering medicines for the rest of your life.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is within 6 hours your next dose is due, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant, are planning to become pregnant or are not taking an effective method of contraception. Stop taking this medicine immediately if you are pregnant.
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

While taking this medicine, you also need to follow a low-fat diet, to control your weight and to exercise regularly.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking rosuvastatin or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Tell your doctor if you notice any of the following:

  • headache
  • constipation
  • dizziness
  • nausea (feeling sick)
  • stomach pain
  • unusual tiredness
  • itchy skin
  • memory loss
  • stiff or painful joints (arthralgia).

Tell your doctor if you notice an increase in your need to urinate if you are more hungry or thirsty than usual.

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

These may be serious side effects and you may need medical attention:

  • aching muscles, muscle tenderness or weakness not caused by exercise, particularly if you also have a fever or generally feel unwell
  • severe skin reaction with painful red areas, large blisters and peeling of layers of the skin, may be accompanied by fever and chills, aching muscles and generally feeling unwell
  • difficulty breathing, coughing, particularly if you also feel generally unwell (e.g. fatigue, weight loss, fever).

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to rosuvastatin, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C and protected from light and moisture.

Do not store your medicine, or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat, light 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 it has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product description

What this medicine looks like*

APO-Rosuvastatin 5mg tablets:

White, round, biconvex, film coated tablet, engraved "APO" on one side, "ROS" over "5" on the other side.

APO-Rosuvastatin 10mg tablets:

White, round, biconvex, film-coated tablet, engraved "APO" on one side, "ROS" over "10" on the other side.

APO-Rosuvastatin 20mg tablets:

White, round, biconvex, film-coated tablet, engraved "APO" on one side, "ROS" over "20" on the other side.

APO-Rosuvastatin 40mg tablets:

White, oval, biconvex, film-coated tablet, engraved "APO" on one side, "ROS40" on the other side.

Tablets are packaged in blister packs of 7 and 30.

Tablets are also packaged in bottles of 30, 100 and 500.

* Not all strengths, pack types and/or pack sizes are marketed. Alternative brands should be used if required.

Ingredients

Each tablet contains 5 mg, 10 mg, 20 mg or 40 mg of rosuvastatin calcium, as the active ingredient.

The tablets also contain the following inactive ingredients:

  • lactose
  • cellulose-microcrystalline
  • crospovidone
  • magnesium stearate
  • colloidal anhydrous silica
  • hypromellose
  • hydroxypropylcellulose
  • macrogol 8000.

This medicine is gluten-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Rosuvastatin 5 mg tablets (blister pack): AUST R 183061.

APO-Rosuvastatin 10 mg tablets (blister pack): AUST R 183073.

APO-Rosuvastatin 20 mg tablets (blister pack): AUST R 183057.

APO-Rosuvastatin 40 mg tablets (blister pack): AUST R 183074.

APO-Rosuvastatin 5 mg tablets (bottle): AUST R 183075.

APO-Rosuvastatin 10 mg tablets (bottle): AUST R 183067.

APO-Rosuvastatin 20 mg tablets (bottle): AUST R 183060.

APO-Rosuvastatin 40 mg tablets (bottle): AUST R 183059.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in August 2018.

Published by MIMS October 2018

BRAND INFORMATION

Brand name

APO-Rosuvastatin

Active ingredient

Rosuvastatin

Schedule

S4

 

1 Name of Medicine

Rosuvastatin calcium.

6.7 Physicochemical Properties

Rosuvastatin calcium is an amorphous solid, which is slightly soluble in water (7.8 mg/mL at 37°C) and has a pKa of 4.6. Rosuvastatin calcium is the (3R, 5S, 6E) enantiomer.
Chemical Name: bis [(3R, 5S, 6E)-7-{4-(4-fluorophenyl)-2-[N-methyl (methanesulfonyl)amino]-6-isopropyl-2-pyrimidin-5-yl}-3,5-dihydroxyhept-6-enoic acid] calcium salt.
Chemical Formula: (C22H27FN3O6S)2Ca. Molecular Weight: 1001.14.

Chemical structure.


CAS number.

147098-20-2.

2 Qualitative and Quantitative Composition

Each tablet contains 5 mg, 10 mg, 20 mg or 40 mg rosuvastatin calcium, as the active ingredient. In addition, each tablet contains the following inactive ingredients: lactose, cellulose-microcrystalline, crospovidone, magnesium stearate, colloidal anhydrous silica, hypromellose, hydroxypropylcellulose, macrogol 8000.

3 Pharmaceutical Form

5 mg tablets.

White, round, biconvex, film coated tablet, engraved "APO" on one side, "ROS" over "5" on the other side.

10 mg tablets.

White, round, biconvex, film-coated tablet, engraved "APO" on one side, "ROS" over "10" on the other side.

20 mg tablets.

White, round, biconvex, film-coated tablet, engraved "APO" on one side, "ROS" over "20" on the other side.

40 mg tablets.

White, oval, biconvex, film-coated tablet, engraved "APO" on one side, "ROS40" on the other side.
Not all strengths, pack types and/or pack sizes may be available.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Rosuvastatin calcium is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor for the treatment of dyslipidaemia.
Rosuvastatin is a fully synthetic competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy- 3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated, with apolipoprotein B (ApoB), into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. VLDL particles are TG rich. Cholesterol rich low density lipoprotein (LDL) is formed from VLDL and is cleared primarily through the high affinity LDL receptor in the liver. Rosuvastatin produces its lipid modifying effects in two ways; it increases the number of hepatic LDL receptors on the cell surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
High density lipoprotein (HDL), which contains ApoA-I, is involved, amongst other functions, in transport of cholesterol from tissues back to the liver (reverse cholesterol transport).
The involvement of LDL-C in atherogenesis has been well documented. Epidemiological studies have established that high LDL-C and TG and low HDL-C and ApoA-I have been linked to a higher risk of cardiovascular disease. Intervention studies have shown the benefits on mortality and CV event rates of lowering LDL-C and TG or raising HDL-C. More recent data has linked the beneficial effects of HMG-CoA reductase inhibitors to the lowering of non-HDL-C (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ ApoA-I ratio.

Clinical trials.

Hypercholesterolaemia (heterozygous familial and nonfamilial) and mixed dyslipidaemia (Fredrickson type IIa and IIb).

Rosuvastatin reduces total-C, LDL-C, ApoB, non-HDL-C and TG, and increases HDL-C, in patients with hypercholesterolaemia and mixed dyslipidaemia.
The clinical trial program showed that rosuvastatin was effective in a wide variety of patient populations regardless of race, age or sex and in special populations, such as diabetics or patients with familial hypercholesterolaemia.

Active controlled study.

Rosuvastatin was compared with the HMG-CoA reductase inhibitors atorvastatin, simvastatin and pravastatin in a multicentre, open label, dose ranging study of 2,239 patients with type IIa and IIb hypercholesterolaemia. After randomization, patients were treated for 6 weeks with a single daily dose of either rosuvastatin, atorvastatin, simvastatin, or pravastatin (Figure 1 and Table 1). The primary endpoint for this study was the percent change from baseline in LDL-C at week 6.
The percentage change from baseline in HDL-C at week 6 is shown in Figure 2.
The mean percent change in HDL-C from baseline to week 6 for each statin treatment group represented in Figure 2 is summarized with 95% CI in Table 2.
Table 3 summarizes the pooled lipid variable data for rosuvastatin 5 and 10 mg from 5 phase III efficacy trials (trials 24-28).

Heterozygous familial hypercholesterolaemia.

In a study of patients with heterozygous familial hypercholesterolaemia, 435 subjects were given rosuvastatin 20 mg to 80 mg in a force titration design. All doses of rosuvastatin showed a beneficial effect on lipid parameters and treatment to target goals. Following titration to 40 mg (12 weeks of treatment), LDL-C was reduced by 53%.

Hypertriglyceridaemia (Fredrickson type IIb and IV).

In a double blind, placebo controlled, dose response study in patients with baseline TG levels from 273 to 817 mg/dL, rosuvastatin given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (see Table 4).

Homozygous familial hypercholesterolaemia.

In a force titration open label study, 42 patients with homozygous familial hypercholesterolaemia were evaluated for their response to rosuvastatin 20-40 mg titrated at a 6 week interval. In the overall population, the mean LDL-C reduction was 22%. In the 27 patients with at least a 15% reduction by week 12 (considered to be the responder population), the mean LDL-C reduction was 26% at the 20 mg dose and 30% at the 40 mg dose. Of the 13 patients with an LDL-C reduction of less than 15%, 3 had no response or an increase in LDL-C.

High risk hypercholesterolaemic patients.

In a 26 week double blind, forced titration study, 871 high risk hypercholesterolaemic patients with established coronary heart disease (CHD) or multiple risk factors for CHD, were randomized to receive either rosuvastatin or atorvastatin. Patients in the rosuvastatin arm were titrated to 40 mg, while in the atorvastatin arm patients were titrated to 80 mg. The primary objective of the study was to compare rosuvastatin 40 mg with atorvastatin 80 mg in high risk patients, by measuring the percentage change in LDL-C from baseline to week 8. Table 5 summarizes the results for the mean percentage change from baseline at 8 weeks in lipid and lipoprotein variables.

Ultrasonographic study in carotid atherosclerosis.

In a multicentre, double blind, placebo controlled clinical study (METEOR), 984 patients between 45 and 70 years of age and at low risk for coronary heart disease (defined as Framingham risk < 10% over 10 years), with a mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (detected by Carotid Intima Media Thickness (CIMT), which is measured using B-mode ultrasonography) were randomized to 40 mg rosuvastatin once daily or placebo for 2 years, using a 5:2 randomisation split (rosuvastatin:placebo).
Rosuvastatin significantly slowed the rate of progression of the maximum CIMT for the 12 carotid artery sites compared to placebo by -0.0145 mm/year (95% confidence interval -0.0196, -0.0093; p < 0.0001). The change from baseline was -0.0014 mm/year [-0.12%/year (nonsignificant)] for rosuvastatin compared to a progression of +0.0131 mm/year [1.12%/year (p < 0.0001)] for placebo.
There was an absence of disease progression in 52.1% of patients in the rosuvastatin group compared to 37.7% of patients in the placebo group (p = 0.0002). A multilevel fixed effects regression model was used for the statistical analysis and the cited results were calculated using the ITT population.
No direct correlation between CIMT decrease and reduction of the risk of cardiovascular events has yet been demonstrated. The population studied in METEOR is low risk for coronary heart disease and does not represent the target population of rosuvastatin 40 mg. The 40 mg dose should only be prescribed in patients with severe hypercholesterolaemia at high cardiovascular risk (see Section 4.2 Dose and Method of Administration).

Prevention of cardiovascular events.

In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of rosuvastatin calcium on the occurrence of major atherosclerotic cardiovascular (CV) disease events was assessed in 17,802 men (≥ 50 years) and women (≥ 60 years) who had no clinically evident cardiovascular disease, LDL-C levels < 3.3 mmol/L (130 mg/dL) and hs-CRP levels ≥ 2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%) or a family history of premature CHD (12%). Study participants had a median baseline LDL-C of 2.8 mmol/L (108 mg/dL) and hsCRP of 4.3 mg/L. The average age of study participants was 66 years. Study participants were randomly assigned to placebo (n = 8901) or rosuvastatin 20 mg once daily (n = 8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin treated subjects.
The primary endpoint was a composite endpoint consisting of the time to first occurrence of any of the following CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalisation for unstable angina or an arterial revascularization procedure.
Rosuvastatin significantly reduced the risk of CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p < 0.001) relative risk reduction of 44%; absolute risk reduction of 1.2% (see Figure 3 and Table 6). The benefit was apparent within the first 6 months of treatment (HR 0.62; 95% CI 0.40-0.96; p = 0.029). The risk reduction was consistent across multiple predefined population subsets based on assessments of age, sex, race, smoking status, family history of premature CHD, body mass index, LDL-C, HDL-C or hsCRP levels at the time of entry into the study.
There were no statistically significant reductions in the rate of noncardiovascular death or the incidence of bone fractures in the rosuvastatin treated group compared to placebo.
The individual components of the primary endpoint are presented in Figure 4. Rosuvastatin significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the rosuvastatin and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.
In a post hoc subgroup analysis of JUPITER subjects (n = 1405; rosuvastatin = 725, placebo = 680) with a hsCRP ≥ 2 mg/L and no other traditional risk factors (smoking, BP ≥ 140/90 or taking antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no significant treatment benefit with rosuvastatin treatment.
At one year, rosuvastatin increased HDL-C (1.41 vs 1.34 mmol/L) and reduced LDL-C (1.59 mmol/L vs. 2.82 mmol/L), hsCRP (2.20 vs. 3.50 mg/L), total cholesterol and serum triglyceride levels (p < 0.001 for all versus placebo).
In separate studies of patients with established heart failure (CORONA study) and those with end stage renal disease (AURORA study), rosuvastatin did not reduce cardiovascular events.

5.2 Pharmacokinetic Properties

A study was conducted which compared this product with the reference product and the two products were shown to be bioequivalent. In this study, the 90% confidence intervals for the ratio of AUC0-t and Cmax were both found to be between 80% and 125%.

Absorption.

Peak plasma levels occur 5 hours after dosing. Absorption increases linearly over the dose range. Absolute bioavailability is 20%. The half-life is 19 hours and does not increase with increasing dose. There is minimal accumulation on repeated once daily dosing.

Distribution.

Volume of distribution of rosuvastatin at steady state is approximately 134 L. Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin.

Metabolism.

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabelled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9 and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin.

Excretion.

Rosuvastatin undergoes limited metabolism (approximately 10%), mainly to the N-desmethyl form, and 90% is eliminated as unchanged drug in the faeces, with the remainder being excreted in the urine.

Clinical efficacy.

A therapeutic response (reduction in LDL-C) to rosuvastatin is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.

Special populations.

Race.

A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group (see Section 4.4 Special Warnings and Precautions for Use and Section 4.2 Dose and Method of Administration).

Genetic polymorphisms.

Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure. The individual polymorphism of SLCO1B1, c.521CC, and the individual polymorphism of ABCG2, c.421AA, are associated with a higher rosuvastatin exposure (AUC) compared to the SLCO1B1 c.521TT and ABCG2 c.421CC genotypes, respectively. This specific genotyping is not established in clinical practice, but for patients who are known to have these types of polymorphisms, a lower daily dose of rosuvastatin is recommended (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Rosuvastatin showed no evidence for mutagenic activity (in vitro assays of reverse mutation in bacterial cells and forward mutation in mammalian cells) or clastogenic activity (in vitro assay in mammalian cells and in vivo in the mouse micronucleus test).
There have been no adequate studies investigating the potential carcinogenic or genotoxic activity of the main human metabolite of rosuvastatin, N-desmethyl rosuvastatin.

Carcinogenicity.

Oral administration of rosuvastatin for 2 years to rats and mice increased the development of benign uterine stromal polyps in both species and malignant uterine sarcomas and adenosarcomas in rats. Systemic concentrations of rosuvastatin (AUC) at the no effect dose for benign and malignant uterine tumours in either species were lower than or similar to those expected in humans taking 40 mg/day rosuvastatin.

4 Clinical Particulars

4.1 Therapeutic Indications

Rosuvastatin should be used as an adjunct to diet when the response to diet and exercise is inadequate.

Prevention of cardiovascular events.

Rosuvastatin is indicated for prevention of major cardiovascular events in men ≥ 50 years old and women ≥ 60 years old with no clinically evident cardiovascular disease but with at least two conventional risk factors for cardiovascular disease (hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease).
Rosuvastatin is indicated to: reduce the risk of nonfatal myocardial infarction; reduce the risk of nonfatal stroke; reduce the risk of coronary artery revascularisation procedures.

In patients with hypercholesterolaemia.

Rosuvastatin is indicated for the treatment of hypercholesterolaemia (including familial hypercholesterolaemia).
Prior to initiating therapy with rosuvastatin, 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.

4.3 Contraindications

Known hypersensitivity to any of the ingredients.
Patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
During pregnancy, in nursing mothers and in women of childbearing potential, unless they are taking adequate contraceptive precautions.
Concomitant use with fusidic acid (see Section 4.4 Special Warnings and Precautions for Use).
Rosuvastatin 40 mg is contraindicated in patients with predisposing factors for myopathy/ rhabdomyolysis. Such factors include:
hypothyroidism;
personal or family history of hereditary muscular disorders;
previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate;
alcohol abuse;
situations where an increase in rosuvastatin plasma levels may occur (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
severe renal impairment (Clcr < 30 mL/min);
Asian patients;
concomitant use of fibrates.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Liver effects.

HMG-CoA reductase inhibitors, like some other lipid lowering therapies, have been associated with biochemical abnormalities of liver function. The incidence of persistent elevations (> 3 x the upper limit of normal [ULN] occurring on 2 or more consecutive occasions) in serum transaminases in fixed dose studies was 0.4, 0, 0 and 0.1% in patients who received rosuvastatin 5, 10, 20 and 40 mg, respectively. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.
Liver function tests should be performed before initiation of treatment and periodically thereafter. Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in ALT or AST of > 3 x ULN persist, reduction of dose or withdrawal of rosuvastatin is recommended.
Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease (see Section 4.4 Special Warnings and Precautions for Use, Special patient populations; Section 4.2 Dose and Method of Administration). Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of rosuvastatin (see Section 4.3 Contraindications).
In a pooled analysis of placebo controlled trials, increases in serum transaminases to > 3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo.

Myopathy/ rhabdomyolysis.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and with other drugs in this class.
Uncomplicated myalgia has been reported in rosuvastatin treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Creatine kinase (CK) elevations (> 10 x upper limit of normal) occurred in 0.2% to 0.4% of patients taking rosuvastatin at doses up to 40 mg in clinical studies. Treatment related myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CK values > 10 x upper limit of normal, was reported in up to 0.1% of patients taking rosuvastatin doses of up to 40 mg in clinical studies. In clinical trials, the incidence of myopathy and rhabdomyolysis increased at doses of rosuvastatin above the recommended dosage range (5 to 40 mg). In postmarketing experience, effects on skeletal muscle, e.g. uncomplicated myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with HMG-CoA reductase inhibitors including rosuvastatin. As with other HMG-CoA reductase inhibitors, reports of rhabdomyolysis with rosuvastatin are rare, but higher at the highest marketed dose (40 mg). Factors that may predispose patients to myopathy with HMG-CoA reductase inhibitors include advanced age (≥ 65 years), hypothyroidism and renal insufficiency. The incidence of myopathy increased at doses of rosuvastatin above the recommended dosage range.
Consequently:
1. Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism.
2. Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Rosuvastatin therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
3. The 40 mg dose of rosuvastatin is reserved only for those patients who are not adequately controlled at the 20 mg dose, considering their level of LDL-C and overall CV risk profile.
4. The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of other lipid lowering therapies, protease inhibitors or cyclosporin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of this combination. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided (see Section 4.2 Dose and Method of Administration and 4.5 Interactions with Other Medicines and Other Forms of Interactions).
5. The risk of myopathy during treatment with rosuvastatin may be increased in circumstances that increase rosuvastatin drug levels (see Section 5.2 Pharmacokinetic Properties, Special populations; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
6. Rosuvastatin therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, or uncontrolled seizures).
There have been very rare reports of an immune mediated necrotising myopathy clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase during treatment or following discontinuation of statins, including rosuvastatin. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.
In rosuvastatin trials there was no evidence of increased skeletal muscle effects when rosuvastatin was dosed with any concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with cyclosporin, nicotinic acid, azole antifungals, macrolide antibiotics and fibric acid derivatives including gemfibrozil (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.2 Dose and Method of Administration).
Fusidic acid must not be coadministered with statins. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In patients where the use of systemic fusidic acid is considered essential, rosuvastatin 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. Rosuvastatin therapy may be reintroduced seven days after the last dose of fusidic acid.

Endocrine effects.

Increases in HbA1c and fasting serum glucose levels have been reported with rosuvastatin. Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

Caution in prevention of cardiovascular events.

The long-term safety and efficacy of rosuvastatin treatment in patients commencing treatment with LDL-C < 3.4 mmol/L who have been assessed to be at risk of cardiovascular events have not been established. There is also uncertainty associated with the safety of long-term intensive reduction of LDL-C to very low levels. Data are currently available for up to 2 years for the 20 mg dose only (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Prevention of cardiovascular events). The risk benefit balance for longer-term use of rosuvastatin in this population has therefore not been established. The benefits of longer-term treatment should be weighed against safety and tolerability risks (see Section 4.8 Adverse Effects (Undesirable Effects)).
Clinically significant benefit in using rosuvastatin in patients without clinically evident cardiovascular disease and who are assessed as having a low risk of cardiovascular events (men ≥ 50 and women ≥ 60 years of age with hsCRP > 2 mg/L, but no other cardiovascular disease risk factor) has not been established.

Use of CRP testing in prevention of cardiovascular effects.

Recent studies indicate that elevated levels of C-reactive protein (≥ 2 mg/L) may be a marker for increased risk of cardiovascular disease. However, elevated CRP is not a widely established marker of cardiovascular disease and concerns remain over its validity to predict cardiovascular disease risk. The JUPITER trial was conducted in a population with elevated CRP levels however there is no comparative data of rosuvastatin in patients with normal CRP levels or in patients with elevated CRP levels compared to other traditional cardiovascular risk factors. In conjunction with cardiovascular risk assessment, testing for CRP levels may be useful to assist in determining those individuals at higher risk of cardiovascular events. In the JUPITER trial, the hsCRP test was used but this specific test is not widely available. The usCRP test is also suitable for identifying patients with elevated CRP levels and is widely available.

Diabetes mellitus.

Increases in HbA1c and serum glucose levels have been observed in patients treated with rosuvastatin. An increased frequency of diabetes mellitus has been reported with rosuvastatin in patients with risk factors for diabetes mellitus (see Section 4.8 Adverse Effects (Undesirable Effects)).

Interstitial lung disease.

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. 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, rosuvastatin therapy should be discontinued.

Special patient populations.

Race.

The result of a large pharmacokinetic study conducted in the US demonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin) compared with a Caucasian control group. This increase should be considered when making rosuvastatin dosing decisions for Asian patients (see Section 5.2 Pharmacokinetic Properties and Section 4.2 Dose and Method of Administration).

Age and sex.

There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin.

Use in hepatic impairment.

Pharmacokinetic evaluation in subjects with varying degrees of hepatic impairment determined that there was no evidence of increased exposure to rosuvastatin other than in 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Pharmacokinetic evaluation in subjects with varying degrees of renal impairment, determined that mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin. However, subjects with severe impairment (Clcr < 30 mL/min) had a 3-fold increase in plasma concentration compared to healthy volunteers (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

The usual dose range applies.

Paediatric use.

The safety and efficacy of rosuvastatin in children has not been established. Use of this agent for the treatment of homozygous familial hypercholesterolaemia in this age group is not recommended.

Effects on laboratory tests.

As with other HMG-CoA reductase inhibitors, a dose-related increase in liver transaminases, CK, glucose, glutamyl transpeptidase, alkaline phosphatase and bilirubin and thyroid function abnormalities have been observed in a small number of patients taking rosuvastatin. Increases in HbA1c have also been observed in patients treated with rosuvastatin. Proteinuria and microscopic haematuria has been detected by dipstick testing in the clinical trial program in a small number of patients taking rosuvastatin and other HMG-CoA reductase inhibitors at their recommended doses. The proteinuria was mostly tubular in origin and was more frequent in patients on rosuvastatin 40 mg. It was generally transient and not associated with worsening renal function. Although the clinical significance is unknown, dose reduction should be considered in patients on rosuvastatin 40 mg with unexplained persistent proteinuria and/or haematuria.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Warfarin and other vitamin K antagonists.

Coadministration of rosuvastatin to patients on stable warfarin therapy resulted in clinically significant rises in the international normalized ratio (INR) (> 4, baseline 2-3). In patients taking vitamin K antagonists and rosuvastatin concomitantly, INR should be determined before starting rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs. Once a stable INR has been documented, INR can be monitored at the intervals usually recommended for patients on vitamin K antagonists. If the dose of rosuvastatin is changed, the same procedure should be repeated. Rosuvastatin therapy has not been associated with bleeding or with changes in INR in patients not taking anticoagulants.

Cyclosporin.

Coadministration of rosuvastatin with cyclosporin resulted in no significant changes in cyclosporin plasma concentration. However, rosuvastatin steady-state AUC(0-t) increased up to 7-fold over that seen in healthy volunteers administered the same dose. These increases are considered to be clinically significant and require special consideration in the dosing of rosuvastatin (see Section 4.2 Dose and Method of Administration).

Digoxin.

Coadministration of digoxin with rosuvastatin resulted in no change to digoxin plasma concentrations.

Fenofibrate.

Coadministration of fenofibrate with rosuvastatin resulted in no significant changes in plasma concentrations of rosuvastatin or fenofibrate. It may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. 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 this combination. If treatment with fusidic acid is necessary, rosuvastatin 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; Section 4.8 Adverse Effects (Undesirable Effects)).

Gemfibrozil.

Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC(0-t). This increase is considered to be clinically significant (see Section 4.2 Dose and Method of Administration). It may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Protease inhibitors.

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by the use of rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and uptitrating rosuvastain doses in patients treated with protease inhibitors.

Antacids.

Simultaneous administration of rosuvastatin and an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after rosuvastatin. The clinical relevance of this interaction has not been studied.

Cytochrome P450 enzymes.

In vitro and in vivo data indicate that rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole).

Ketoconazole.

Coadministration of ketoconazole (200 mg twice daily for 7 days) with rosuvastatin (80 mg) resulted in no change in plasma concentrations of rosuvastatin.

Erythromycin.

Coadministration of erythromycin (500 mg four times daily for 7 days) with rosuvastatin (80 mg) decreased AUC and Cmax of rosuvastatin by 20% and 31%, respectively. These reductions are not considered clinically significant.

Itraconazole.

Itraconazole (200 mg twice daily for 5 days) resulted in a 39% and 28% increase in AUC of rosuvastatin after 10 mg and 80 mg dosing, respectively. These increases are not considered clinically significant.

Fluconazole.

Coadministration of fluconazole (200 mg twice daily for 11 days) with rosuvastatin (80 mg) resulted in a 14% increase in AUC of rosuvastatin. This increase is not considered clinically significant.

Oral contraceptives.

Coadministration of oral contraceptives (ethinyl estradiol and norgestrel) with rosuvastatin resulted in an increase in plasma concentrations of ethinyl estradiol and norgestrel by 26% and 34%, respectively. This increase is not considered clinically significant.

Other medications.

In clinical studies, rosuvastatin was coadministered with antihypertensive agents and antidiabetic agents. These studies did not produce any evidence of clinically significant adverse interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In 1 of 3 monkeys treated with rosuvastatin PO at 30 mg/kg/day for 6 months degenerative changes in the testicular epithelium were seen. The no effect dose of 10 mg/kg/day was associated with rosuvastatin plasma concentrations (AUC) similar to those expected in humans taking 40 mg rosuvastatin daily.
Rosuvastatin had no effect on male or female fertility when administered to rats at PO doses of 50 mg/kg/day (systemic rosuvastatin concentrations (AUC) 4.8-6.6x those expected in humans). The main human metabolite of rosuvastatin, N-desmethyl rosuvastatin, has not been assessed for activity in rat fertility studies.
The results of animal and in vitro studies of rosuvastatin are summarized below.

Animal studies.

Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20x the human exposure at 40 mg/day based on AUC comparisons). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60x the human exposure at 40 mg/day based on AUC comparisons).
(Category D)
Category D - drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Cholesterol and other products of cholesterol biosynthesis are essential components for foetal development, including synthesis of steroids and cell membranes. Since HMG-CoA reductase inhibitors decrease cholesterol synthesis, rosuvastatin is contraindicated during pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 143 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.
The safety of rosuvastatin while breastfeeding has not been established. It is not known if rosuvastatin is excreted into human milk, but a study in rats showed that unchanged drug and metabolites are excreted in milk at concentrations up to 3x greater than those in maternal plasma. Therefore rosuvastatin is contraindicated in breastfeeding women.

4.8 Adverse Effects (Undesirable Effects)

Rosuvastatin is generally well tolerated. The adverse events seen with rosuvastatin are generally mild and transient. In controlled clinical trials less than 4% of rosuvastatin treated patients were withdrawn due to adverse events. This withdrawal rate was comparable to that reported in patients receiving placebo.
Adverse reactions within each body system are listed in descending order of frequency: very common ≥ 10; common ≥ 1% and < 10%; uncommon ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare < 0.01%.
These include the following.

Central nervous system.

Common: dizziness.

Endocrine system disorders.

Common: Diabetes mellitus (observed in the JUPITER study, see below).

Gastrointestinal.

Common: constipation, nausea, abdominal pain. Rare: pancreatitis.

Musculoskeletal.

Common: myalgia, asthenia. Rare: myopathy (including myositis) and rhabdomyolysis.

Skin.

Uncommon: pruritus, rash, urticaria. Rare: hypersensitivity reactions including angioedema.

Miscellaneous.

Common: headache.
As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to increase with increasing dose.

Skeletal muscle effects.

Rare cases of rhabdomyolysis, which were occasionally associated with impairment of renal function, have been reported with rosuvastatin. Rhabdomyolysis may be fatal. Examples of signs and symptoms of rhabdomyolysis are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure, cardiac arrhythmia (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Other effects.

In a long-term controlled clinical trial rosuvastatin was shown to have no harmful effects on the ocular lens.
In rosuvastatin treated patients, there was no impairment of adrenocortical function.
In the JUPITER study the safety profile for subjects taking rosuvastatin 20 mg was generally similar to that of subjects taking placebo. There were 6.6% of rosuvastatin and 6.2% of placebo subjects who discontinued study medication due to an adverse event, irrespective of treatment causality. The most common adverse reactions that led to treatment discontinuation were: myalgia (0.3% rosuvastatin, 0.2% placebo), abdominal pain (0.03% rosuvastatin, 0.02% placebo) and rash (0.03% rosuvastatin, 0.03% placebo). In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin treated patients compared to placebo treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin treated versus placebo treated patients.
In JUPITER, increased hepatic transaminases were observed in 1.9% of rosuvastatin and 1.5% of placebo subjects and renal events were reported in 6.0% of rosuvastatin and 5.4% of placebo subjects. Confusion was reported in 0.2% of rosuvastatin and 0.1% of placebo subjects.
Adverse reactions in JUPITER reported in ≥ 2% of patients and at a rate greater than or equal to placebo were myalgia (7.6% rosuvastatin, 6.6% placebo), arthralgia (3.8% rosuvastatin, 3.2% placebo), constipation (3.3% rosuvastatin, 3.0% placebo) nausea (2.4% rosuvastatin, placebo, 2.3%) and haematuria (2.4% rosuvastatin, placebo 2.0%).
In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n = 700) or placebo (n = 281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea.
Adverse reactions in METEOR reported in ≥ 2% of patients and at a rate greater than placebo were myalgia (12.7% rosuvastatin, 12.1% placebo), arthralgia (10.1% rosuvastatin, 7.1% placebo), headache (6.4% rosuvastatin, 5.3% placebo), dizziness (4.0% rosuvastatin, 2.8% placebo), increased CPK (2.6% rosuvastatin, 0.7% placebo), abdominal pain (2.4% rosuvastatin, 1.8 placebo) and ALT > 3 x ULN (2.2% rosuvastatin, 0.7% placebo).

Postmarketing experience.

In addition to the above, the following adverse events have been reported during postmarketing experience for rosuvastatin.

Musculoskeletal disorders.

Very rare: arthralgia. Frequency unknown: immune mediated necrotising myopathy.
As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in postmarketing use is higher at the highest marketed dose. Rhabdomyolysis may be fatal. Examples of signs and symptoms of rhabdomyolysis are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure, cardiac arrhythmia (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Haematological disorders.

Frequency unknown: thrombocytopenia.

Hepatobiliary disorders.

Rare: increased hepatic transaminases. Very rare: jaundice, hepatitis. Frequency unknown: hepatic failure.

Nervous system disorder.

Very rare: memory loss. Frequency unknown: peripheral neuropathy.

Psychiatric disorders.

Frequency unknown: depression, sleep disorders (including insomnia and nightmares).

Reproductive system and breast disorders.

Frequency unknown: gynaecomastia.

Reporting suspected adverse effects.

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

4.2 Dose and Method of Administration

Prior to initiating rosuvastatin, the patient should be placed on a standard cholesterol lowering diet. The dose should be individualised according to the goal of therapy and patient response and should take into account the potential risk for adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)).
Rosuvastatin may be given at any time of the day, with or without food. Tablets must not be broken or crushed and must be swallowed whole with a glass of water.

Hypercholesterolaemia.

The recommended starting dose is 5 mg or 10 mg once per day both in statin naive patients and in those switched from another HMG-CoA reductase inhibitor. The choice of starting dose should take into account the individual patient's cholesterol level and future cardiovascular risk.
A dose adjustment can be made after 4 weeks of therapy where necessary. The usual maximum dose of rosuvastatin is 20 mg once per day.
A dose of 40 mg once per day should only be considered in patients who are still at high cardiovascular risk after their response to a dose of 20 mg once per day is assessed. This may particularly apply to patients with familial hypercholesterolaemia. It is recommended that the 40 mg dose is used only in patients in whom regular follow-up is planned. A dose of 40 mg must not be exceeded in any patient taking rosuvastatin.
Specialist supervision should be considered when the dose is titrated to 40 mg.
Specialist supervision should also be considered when initiating co‐administration of rosuvastatin with other medicinal products known to increase exposure to rosuvastatin (see Dosage in Patients taking other drugs; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Prevention of cardiovascular events.

A dose of 20 mg once daily has been found to reduce the risk of major cardiovascular events (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Dosage in Asian patients.

Initiation of rosuvastatin therapy with 5 mg once daily should be considered for Asian patients. The potential for increased systemic exposures relative to Caucasians is relevant when considering escalation of dose in cases where hypercholesterolaemia is not adequately controlled at doses of 5, 10 or 20 mg once daily (see Section 5.2 Pharmacokinetic Properties and Section 4.4 Special Warnings and Precautions for Use).

Dosage in patients taking other drugs.

Concomitant therapy.

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. cyclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir). It is recommended that prescribers consult the relevant product information when considering administration of such products together with rosuvastatin. Whenever possible, alternative medications should be considered, and if necessary, consider temporarily discontinuing rosuvastatin therapy. In situations where co-administration of these medicinal products with rosuvastatin is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cyclosporin.

In patients taking cyclosporin, rosuvastatin dosage should be limited to 5 mg once daily (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gemfibrozil.

Increased systemic exposure to rosuvastatin has been observed in subjects taking concomitant rosuvastatin and gemfibrozil (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If rosuvastatin is used in combination with gemfibrozil, the dose of rosuvastatin should be limited to 10 mg once daily.

Use in children.

The safety and efficacy of rosuvastatin in children has not been established. Use of this agent for the treatment of homozygous familial hypercholesterolaemia in this age group is not recommended.

Geriatrics.

The usual dose range applies.

Hepatic insufficiency.

The usual dose range applies for patients with mild to moderate hepatic impairment.
Patients with severe hepatic impairment should start therapy with 5 mg rosuvastatin. Increased systemic exposure to rosuvastatin has been observed in patients, therefore the use of doses above 10 mg rosuvastatin should be carefully considered (see Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use).

Renal insufficiency.

The usual dose range applies in patients with mild to moderate renal impairment.
For patients with severe renal impairment (Clcr < 30 mL/min/1.73 m2) not on dialysis the dose of rosuvastatin should be started at 5 mg once daily and not exceed 10 mg once daily (see Section 4.4 Special Warnings and Precautions for Use).

Genetic polymorphisms.

Genotypes of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have been shown to be associated with an increase in rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT and ABCG2 c.421CC. For patients who are known to have such specific types of polymorphisms, a lower daily dose of rosuvastatin is recommended (see Section 5.2 Pharmacokinetic Properties).

4.7 Effects on Ability to Drive and Use Machines

Pharmacological testing revealed no evidence of a sedative effect of rosuvastatin. From the safety profile, rosuvastatin is not expected to adversely affect the ability to drive or operate machinery.

4.9 Overdose

Treatment.

There is no specific treatment for overdose. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilized. Haemodialysis is unlikely to be of benefit.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, the 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 30°C. Protect from light and moisture.

6.5 Nature and Contents of Container

5 mg tablets.

Blister packs (aluminium/aluminium silver foil) of 7 and 30 tablets.
Bottles (white, round HDPE bottle with blue child-resistant cap and desiccant) of 30 tablets.
Bottles (white, round HDPE bottle with blue PP Lift N Peel cap and desiccant) of 100 and 500 tablets.
AUST R 183061, AUST R 183075, AUST R 183075.

10 mg tablets.

Blister packs (aluminium/aluminium silver foil) of 7 and 30 tablets.
Bottles (white, round HDPE bottle with blue child-resistant cap and desiccant) of 30 tablets.
Bottles (white, round HDPE bottle with blue PP Lift N Peel cap and desiccant) of 100 and 500 tablets.
AUST R 183073, AUST R 183067, AUST R 183067.

20 mg tablets.

Blister packs (aluminium/aluminium silver foil) of 7 and 30 tablets.
Bottles (white, round HDPE bottle with blue child-resistant cap and desiccant) of 30 tablets.
Bottles (white, round HDPE bottle with blue PP Lift N Peel cap and desiccant) of 100 and 500 tablets.
AUST R 183057, AUST R 183060, AUST R 183060.

40 mg tablets.

Blister packs (aluminium/aluminium silver foil) of 7 and 30 tablets.
Bottles (white, round HDPE bottle with blue child-resistant cap and desiccant) of 30 tablets.
Bottles (white, round HDPE bottle with blue PP Lift N Peel cap and desiccant) of 100 and 500 tablets.
AUST R 183074, AUST R 183059, AUST R 183059.
Not all strengths, pack types and/or pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes