Consumer medicine information

Noumed Rosuvastatin

Rosuvastatin

BRAND INFORMATION

Brand name

Noumed Rosuvastatin

Active ingredient

Rosuvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Noumed Rosuvastatin.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Noumed Rosuvastatin.

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 this medicine 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.

WHAT NOUMED ROSUVASTATIN IS USED FOR

This medicine is used to:

  • Lower high blood cholesterol levels (hypercholesterolaemia).
  • reduce the risk of you having a stroke or heart attack if you are a man 50 or more years old or a women 60 or more years old and have at least 2 risk factors for having a heart attack or stroke, such as high blood pressure, low levels of good cholesterol (HDL), smoking or a family history of premature coronary heart disease.

It contains the active ingredient rosuvastatin calcium.

Rosuvastatin calcium belongs to a group of medicines called HMG-CoA reductase inhibitors (also known as 'statins').

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

There are different types of cholesterol. Too much of the "bad" cholesterol (LDL) can block the blood vessels 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.

Noumed Rosuvastatin works by reducing the level of "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. It does not reduce the cholesterol that comes from fat in food. Because of this, when you are taking Noumed Rosuvastatin, you need to follow a low-fat diet, control your weight and exercise regularly.

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

This medicine is not addictive.

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

There is not enough information to recommend the use of this medicine for children.

BEFORE YOU TAKE NOUMED ROSUVASTATIN

When you must not take it

Do not take this medicine if you have an allergy to:

  • rosuvastatin calcium, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description
  • any other similar medicine in the same drug class as Noumed Rosuvastatin (statins), such as simvastatin (e.g. ZOCOR, LIPEX); pravastatin (e.g. PRAVACHOL); atorvastatin (e.g. LIPITOR); fluvastatin (e.g. VASTIN).

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant or plan to become pregnant. It 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.

Do not breastfeed if you are taking this medicine. It is not known whether Noumed Rosuvastatin passes into breast milk.

Do not take this medicine if you have active liver disease or if tests show you have elevated levels of liver enzymes which may show that you have a problem with your liver.

Do not take Noumed Rosuvastatin 40 mg if you have:

  • low thyroid hormone levels (hypothyroidism)
  • a personal or family history of hereditary muscular disorders
  • a previous history of muscular problems from using other lipid-lowering agents
  • a history of very heavy alcohol use
  • Asian heritage
  • been prescribed another class of lipid lowering agent called a fibrate
  • severe kidney impairment
  • been prescribed any medicine called fusidic acid
  • situations that may increase Noumed Rosuvastatin blood levels.

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

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver disease
  • kidney problems
  • low thyroid hormone levels (hypothyroidism)
  • a personal or family history of muscle disorders
  • a history of muscle problems from using other lipid-lowering agents

It may not be safe for you to take Noumed Rosuvastatin if you have any of these conditions. Your doctor may do a blood test to check if you have any problems, and may adjust the dose of Noumed Rosuvastatin.

  • any unexplained aches or pains in your muscles.
  • you regularly drink large amounts of alcohol

Excessive alcohol consumption may not be safe in patients taking Noumed Rosuvastatin.

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

If you have not told your doctor about any of the above, tell him/her before you start taking Noumed Rosuvastatin.

Taking other medicines

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

Some medicines and Noumed Rosuvastatin may interfere with each other. These include:

  • medicines used after organ transplant such as cyclosporin (e.g. SANDIMMUN and NEORAL)
  • medicines used to treat heartburn and indigestion such as antacids. Noumed Rosuvastatin can be taken 2 hours before or 2 hours after taking an antacid
  • warfarin (e.g. COUMADIN and MAREVAN), a medicine used to prevent blood clots
  • clopidogrel (e.g. PLAVIX), a medicine used to prevent blood clots
  • medicines used to lower blood lipids such as gemfibrozil (e.g. LOPID, JEZIL, and AUSGEM)
  • medicines used to treat HIV infection such as various protease inhibitor combinations with ritonavir (e.g. KALETRA)
  • fusidic acid (eg FUCIDIN), a medicine used to treat some infections
  • simeprevir (OLYSIO), a medicine used for treatment of chronic hepatitis C
  • eltrombopag (REVOLADE), used to increase your platelet count in your blood.

These medicines may be affected by Noumed Rosuvastatin or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

If you have not told your doctor about any of these things, tell them before you take Noumed Rosuvastatin.

Effects on driving and using machinery

Be careful driving a car or operating machinery until you know if Noumed Rosuvastatin affects you.

Noumed Rosuvastatin generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, Noumed Rosuvastatin may cause dizziness in some people.

HOW TO TAKE NOUMED ROSUVASTATIN

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

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

How much to take it

The standard dose for this medicine is one tablet a day.

Your doctor may have prescribed a different dose.

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

DO NOT INCREASE OR ADJUST YOUR NOUMED ROSUVASTATIN DOSE YOURSELF.

Follow the instructions they give you. If you take the wrong dose, Noumed Rosuvastatin may not work as well and your problem may not improve.

If you have high cholesterol, your doctor will probably start you on 5 mg or 10 mg tablet taken once daily.

Your doctor will monitor your cholesterol and triglyceride levels during your treatment, and, if needed, may increase your dose to 20 mg once daily. For most patients a maximum 20 mg daily dose is sufficient to treat their condition.

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

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

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.

How to take it

Swallow the tablets whole with a full glass of water.

When to take Noumed Rosuvastatin

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take your medicine at any time of the day with food or on an empty stomach.

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

How long to take Noumed Rosuvastatin

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

This medicine helps to control your condition, but does not cure it. If you stop taking your medicine, your cholesterol and triglycerides levels may rise again.

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

If you forget to take it

If you forget to take a dose of Noumed Rosuvastatin, take it as soon as you remember, as long as it is more than 6 hours before your next dose is due.

Otherwise, wait until your next dose is due and take it as normal Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Noumed Rosuvastatin. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING NOUMED ROSUVASTATIN

Things you must do

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

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, stop taking it and tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may check your blood cholesterol and triglycerides level from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Noumed Rosuvastatin to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Noumed Rosuvastatin affects you. This medicine may cause dizziness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

SIDE EFFECTS

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

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

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

These are mild side effects of the medicine.

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

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

  • aching muscles, muscle tenderness or weakness not caused by exercise, particularly if you also have a fever or generally feel unwell
  • difficulty breathing, swelling of the face, eyelids and lips.
  • difficulty breathing, coughing, particularly if you also feel generally unwell (eg fatigue, weight loss, fever).

The above list includes serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER TAKING NOUMED ROSUVASTATIN

Storage

Keep your medicine in the original container.

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

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

Do not store Noumed Rosuvastatin or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

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

Disposal

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

PRODUCT DESCRIPTION

What it looks like

Noumed Rosuvastatin comes in four types of tablets:

Noumed Rosuvastatin 5mg - White to off-white round, film coated tablets with "RSV 5" debossed on one side.

Noumed Rosuvastatin 10mg - White to off-white round, film coated tablets with "RSV 10" debossed on one side.

Noumed Rosuvastatin 20mg - White to off-white, round, film coated tablets with "RSV 20" debossed on one side.

Noumed Rosuvastatin 40mg - White to off-white, round, film coated tablets with "RSV 40" debossed on one side.

Available in blister packs of 30 tablets.

Ingredients

Active ingredients:

  • Noumed Rosuvastatin 5mg - 5mg rosuvastatin (as calcium)
  • Noumed Rosuvastatin 10mg - 10mg rosuvastatin (as calcium)
  • Noumed Rosuvastatin 20mg - 20mg rosuvastatin (as calcium)
  • Noumed Rosuvastatin 40mg - 40mg rosuvastatin (as calcium)

Inactive ingredients:

  • lactose
  • colloidal anhydrous silica
  • starch maize
  • purified talc
  • sodium stearyl
  • fumarate
  • hypromellose
  • mannitol
  • macrogol 6000
  • cellulose microcrystalline
  • silicon dioxide.

Sponsor

Avallon Pharmaceuticals Pty Ltd
Level 5, 7 Eden Park Avenue,
Macquarie Park,
North Ryde, NSW 2113,

Supplied by:

Australian Pharmaceutical Industries
11 Grand Avenue
Camellia, NSW 2142
Australia

This leaflet was prepared in July 2019.

Australian Register Number(s)

5mg tablet: AUST R 285680

10mg tablet: AUST R 285681

20mg tablet: AUST R 285682

40mg tablet: AUST R 285683

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Noumed Rosuvastatin

Active ingredient

Rosuvastatin

Schedule

S4

 

1 Name of Medicine

Rosuvastatin, as rosuvastatin calcium.

2 Qualitative and Quantitative Composition

Noumed Rosuvastatin 5 mg tablet contain 5 mg rosuvastatin (as calcium).
Noumed Rosuvastatin 10 mg tablet contain 10 mg rosuvastatin (as calcium).
Noumed Rosuvastatin 20 mg tablet contain 20 mg rosuvastatin (as calcium).
Noumed Rosuvastatin 40 mg tablet contain 40 mg rosuvastatin (as calcium).
Rosuvastatin calcium is an amorphous solid, which is slightly soluble in water (7.8 mg/mL at 37°C), methanol, and ethanol, and has a pKa of 4.6. Rosuvastatin calcium is the (3R,5S,6E) enantiomer.
Noumed Rosuvastatin tablets also contain the inactive ingredients lactose, colloidal anhydrous silica, microcrystalline cellulose and silicon dioxide, starch maize, purified talc, sodium stearylfumarate, hypromellose, mannitol and macrogol 6000.

3 Pharmaceutical Form

Noumed Rosuvastatin 5 mg tablets.

White to off-white round, film coated tablets with "RSV 5" debossed on one side.

Noumed Rosuvastatin 10 mg tablets.

White to off-white round, film coated tablets with "RSV 10" debossed on one side.

Noumed Rosuvastatin 20 mg tablets.

White to off-white round, film coated tablets with "RSV 20" debossed on one side.

Noumed Rosuvastatin 40 mg tablets.

White to off-white round, film coated tablets with "RSV 40" debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Noumed Rosuvastatin is indicated as an adjunct to diet when the response to diet and exercise is inadequate.

Prevention of cardiovascular events.

Noumed 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). Noumed 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.

Noumed Rosuvastatin is indicated for the treatment of hypercholesterolaemia (excluding heterozygous familial hypercholesterolaemia).
Prior to initiating therapy with Noumed 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.

4.2 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)).
Noumed Rosuvastatin may be given at any time of the day, with or without food.

Hypercholesterolaemia.

The recommended starting dose is 5 mg or 10 mg once per day both in statin naïve 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. 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; 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).

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, Prevention of cardiovascular events).

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; 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 rosuvastatin 5 mg. Increased systemic exposure to rosuvastatin has been observed in these patients, therefore the use of doses above rosuvastatin 10 mg should be carefully considered (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).

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).

4.3 Contraindications

Known hypersensitivity to any of the ingredients.
Patients with active liver disease including unexplained persistent elevations of serum transaminases 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 of fusidic acid (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Rosuvastatin 40 mg is contraindicated in patients with pre-disposing 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 (CrCl < 30 mL/min);
Asian patients;
concomitant use of fibrates.

4.4 Special Warnings and Precautions for Use

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 times 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 times 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 Special patient populations; see 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 times 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 times 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; Section 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 necrotizing myopathy clinically characterized 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 co-administered 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 re-introduced 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 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, including increases that exceeded the threshold for the diagnosis of diabetes mellitus in some cases (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

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, non-productive 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.

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 (CrCl < 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.

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

Paediatric use.

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

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.

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; Section 4.2 Dose and Method of Administration).

Sex.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro and in vivo data indicate that rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent (see Table 1 for interaction studies with ketoconazole, erythromycin, fluconazole and itraconazole).
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 Table 1; see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Interactions requiring rosuvastatin dose adjustments.

(See also Table 1; see Section 4.2 Dose and Method of Administration).
When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses of rosuvastatin should be adjusted. It is recommended that prescribers also consult the relevant product information when considering administration of such products together with rosuvastatin. Start with the lowest dose of rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of the daily recommended dose of rosuvastatin taken without interacting medicinal products (see Section 4.2 Dose and Method of Administration). Note, the 40 mg dose is not approved for use in prevention of cardiovascular events. Please also see Section 4.3 Contraindications for use of the 40 mg dose.

Other interacting medicinal products.

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.

Gemfibrozil/fenofibrates/fibric acid derivatives.

Co-administration of rosuvastatin with gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see Table 1; see Section 4.2 Dose and Method of Administration). Co-administration of fenofibrate with rosuvastatin resulted in no significant changes in plasma concentrations of rosuvastatin or fenofibrate (see Table 1). However, a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate and other fibric acids, including nicotinic acid, may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Warfarin and other vitamin K antagonists.

Co-administration of rosuvastatin to patients on stable warfarin therapy resulted in clinically significant rises in 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.

Co-administration of rosuvastatin with cyclosporin resulted in no significant changes in cyclosporin plasma concentration and a 7-fold increase in rosuvastatin exposure (see Table 1 and see Section 4.2 Dose and Method of Administration).

Digoxin.

Co-administration of digoxin with rosuvastatin resulted in no change to digoxin plasma concentrations.

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 rosuvastatin 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)).

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 up-titrating rosuvastatin doses in patients treated with protease inhibitors (see Table 1 and see Section 4.2 Dose and Method of Administration).

Oral contraceptives.

Co-administration 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 co-administered with anti-hypertensive agents and anti-diabetic 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 - 6.6 times those expected in humans). The main human metabolite of rosuvastatin, N-desmethyl rosuvastatin, has not been assessed for activity in rat fertility studies.
(Category D)
Category D is defined as 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 breast-feeding 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 3 times greater than those in maternal plasma. Therefore rosuvastatin is contraindicated in breastfeeding women.

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.

4.8 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.

JUPITER study.

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).
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 (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).
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%).

METEOR study.

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 > 3x ULN (2.2% rosuvastatin, 0.7% placebo).

Post marketing experience.

In addition to the above, the following adverse events have been reported during post marketing 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 post-marketing 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.
The following adverse events have been reported with some statins: sexual dysfunction, exceptional cases of interstitial lung disease, especially with long term therapy and tendon disorders, sometimes complicated by rupture.

Reporting suspected adverse effects.

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

4.9 Overdose

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 nonHDL-C (i.e. all circulating cholesterol not in HDL) and ApoB or reducing the ApoB/ApoA-I ratio.

Clinical trials.

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

Rosuvastatin reduces total-C, LDL-C, ApoB, nonHDL-C, and TG, and increases HDLC, in patients with hypercholesterolaemia and mixed dyslipidaemia.
The clinical trial program showed that rosuvastatin is 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 multicenter, 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 2). The primary endpoint for this study was the percent change from baseline in LDL-C at week 6.
The percent 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 summarised with 95% CI in Table 3.
Table 4 summarises the pooled lipid variable data for rosuvastatin 5 and 10 mg from 5 Phase III efficacy trials (Trials 24-28).

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 (Table 5).

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 CHD or multiple risk factors for CHD, were randomised 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 6 summarises the results for the mean percentage change from baseline at 8 weeks in lipid and lipoprotein variables.

Ultrasonographic study in carotid atherosclerosis.

In a multi-centre, 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, which is measured using B-mode ultrasonography) were randomised 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 (non-significant) 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 multi-level 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 (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, non-fatal myocardial infarction, non-fatal 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 7). 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.
In JUPITER, there was a statistically significant increase in the frequency of diabetes mellitus reported by investigators; 2.8% of patients in the rosuvastatin group and 2.3% of patients in the placebo group (HR: 1.27, 95% CI: 1.05-1.53, p=0.015). The difference between treatment groups (rosuvastatin versus placebo) in mean HbA1c change from baseline was approximately 0.1%. The number of patients with HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.
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 end point 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 LDLC (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

In a bioequivalence study comparing 40 mg Noumed Rosuvastatin tablets with the innovator's tablets, following an oral administration of a single-dose of Noumed Rosuvastatin to healthy subjects under fasting conditions, a mean peak plasma concentration (Cmax) of Rosuvastatin of approximately 26.18 nanogram/mL was achieved within approximately 3.62 hours (Tmax).

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 litres. Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin.

Metabolism.

Rosuvastatin is not extensively metabolised; 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; 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

The results of animal and in vitro studies of rosuvastatin are summarised below.

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.

Animal studies.

Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times 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 60 times the human exposure at 40 mg/day based on AUC comparisons).

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Noumed Rosuvastatin 5 mg tablets.

White to off-white round, film coated tablets with "RSV 5" debossed on one side. Available in blister packs (Al/Al) of 30 tablets.

Noumed Rosuvastatin 10 mg tablets.

White to off-white round, film coated tablets with "RSV 10" debossed on one side. Available in blister packs (Al/Al) of 30 tablets.

Noumed Rosuvastatin 20 mg tablets.

White to off-white round, film coated tablets with "RSV 20" debossed on one side. Available in blister packs (Al/Al) of 30 tablets.

Noumed Rosuvastatin 40 mg tablets.

White to off-white round, film coated tablets with "RSV 40" debossed on one side. Available in blister packs (Al/Al) of 30 tablets.
* Not marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical name: bis [(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt.
Empirical formula: (C22H27FN3O6S)2Ca. MW: 1001.14.

Chemical structure.


CAS number.

147098-20-2.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes