Consumer medicine information

Rosuvastatin Sandoz

Rosuvastatin

BRAND INFORMATION

Brand name

Rosuvastatin Sandoz

Active ingredient

Rosuvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

Rosuvastatin Sandoz®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Rosuvastatin Sandoz?

Rosuvastatin Sandoz contains the active ingredient rosuvastatin calcium. Rosuvastatin Sandoz is used to lower high cholesterol levels. Even though you may have normal cholesterol, Rosuvastatin Sandoz can also be used to reduce the risk of you having a stroke or heart attack. For more information, see Section 1. Why am I using Rosuvastatin Sandoz? in the full CMI.

2. What should I know before I use Rosuvastatin Sandoz?

Do not use if you have ever had an allergic reaction to Rosuvastatin Sandoz or any of the ingredients listed at the end of the CMI, or if you become pregnant while you are taking Rosuvastatin Sandoz. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Rosuvastatin Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Rosuvastatin Sandoz and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Rosuvastatin Sandoz?

  • The usual dose is 5 mg to 20 mg taken once daily, but some patients may need to increase this to 40 mg once daily. Your doctor will monitor your cholesterol and triglyceride levels during your treatment and, if needed, may increase your dose.
  • Swallow each tablet whole with a drink of water. You can take your tablet at any time of the day, with or without food.

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

5. What should I know while using Rosuvastatin Sandoz?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Rosuvastatin Sandoz.
  • Have your blood cholesterol and triglycerides checked when your doctor says so.
  • Stop taking Rosuvastatin Sandoz and seek medical attention immediately if you experience any of the serious side effects listed in Section 6 in the full CMI.
Things you should not do
  • Do not stop taking Rosuvastatin Sandoz unless you have discussed it with your doctor.
Driving or using machines
  • Be careful driving a car or operating machinery as Rosuvastatin Sandoz may cause dizziness in some people.
Drinking alcohol
  • Excessive alcohol consumption may not be safe in patients taking Rosuvastatin Sandoz.
Looking after your medicine
  • Keep your tablets in the blister pack until it is time to take them. Store your medicine in a cool dry place below 25°C. Keep your medicine where children cannot reach it.
  • Protect from light.

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

6. Are there any side effects?

The most common side effects of Rosuvastatin Sandoz are headache, constipation, dizziness, nausea, stomach pain, unusual tiredness or a general feeling of weakness, muscle pain, and stiff or painful joints. 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. Seek medical attention immediately if you experience any of the following, particularly if you also generally feel unwell: muscle aches, tenderness or weakness not caused by exercise, particularly if you also have fever; difficulty breathing, coughing, swelling of the face, eyelids or lips; widespread rash, high body temperature, enlarged lymph nodes; or skin rash or sores in the mouth. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Rosuvastatin Sandoz®

Active ingredient(s): rosuvastatin calcium


Consumer Medicine Information (CMI)

This leaflet provides important information about using Rosuvastatin Sandoz. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Rosuvastatin Sandoz.

Where to find information in this leaflet:

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

1. Why am I using Rosuvastatin Sandoz?

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

Rosuvastatin Sandoz is used to lower high cholesterol levels.

Even though you may have normal cholesterol, Rosuvastatin Sandoz 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, such as high blood pressure, low levels of good cholesterol, 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 Rosuvastatin Sandoz 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 essential for 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 can block the blood vessels that supply your heart and brain with blood, and can cause heart attack, angina and stroke. The "good" cholesterol 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.

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

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

2. What should I know before I use Rosuvastatin Sandoz?

Warnings

Do not use Rosuvastatin Sandoz if:

  • you are allergic to rosuvastatin calcium, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take this medicine.
  • you are pregnant, become pregnant while taking Rosuvastatin Sandoz, are breastfeeding, or trying to become pregnant unless you are taking adequate contraceptive precautions
  • 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 Rosuvastatin Sandoz 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
  • been prescribed any medicine containing fusidic acid
  • severe kidney impairment
  • situations that may increase Rosuvastatin Sandoz blood levels.

Check with your doctor if you:

  • have allergies to any other statins such as simvastatin, pravastatin, atorvastatin, or fluvastatin. If you have an allergic reaction, you may get a skin rash, hay fever, difficulty in breathing or feel faint
  • have any other medical conditions:
    - liver problems
    - 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 Rosuvastatin Sandoz 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 Rosuvastatin Sandoz.
  • have any unexplained aches or pains in your muscles
  • regularly drink large amounts of alcohol. Excessive
  • alcohol consumption may not be safe in patients taking Rosuvastatin Sandoz.

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

Pregnancy and breastfeeding

Do not take Rosuvastatin Sandoz if you are pregnant or intend to become pregnant. Ask your doctor about effective methods of contraception.

If you become pregnant, stop taking Rosuvastatin Sandoz as soon as you find out and see your doctor immediately.

Do not take Rosuvastatin Sandoz if you are breastfeeding. Your baby may absorb this medicine from breast milk and there is a possibility of harm to the baby.

3. What if I am taking other medicines?

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

Some medicines may interfere with Rosuvastatin Sandoz and affect how it works. These include:

  • ciclosporin, used for example, after organ transplant
  • antacids (medicines used to treat heartburn and indigestion). Rosuvastatin Sandoz can be taken 2 hours before or 2 hours after taking an antacid
  • warfarin, used to stop blood clots
  • clopidogrel or ticagrelor, used to prevent blood clots
  • gemfibrozil, used to lower blood lipids
  • fusidic acid, used to treat some infections
  • fostamatinib, used to treat low platelet counts
  • febuxostat, used to treat and prevent high blood levels of uric acid
  • teriflunomide, used to treat relapsing remitting multiple sclerosis
  • antiviral medications (alone or in combination), such as atazanavir, darunavir, glecaprevir, lopinavir, pibrentasvir, ritonavir, sofosbuvir, velpatasvir, and voxilaprevir, used to fight infections, including the HIV infection
  • anti-cancer medications, such as regorafenib and darolutamide, used to treat cancer
  • eltrombopag, used to increase your platelet count in your blood
  • tafamidis, used to treat a protein disorder.

Your doctor will consider if Rosuvastatin Sandoz should be used together with any of these medicines, or may wish to adjust the dose of Rosuvastatin Sandoz or the other medicines. These medicines may affect the way Rosuvastatin Sandoz works.

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

4. How do I use Rosuvastatin Sandoz?

How much to take

  • Depending on your condition and ethnic background, your doctor will decide the most appropriate starting dose for you.
  • If you have high cholesterol, your doctor will probably start you on a 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 Sandoz dose to 20 mg once daily. For most patients a maximum 20 mg Rosuvastatin Sandoz daily dose is sufficient to treat high cholesterol.
  • A small number of patients may need to further increase their Rosuvastatin Sandoz 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 Sandoz must not exceed 40 mg daily.
    DO NOT INCREASE OR ADJUST YOUR ROSUVASTATIN SANDOZ DOSE YOURSELF.

When to take Rosuvastatin Sandoz

  • Take Rosuvastatin Sandoz once a day, at about the same time each day. Keeping a regular time for taking Rosuvastatin Sandoz will help to remind you to take it.
  • Rosuvastatin Sandoz can be taken at any time of the day. It does not matter whether you take Rosuvastatin Sandoz with food or on an empty stomach.

How to take Rosuvastatin Sandoz

  • Swallow each tablet whole with a drink of water.

How to long to take Rosuvastatin Sandoz

  • You must continue to take it as directed.
  • Rosuvastatin Sandoz helps lower your blood cholesterol and triglycerides. It does not cure your condition. If you stop taking Rosuvastatin Sandoz, 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 use Rosuvastatin Sandoz

Rosuvastatin Sandoz should be taken regularly at the same time each day. If you forget to take a dose of Rosuvastatin Sandoz, 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 you missed.

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

If you use too much Rosuvastatin Sandoz

If you think that you have used too much Rosuvastatin Sandoz, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Rosuvastatin Sandoz?

Things you should do

Have your blood cholesterol and triglycerides checked when your doctor says so to make sure Rosuvastatin Sandoz is working.

Call your doctor straight away if you:

  • Become pregnant while you are taking Rosuvastatin Sandoz.

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

Things you should not do

  • Do not stop taking Rosuvastatin Sandoz unless you have discussed it with your doctor.

Things that may help your condition

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

Driving or using machines

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

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

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them. If you take Rosuvastatin Sandoz out of the blister pack, it will not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place below 25°C away from moisture, heat or sunlight; for example, do not store it:

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not take this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
General disorders
  • headache
  • dizziness
  • unusual tiredness or a general feeling of weakness (asthenia)
Gastrointestinal or Gut related
  • nausea (feeling sick)
  • stomach pain
  • constipation
Muscle-joint related
  • muscle pain (myalgia)
  • stiff or painful joints (arthralgia)
Speak to your doctor if you have any of these less serious side effects and they worry you.
They are generally mild and do not cause patients to stop taking Rosuvastatin Sandoz.

Serious side effects

Serious side effectsWhat to do
Metabolism-related
  • significant increase in your need to urinate or if you are significantly more hungry or thirsty than usual
Muscle-related
  • aching muscles, muscle tenderness or weakness not caused by exercise (including eye muscles, or muscles used when breathing), particularly if you also have a fever or generally feel unwell
Allergic and severe skin reaction-related
  • difficulty breathing, swelling of the face, eyelids or lips
  • widespread rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome
  • rash on the skin or sores in the mouth
Lung-related
  • difficulty breathing, coughing, particularly if you also feel generally unwell (e.g. fatigue, weight loss, fever)
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Rosuvastatin Sandoz contains

Active ingredient
(main ingredient)
rosuvastatin calcium
Other ingredients
(inactive ingredients)
  • lactose
  • colloidal anhydrous silica
  • maize starch
  • purified talc
  • sodium stearylfumarate
  • hypromellose
  • mannitol
  • macrogol 6000
  • titanium dioxide
  • iron oxide yellow
  • iron oxide red
  • microcrystalline cellulose
  • silicon dioxide
Potential allergens
  • lactose

Do not take this medicine if you are allergic to any of these ingredients.

What Rosuvastatin Sandoz looks like

Rosuvastatin Sandoz 5mg - Brown, round, film coated tablets (AUST R 311400).

Rosuvastatin Sandoz 10mg - Brown, round, film coated tablets with "RSV 10" debossed on one side (AUST R 311401).

Rosuvastatin Sandoz 20mg - Brown, round, film coated tablets with "RSV 20" debossed on one side (AUST R 311402).

Rosuvastatin Sandoz 40mg - Brown, round, film coated tablets with "RSV 40" debossed on one side (AUST R 311403).

Available in blister packs of 30 tablets.

Who distributes Rosuvastatin Sandoz

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was revised in December 2023.

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Rosuvastatin Sandoz

Active ingredient

Rosuvastatin

Schedule

S4

 

1 Name of Medicine

Rosuvastatin, as rosuvastatin calcium.

2 Qualitative and Quantitative Composition

Rosuvastatin Sandoz 5 mg tablets contain 5 mg rosuvastatin (as calcium).
Rosuvastatin Sandoz 10 mg tablets contain 10 mg rosuvastatin (as calcium).
Rosuvastatin Sandoz 20 mg tablets contain 20 mg rosuvastatin (as calcium).
Rosuvastatin Sandoz 40 mg tablets contain 40 mg rosuvastatin (as calcium).

Excipients with known effect.

Lactose (as sugars).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Rosuvastatin Sandoz 5 mg tablets.

Brown, round, film coated tablets.

Rosuvastatin Sandoz 10 mg tablets.

Brown, round, film coated tablets with "RSV 10" debossed on one side.

Rosuvastatin Sandoz 20 mg tablets.

Brown, round, film coated tablets with "RSV 20" debossed on one side.

Rosuvastatin Sandoz 40 mg tablets.

Brown, round, film coated tablets with "RSV 40" debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

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

Prevention of cardiovascular events.

Rosuvastatin Sandoz 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 Sandoz 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 Sandoz is indicated for the treatment of hypercholesterolaemia (excluding heterozygous familial hypercholesterolaemia).
Prior to initiating therapy with Rosuvastatin Sandoz, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, alcoholism) should be identified and treated.

4.2 Dose and Method of Administration

Dosage.

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)).

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. 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 coadministration of rosuvastatin with other medicinal products known to increase exposure to rosuvastatin (see Dosage adjustment, 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).

Method of administration.

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

Dosage adjustment.

Renal impairment. The usual dose range applies in patients with mild to moderate renal impairment.
For patients with severe renal impairment (CrCl < 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).
Hepatic impairment. 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).
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, Special populations, Genetic polymorphism).
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).
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.
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. ciclosporin 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 coadministration 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).

Ciclosporin.

In patients taking ciclosporin, 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.

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 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 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 (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 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 alanine aminotransferase (ALT) or aspartate aminotransferase (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 Use in hepatic impairment; 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 ULN 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 ULN) 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 ULN, 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 ciclosporin (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, Race; 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 CK during treatment or following discontinuation of statins, including rosuvastatin. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.
HMG-CoA reductase inhibitors may in rare instances induce or aggravate myasthenia gravis or ocular myasthenia (see Section 4.8 Adverse Effects (Undesirable Effects)) including reports of recurrence when the same or a different HMG-CoA reductase inhibitor was administered. Rosuvastatin should be used with caution in patients with these conditions and should be discontinued if these conditions are induced or aggravated.
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 ciclosporin, 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 hs-CRP > 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 hs-CRP test was used but this specific test is not widely available. The us-CRP 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, 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.

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, Special populations, Race; 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.

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).

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.

No data available.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

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

Effect of co-administration medicinal products on rosuvastatin.

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 and see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Ticagrelor.

Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CK level and rhabdomyolysis.
Interactions requiring rosuvastatin dose adjustments (also see Table 1 and see Section 4.2 Dose and Method of Administration). When it is necessary to coadminister 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.
If medicinal product is observed to increase rosuvastatin AUC approximately 2-fold or higher, the starting dose of rosuvastatin should not exceed 5 mg once daily. 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.
If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the rosuvastatin dose above 20 mg.

Protease inhibitors.

Coadministration of rosuvastatin with certain protease inhibitors or combination of protease inhibitors may increase the rosuvastatin exposure (AUC) up to 7-fold (see Table 1). Dose adjustment are needed depending on the level of effect on rosuvastatin exposure (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
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.

Coadministration of rosuvastatin with gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see Table 1 and see Section 4.2 Dose and Method of Administration). Coadministration 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.

Coadministration 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.

Ciclosporin.

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

Digoxin.

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

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) 4.8-6.6 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 fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development, including synthesis of steroids and cell membranes. Since HMG-CoA reductase inhibitors decrease cholesterol synthesis, rosuvastatin is contraindicated during pregnancy as there is a potential risk for adverse effects in the fetus. The risk of fetal 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 fetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and fetal deaths. The exact risk of injury to the fetus 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 fetal 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 fetal injury and discuss the implications with her pregnancy specialist. It is recommended that rosuvastatin is discontinued as soon as pregnancy is recognised.
The safety of rosuvastatin while breastfeeding has not been established. 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. Limited data from published reports indicate that rosuvastatin is present in human milk. Due to rosuvastatin's mechanism of action, there is a potential risk for adverse reactions in the infant. 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 CK, 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 was 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 > 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.

Eye disorders.

Frequency unknown: ocular myasthenia.

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 CK, 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, myasthenia gravis.

Psychiatric disorders.

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

Reproductive system and breast disorders.

Frequency unknown: gynaecomastia.

Skin and subcutaneous tissue disorders.

Frequency unknown: drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption.
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 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.

4.9 Overdose

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Rosuvastatin is a fully synthetic competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (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 apolipoprotein A-I (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 cardiovascular (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 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 is effective in a wide variety of patient populations regardless of race, age or sex, and in special populations such as patients with diabetes or 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 (see 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 (see 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 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, 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 (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 (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 hs-CRP 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 revascularisation 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 hs-CRP 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 non-cardiovascular 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 hs-CRP ≥ 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), hs-CRP (2.20 vs. 3.50 mg/L), total cholesterol and serum TG levels (p < 0.001 for all versus placebo).
In separate studies of patients with established heart failure (CORONA study) and those with endstage renal disease (AURORA study), rosuvastatin did not reduce cardiovascular events.

5.2 Pharmacokinetic Properties

In a bioequivalence study comparing 40 mg Rosuvastatin Sandoz tablets with the innovator's tablets, following an oral administration of a single dose of Rosuvastatin Sandoz 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 L. 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

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Rosuvastatin Sandoz tablets also contain the inactive ingredients lactose, colloidal anhydrous silica, microcrystalline cellulose and silicon dioxide, maize starch, purified talc, sodium stearylfumarate, hypromellose, mannitol and macrogol 6000, titanium dioxide, iron oxide yellow and iron oxide red.

6.2 Incompatibilities

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

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

Rosuvastatin Sandoz 5 mg tablets.

Available in blister packs of 7* and 30 tablets.

Rosuvastatin Sandoz 5 mg tablets.

Available in bottles* of 30 tablets.

Rosuvastatin Sandoz 10 mg tablets.

Available in blister packs of 7* and 30 tablets.

Rosuvastatin Sandoz 10 mg tablets.

Available in bottles* of 30 tablets.

Rosuvastatin Sandoz 20 mg tablets.

Available in blister packs of 7* and 30 tablets.

Rosuvastatin Sandoz 20 mg tablets.

Available in bottles* of 30 tablets.

Rosuvastatin Sandoz 40 mg tablets.

Available in blister packs of 30 tablets.

Rosuvastatin Sandoz 40 mg tablets.

Available in bottles* of 30 tablets.
* Not currently 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

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.

Chemical structure.

The chemical name of rosuvastatin calcium is 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. Its empirical formula is (C22H27FN3O6S)2Ca. (MW: 1001.14) and its chemical structure is:

CAS number.

147098-20-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes