Consumer medicine information

Clopidogrel Winthrop Tablets

Clopidogrel

BRAND INFORMATION

Brand name

Clopidogrel Winthrop

Active ingredient

Clopidogrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clopidogrel Winthrop Tablets.

SUMMARY CMI

Clopidogrel Winthrop® Tablets

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 Clopidogrel Winthrop?

Clopidogrel Winthrop contains the active ingredient clopidogrel. Clopidogrel Winthrop is used to prevent blood clots forming in hardened blood vessels (a process known as atherothrombosis) which can lead to events such as stroke, heart attack or death. For more information, see Section 1. Why am I using Clopidogrel Winthrop? in the full CMI.

2. What should I know before I use Clopidogrel Winthrop?

Do not use if you have ever had an allergic reaction to Clopidogrel Winthrop or any of the ingredients listed at the end of the CMI. 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 Clopidogrel Winthrop? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Clopidogrel Winthrop 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 Clopidogrel Winthrop?

  • Take Clopidogrel Winthrop only as prescribed by your doctor and follow his or her directions carefully.

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

5. What should I know while using Clopidogrel Winthrop?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Clopidogrel Winthrop. Clopidogrel Winthrop may increase the risk of bleeding during an operation or some dental work.
  • Tell your doctor immediately if you are injured while taking Clopidogrel Winthrop. It may take longer than usual to stop bleeding while you are taking Clopidogrel Winthrop.
  • Tell your doctor that you are taking Clopidogrel Winthrop if you are about to start on any new medicine.
Things you should not do
  • Do not use Clopidogrel Winthrop during pregnancy.
  • Do not use Clopidogrel Winthrop if you are breast feeding or intend to breast feed.
  • Do not stop using this medicine suddenly.
  • Do not take Clopidogrel Winthrop if you have a medical condition that is causing bleeding such as a stomach ulcer or bleeding within your head.
Driving or using machines
  • Clopidogrel Winthrop may cause faintness or dizziness in some people. Make sure you know how you react to Clopidogrel Winthrop before you drive a car or operate machinery or do anything else that could be dangerous if you are faint or dizzy. If this occurs, do not drive.
Looking after your medicine
  • Keep Clopidogrel Winthrop in a cool, dry place where the temperature stays below 25°C.

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

6. Are there any side effects?

Like other medicines Clopidogrel Winthrop can cause some side effects. Most are likely to be minor and temporary. However, some may be serious and need medical attention such as bleeding or bruising more easily, blood in the urine and in the eye, coughing up blood, diarrhoea with blood, tightness of the chest, swelling of the face, lips, mouth, tongue or throat which may cause difficulty swallowing or breathing. 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

Clopidogrel Winthrop® Tablets

Active ingredient: Clopidogrel (clop-id-o(h)-grel)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Clopidogrel Winthrop. 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 Clopidogrel Winthrop.

Where to find information in this leaflet:

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

1. Why am I using Clopidogrel Winthrop?

Clopidogrel Winthrop contains the active ingredient clopidogrel. Clopidogrel Winthrop belongs to a group of medicines called anti-platelet medicines.

Platelets are very small blood cells which clump together during blood clotting. By preventing this clumping, anti-platelet medicines reduce the chances of blood clots forming (a process called thrombosis).

Clopidogrel Winthrop is used to prevent blood clots forming in hardened blood vessels (a process known as atherothrombosis) which can lead to events such as stroke, heart attack or death.

You may have been prescribed Clopidogrel Winthrop to help prevent blood clots forming and to reduce the risk of stroke, heart attack and death because:

  • You have previously suffered a heart attack, stroke or have a condition known as peripheral arterial disease (leg pain on walking or at rest).
  • You have suffered Acute Coronary Syndrome (either a severe type of chest pain called unstable angina, or a heart attack). In this case you may also be prescribed aspirin.

Your doctor may have prescribed this medicine for another use. If you want more information, ask your doctor.

Clopidogrel Winthrop is only available on a doctor's prescription.

2. What should I know before I use Clopidogrel Winthrop?

Warnings

Do not use Clopidogrel Winthrop if:

  • you are allergic to clopidogrel, or any of the ingredients listed at the end of this leaflet.
  • you have a medical condition that is causing bleeding such as a stomach ulcer or bleeding within your head.
  • you suffer from severe liver disease.
  • the packaging shows signs of tampering.
  • the expiry date on the pack has passed. If you use this product after the expiry date has passed, it may not work.

Do not take Clopidogrel Winthrop to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

Check with your doctor if you:

  • have any other medical conditions, especially the following:
    - bleeding disorders or blood clotting problems
    - liver or kidney problems
    - any illness or disability that was caused by bleeding, for example impaired sight or vision because of bleeding within the eye
    - recent serious injury
    - recent surgery (including dental surgery)
    - allergic to other antiplatelet medicines (such as ticlopidine, prasugrel)
    - rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
  • take any medicines for any other condition
  • are planning to have an operation (including dental surgery) in the next two weeks. Your doctor will decide whether or not you need to stop Clopidogrel Winthrop prior to surgery

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

Some patients may not convert Clopidogrel Winthrop to its active form as well as other patients. These patients may not get the same benefit from Clopidogrel Winthrop. Your doctor may advise you to go for tests to determine if Clopidogrel Winthrop will adequately work for you. Based on the test results, your doctor may change your dose of Clopidogrel Winthrop or consider alternative treatments for you.

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

Check with your doctor if you are pregnant or intend to become pregnant.

Do not use Clopidogrel Winthrop during pregnancy unless in the opinion of your doctor there is a clear need.

Your doctor will discuss the possible risks and benefits of taking Clopidogrel Winthrop during pregnancy.

Do not use Clopidogrel Winthrop if you are breast feeding or intend to breast feed. Clopidogrel Winthrop passes into breast milk and, therefore, there is the possibility that the breast fed baby may be affected.

Use in Children

Clopidogrel Winthrop is not recommended for children as its safety and effectiveness in children have not been established.

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 Clopidogrel Winthrop and affect how it works. These include:

  • medicines that "thin the blood". The most common examples of these include aspirin, heparins and warfarin. There are others so please check with your doctor.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) - medicines used to treat arthritis, period pain, aches and pains
  • medicines used to treat stomach ulcers or reflux disease (also called heartburn)
  • Some medicines used to treat infections (eg ciprofloxacin, chloramphenicol, fluconazole and voriconazole)
  • Some antidepressant medicines.
  • medicines used to treat epilepsy (e.g. carbamazepine, oxcarbazepine and phenytoin)
  • medicines used to treat diabetes (eg. tolbutamide, repaglinide)
  • medicines used to treat breast cancer (e.g tamoxifen, paclitaxel)
  • fluvastatin - a medicine used to lower cholesterol
  • medicines used to prevent gastric reflux - proton pump inhibitors (e.g. omeprazole)
  • certain type of pain relief medicines called opiates
  • rosuvastatin (used to lower your cholesterol level)

These medicines may be affected by Clopidogrel Winthrop or affect how well Clopidogrel Winthrop works.

Your doctor may need to change the amount of your medicines, or you may need to take different medicines.

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

4. How do I use Clopidogrel Winthrop?

How much to take

  • Your doctor will tell you how many tablets to take each day. Take Clopidogrel Winthrop only as prescribed by your doctor and follow his or her directions carefully. They may differ from the information contained in this leaflet.
  • The usual dose of Clopidogrel Winthrop is one 75 mg tablet daily.
  • If you are prescribed Clopidogrel Winthrop for the treatment of Acute Coronary Syndrome, you may receive a starting dose of 300 mg (four 75 mg tablets), then one 75 mg tablet daily.

When to take Clopidogrel Winthrop

  • You can take Clopidogrel Winthrop before or after meals. You should swallow the tablet with a glass of water.
  • You should take Clopidogrel Winthrop for as long as your doctor continues to prescribe it.

If you forget to use Clopidogrel Winthrop

Clopidogrel Winthrop should be used regularly at the same time each day Taking your tablet at the same time each day will have the best effect. It will also help you to remember when to take it.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

  • 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 use too much Clopidogrel Winthrop

If you think that you have used too much Clopidogrel Winthrop, 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 Clopidogrel Winthrop?

Things you should do

Call your doctor straight away if you:

  • if you become pregnant while taking Clopidogrel Winthrop.
  • if you decide to breast feed your baby. Your doctor may want to discuss this and change your medicine.
  • if you are about to start on any new medicine
  • if you are injured while taking Clopidogrel Winthrop. It may take longer than usual to stop bleeding while you are taking Clopidogrel Winthrop.
  • if you notice any of the following:
    - abnormal bruising or bleeding
    - abnormal nose bleeds
    - bloody or black bowel motions
    - red or purple blotches on your skin
    - swelling of the face, lips, mouth, tongue or throat which may cause difficulty swallowing or breathing (see also 'Side effects' section)

Take Clopidogrel Winthrop exactly as your doctor has prescribed, and have any blood tests promptly if your doctor orders them.

Ask your doctor whether there are any activities you should avoid while taking Clopidogrel Winthrop, for example certain sports. Sometimes after an injury bleeding may occur inside your body without you knowing about it.

Remind any doctor, dentist or pharmacist you visit that you are using Clopidogrel Winthrop. Clopidogrel Winthrop may increase the risk of bleeding during an operation or some dental work. Therefore, treatment may need to be stopped before surgery. Your doctor will decide whether to stop Clopidogrel Winthrop and if so, how long before surgery or dental work.

Things you should not do

  • Do not stop using this medicine suddenly without telling your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Clopidogrel Winthrop affects you.

Clopidogrel Winthrop may cause faintness or dizziness in some people. Make sure you know how you react to Clopidogrel Winthrop before you drive a car or operate machinery, or do anything else that could be dangerous if you are faint or dizzy. If this occurs, do not drive. If you drink alcohol, faintness or dizziness may be worse.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them.
  • If you take your tablets out of the box or blister pack they 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 where the temperature stays 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.

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

Getting rid of any unwanted medicine

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

Do not use 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
  • things taste different
  • hunger
  • a fast, pounding heart beat
Gut-related
  • diarrhoea
Skin-related
  • itching
  • flushing
Nervous system-related
  • trembling
Joint-related
  • pain or stiffness in the joints
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Blood-related
  • anaemia (being tired and looking pale)
  • coughing up blood
  • blood in the urine
  • blood in the eyes
  • unusually heavy bleeding or oozing from cuts or wounds
  • bleeding (including nose bleeds) or bruising more easily than normal
  • unusually heavy or unexpected menstrual bleeding
Gut-related
  • bloody or black bowel motions
  • diarrhoea with blood, mucus, stomach pain and fever
  • abdominal or stomach pain
  • vomiting of blood or vomit that looks like coffee grounds
  • nausea or vomiting
  • pale stools and dark urine with vomiting and stomach pain
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.

NOTE: If you take both Clopidogrel Winthrop and aspirin the risk of side effects related to bleeding may be increased.
Serious side effectsWhat to do
Allergic-reaction
  • tightness of the chest, wheezing, coughing or difficulty breathing
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
General
  • weight loss
  • muscle weakness
  • muscle pain
  • breast enlargement in men
  • fever or other signs of infection, such as a sore throat
  • faintness or dizziness
  • light-headedness or blurred vision
  • loss of appetite and fatigue
  • slurred speech or other difficulty in speaking
  • headache (severe and continuing)
Skin-related
  • rash or hives
  • red or purple spots visible through your skin
  • itching, inflamed, cracking or red skin
  • yellowing of the skin or the whites of the eyes
  • chills, sweating or clammy skin
Nervous system-related
  • confusion or hallucinations
  • numbness (paralysis) or problems with co-ordination
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.

NOTE: If you take both Clopidogrel Winthrop and aspirin the risk of side effects related to bleeding may be increased.

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 Clopidogrel Winthrop contains

Active ingredient
(main ingredient)		clopidogrel (75 mg)
Other ingredients
(inactive ingredients)		mannitol
macrogol 6000
microcrystalline cellulose
hydrogenated castor oil
hyprolose
carnauba wax
OPADRY II complete film coating system 32K14834 Pink
The coating contains lactose monohydrate

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

What Clopidogrel Winthrop looks like

Clopidogrel Winthrop 75mg tablets come as pink round tablets with '75' engraved on one side and '1171' on the other (AUST R 148947).

A box contains 28 tablets.

Who distributes Clopidogrel Winthrop

Clopidogrel Winthrop is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Rd,
Macquarie Park NSW 2113

This leaflet was prepared in May 2022.

® Clopidogrel Winthrop is a registered trademark of sanofi-aventis.

clop-winth-ccdsv29-cmiv13-02may22

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Clopidogrel Winthrop

Active ingredient

Clopidogrel

Schedule

S4

 

1 Name of Medicine

Clopidogrel hydrogen sulfate.

2 Qualitative and Quantitative Composition

Clopidogrel Winthrop 75 mg contains 97.875 mg of clopidogrel hydrogen sulfate which is the molar equivalent of 75 mg of clopidogrel base.

Excipient with known effect.

The coating contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

75 mg film coated tablets.

Pink round slightly biconvex film coated tablets, engraved "75" on one side and "1171" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Prevention of vascular ischaemia associated with atherothrombotic events (myocardial infarction, stroke and vascular death) in patients with a history of symptomatic atherosclerotic disease.

Acute coronary syndrome.

Clopidogrel Winthrop is indicated in combination with aspirin for patients with:
Unstable angina or non-ST-elevation myocardial infarction in order to prevent early and long-term atherothrombotic events (myocardial infarction, stroke, vascular death or refractory ischaemia). Clopidogrel Winthrop is indicated for the treatment of acute coronary syndrome whether or not patients undergo cardiac revascularisation (surgical or PCI, with or without stent).
ST-segment elevation acute myocardial infarction in order to prevent atherothrombotic events. In this population, Clopidogrel Winthrop has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke in medically treated patients eligible for thrombolytic therapy.

4.2 Dose and Method of Administration

Clopidogrel should be taken once a day with or without food.

Adults.

Generally, clopidogrel should be given as a single daily dose of 75 mg.

In patients with acute coronary syndrome.

Unstable angina or non-ST-elevation myocardial infarction - clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued long-term at 75 mg once a day (with aspirin 75 mg-325 mg daily).
ST segment elevation acute myocardial infarction - clopidogrel treatment should be given as a single daily dose of 75 mg initiated with or without a 300 mg loading dose in combination with aspirin and with or without thrombolytics. Combined therapy should be started as early as possible after symptoms start. The benefit of the combination of clopidogrel with aspirin beyond four weeks has not been studied in this setting. There are no data on the use of a 300 mg loading dose in elderly patients (aged 75 years or more) with ST-segment acute myocardial infarction, as no patients over 75 years old were included in the CLARITY study and no loading dose was used in the COMMIT study.
In patients who have had percutaneous coronary intervention with stent insertion, clopidogrel and aspirin should be continued for as long as is currently recommended in evidence-based guidelines for the type of stent and circumstances of implantation or for as long as otherwise indicated, taking into account the overall atherothrombotic risk profile of the patient.
No dosage adjustment is necessary for either elderly patients or patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Pharmacogenetics.

CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolisers increases antiplatelet response (see Section 5.2 Pharmacokinetic Properties, Excretion, Pharmacogenetics), an appropriate dose regimen for this patient population has not been established in clinical outcome trials. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolisers.

Children and adolescents.

Safety and efficacy in subjects below the age of 18 have not been established.

4.3 Contraindications

Hypersensitivity to clopidogrel or any of the excipients.
Severe liver impairment.
Active pathological bleeding such as peptic ulcer and intracranial haemorrhage.
Breast-feeding (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

General.

As with the other anti-platelet agents, clopidogrel prolongs bleeding time and should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions, and in patients receiving treatment with acetylsalicylic acid, heparin, glycoprotein IIb/IIIa inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers. Due to the increased risk of hemorrhage, triple antiplatelet therapy (clopidogrel + aspirin + dipyridamole) for stroke secondary prevention is not recommended in patients with acute non-cardioembolic ischemic stroke or TIA (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If a patient is to undergo elective surgery and an anti-platelet effect is not desired, clopidogrel should be discontinued at least 5 days prior to surgery.
If the patient is at high risk of ophthalmic bleeding due to intraocular lesions clopidogrel should be used with extra caution.
Although clopidogrel has shown a lower incidence of gastrointestinal bleeding compared to aspirin in a large controlled clinical trial (CAPRIE), clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Drugs that might induce such lesions (such as aspirin and non-steroidal anti-inflammatory drugs) should be used with caution in patients taking clopidogrel (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients should be told that it may take longer than usual for bleeding to stop when they take clopidogrel (alone or in combination with aspirin), and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of aspirin and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Coronary artery bypass surgery.

When coronary artery bypass surgery is to be performed, clopidogrel should be suspended at least 5 days before surgery to reduce the risk of bleeding (see Section 4.8 Adverse Effects (Undesirable Effects)).

Pharmacogenetics.

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is mainly due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite. In patients who are CYP2C19 poor metabolisers clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Poor metabolisers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties, Excretion, Pharmacogenetics).
Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Although a higher dose regimen in poor metabolisers increases antiplatelet response (see Section 5.2 Pharmacokinetic Properties, Excretion, Pharmacogenetics), an appropriate dose regimen for this patient population has not been established in clinical outcome trials. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolisers (see Section 4.2 Dose and Method of Administration, Pharmacogenetics).

CYP2C19 metabolism.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g. omeprazole) should be discouraged (see Section 5.2 Pharmacokinetic Properties, Excretion, Pharmacogenetics; Section 4.4 Special Warnings and Precautions for Use). If a proton pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity, such as pantoprazole.
Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Haematological.

Thrombotic thrombocytopenic purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment, including plasmapheresis (plasma exchange).
Thrombocytopenia, neutropenia, aplastic anaemia and pancytopenia have also been reported very rarely in patients taking clopidogrel (see Section 4.8 Adverse Effects (Undesirable Effects)).
Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment. Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel is not recommended.
As with other anti-platelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with aspirin, non-steroidal anti-inflammatory drugs, heparin, glycoprotein IIb/IIIa inhibitors or thrombolytics. Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery.

Acquired haemophilia.

Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated partial thromboplastin time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists and clopidogrel should be discontinued.

Cross-reactivity among thienopyridines.

Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as ticlopidine, prasugrel) since cross reactivity among thienopyridines has been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is advised.

Use in hepatic impairment.

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
In the CAPRIE study, it was not mandatory to discontinue study medication in the case of an acute outcome event (acute myocardial infarction, ischaemic stroke or lower extremity amputation) and the patients had a favourable outcome as compared to the aspirin group.
In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (less than 7 days).

Use in renal impairment.

Experience with clopidogrel is limited in patients with severe renal impairment. Therefore clopidogrel should be used with caution in this population.

Use in the elderly.

No data available.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Children and adolescents.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Aspirin.

A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and aspirin have been administered together for up to one year. Also see Section 4.4 Special Warnings and Precautions for Use, General.

Oral anticoagulants (including warfarin).

The concomitant administration of Clopidogrel Winthrop with warfarin is not recommended since it may increase the intensity of bleeding.

Glycoprotein IIb/IIIa inhibitors.

Clopidogrel Winthrop should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions that receive concomitant glycoprotein IIb/IIIa inhibitors.

Injectable anticoagulants.

A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Anti-platelet agents (such as eptifibatide, ticlopidine, tirofiban).

The effects of Clopidogrel Winthrop and other drugs which inhibit platelet aggregation may be additive, leading to an increased risk of bleeding.

Thrombolytics.

The safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparins are co-administered with aspirin. The safety of concomitant administration of Clopidogrel Winthrop with thrombolytic agents has not been formally established and should be undertaken with caution.

Drugs associated with bleeding risk.

There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of drugs associated with bleeding risk should be undertaken with caution (see Section 4.4 Special Warnings and Precautions for Use).

Non-steroidal anti-inflammatory drugs (NSAIDs).

In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs, it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, there is a potential increased risk of gastrointestinal bleeding and NSAIDs and clopidogrel should be co-administered with caution (see Section 4.4 Special Warnings and Precautions for Use).

Selective serotonin reuptake inhibitors (SSRIs).

Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.

Drugs metabolised by cytochrome P450 2C9.

At high concentrations in vitro, clopidogrel inhibits cytochrome P450 (2C9). Accordingly, Clopidogrel Winthrop may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is co-administered with Clopidogrel Winthrop.

Other concomitant therapy.

Inducers of CYP2C19. Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel.
Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see Section 4.4 Special Warnings and Precautions for Use).
Inhibitors of CYP2C19. Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g. omeprazole) should be discouraged (see Section 5.2 Pharmacokinetic Properties, Excretion, Pharmacogenetics; Section 4.4 Special Warnings and Precautions for Use). If a proton pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity, such as pantoprazole.
Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

Proton pump inhibitors (PPI).

In a crossover clinical study (N = 72 healthy subjects), clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. Mean maximal platelet aggregation intensity % (MAI) was the primary pharmacodynamic endpoint of the clinical study and was used in the calculation of the mean inhibition of platelet aggregation % (IPA). Similar trends in results were seen across both the MAI% and IPA%. The exposure to the active metabolite of clopidogrel was decreased by 45% (day 1) and 40% (day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation with 5 microM ADP was diminished by 39% (24 hours) and 21% (day 5) when clopidogrel and omeprazole were administered together. The same results were observed when omeprazole 80 mg was administered 12 hours apart.
In a crossover clinical study (N = 66), healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. Mean maximal platelet aggregation intensity % was the primary pharmacodynamic endpoint of the clinical study and was used in the calculation of the mean inhibition of platelet aggregation %. Similar trends in results were seen across both the MAI% and IPA%. The exposure to the active metabolite of clopidogrel was decreased by 20% (day 1) and 14% (day 5) when clopidogrel and pantoprazole were administered together. Mean inhibition of platelet aggregation was diminished by 15% (24 hours) and 11% (day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.
Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies.
A number of other clinical studies have been conducted with clopidogrel and other concomitant medications to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital, or oestrogen.
In a study comparing administration of warfarin with either clopidogrel (N = 20) or placebo (N = 23) the administration of clopidogrel 75 mg/day for 8 days did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy (at least 2 months). Coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel interferes with the metabolism of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

CYP2C8 substrate drugs.

Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g. repaglinide, paclitaxel) should be undertaken with caution.
In addition to the above specific interaction studies, patients entered into clinical trials with clopidogrel (including CAPRIE, CURE, CLARITY and COMMIT) received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, anti-diabetic agents (including insulin), anti-epileptic agents, GPIIb/IIIa antagonists and hormone replacement therapy without evidence of clinically significant adverse interactions.
As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

Rosuvastatin.

Clopidogrel has been shown to increase rosuvastatin exposure in patients by 2-fold (AUC) and 1.3-fold (Cmax) after administration of a 300 mg clopidogrel dose, and by 1.4-fold (AUC) without effect on Cmax after repeated administration of a 75 mg clopidogrel dose.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day and was not teratogenic in rats (up to 500 mg/kg per day) and rabbits (up to 300 mg/kg per day).
(Category B1)
Clopidogrel and/or its metabolites are known to cross the placenta in pregnant rats and rabbits. However, teratology studies in rats and rabbits at doses up to 500 mg and 300 mg/kg/day PO, respectively, revealed no evidence of embryotoxicity or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should not be used in women during pregnancy.
 Studies in rats have shown that clopidogrel and/or its metabolites are excreted in breast milk (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

No impairment of driving or psychometric performance was observed following clopidogrel administration.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies experience.

Clopidogrel has been evaluated for safety in more than 42,000 patients, including over 9,000 patients treated for 1 year or more. The clinically relevant adverse events observed in CAPRIE, CURE, CLARITY and COMMIT are discussed below.
Clopidogrel was well tolerated compared to aspirin in a large controlled clinical trial (CAPRIE). The overall tolerability of clopidogrel in this study was similar to aspirin, regardless of age, gender and race.

Haemorrhagic disorders.

In CAPRIE, the overall incidence of any bleeding in patients treated with either clopidogrel or aspirin was similar (9.3%). The incidence of severe bleeds was 1.4% in the clopidogrel group and 1.6% in the aspirin group.
Gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) compared to aspirin (2.66%). The incidence of intracranial haemorrhage was 0.35% for clopidogrel compared to 0.49% for aspirin.
In CURE, there was a significant difference between the two treatment groups for nonlife-threatening major bleeds (1.6% clopidogrel + aspirin vs. 1.0% placebo + aspirin), primarily gastrointestinal and at puncture sites, and minor bleeds (5.1% clopidogrel + aspirin vs. 2.4% placebo + aspirin). The major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin (< 100 mg: 2.6%; 100-200 mg: 3.5%; > 200 mg: 4.9%) as was the major bleeding event rate for placebo + aspirin (< 100 mg: 2.0%; 100-200 mg: 2.3%; > 200 mg: 4.0%).
The administration of clopidogrel + aspirin as compared to placebo + aspirin, was not associated with an increase in life-threatening or fatal bleeds (event rates 2.2% vs. 1.8% and 0.2% vs. 0.2%, respectively). The incidence of intra-cranial bleeding was 0.1% in both groups.
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel + aspirin vs. 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin.
In CLARITY, there was an overall increase in bleeding in the clopidogrel + aspirin group (17.4%) versus the placebo + aspirin group (12.9%), with the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in haemoglobin > 5 g/dL) being similar between groups (1.3% versus 1.1% in the clopidogrel + aspirin and the placebo + aspirin groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel + aspirin and in the placebo + aspirin groups, respectively) and intracranial haemorrhage (0.5% versus 0.7%, respectively) was low and similar in both groups.
The overall rate of major bleeding in COMMIT was low and similar in both groups, as shown in Table 1.
In CHARISMA, a study conducted in a broad patient population including patients with prior documented coronary artery disease, cerebrovascular disease or peripheral arterial disease as well as patients with a combination of atherothrombotic risk factors only, all receiving a background therapy with low dose aspirin (75-162 mg), there was an excess in moderate and severe bleeding, as adjudicated to the GUSTO definitions, in the clopidogrel group. This represented a number needed to treat, to harm, of 84 in 23 months of follow-up. (See Table 2.)

Haematological disorders.

In CAPRIE, patients were intensively monitored for thrombocytopenia and neutropenia.
Clopidogrel was not associated with an increase in the incidence of thrombocytopenia compared to aspirin. Very rare cases of platelet count < 30 x 109/L have been reported.
Aplastic anaemia has occurred whilst on clopidogrel treatment.
Severe neutropenia (< 0.45 x 109/L) was observed in four patients (0.04%) that received clopidogrel and in two patients that received aspirin. Two of the 9599 patients who received clopidogrel and none of the patients who received aspirin had a neutrophil count of zero. One of the clopidogrel treated patients was receiving cytostatic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with clopidogrel.
In CURE and CLARITY, the numbers of patients with thrombocytopenia or neutropenia were similar in both groups.
Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other signs of infection.

Gastrointestinal.

In CAPRIE, overall the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving clopidogrel was significantly lower than in those receiving aspirin. The incidence of peptic, gastric, or duodenal ulcers was 0.68% for clopidogrel and 1.15% for aspirin. Cases of diarrhoea were reported at a higher frequency in the clopidogrel group (4.46%) compared to the aspirin group (3.36%).
In CURE, there was no significant difference in the incidence of non-haemorrhagic gastrointestinal effects in the clopidogrel or placebo groups.
In CLARITY, the incidence of gastrointestinal adverse events was 6.9% for clopidogrel treated patients, compared to 7.2% in placebo treated patients.
In COMMIT, 2 patients reported gastrointestinal adverse events in the clopidogrel treated group, compared to one in the placebo treated group.

Rash.

In CAPRIE, there were significantly more patients with rash in the clopidogrel group (4.2%) compared to the aspirin group (3.5%). In CURE, rash occurred in more patients in the clopidogrel group. In CLARITY, 0.7% of patients in the clopidogrel group reported a rash, compared to 0.5% in the placebo group.

Treatment discontinuation.

In the clopidogrel and aspirin treatment groups of the CAPRIE study, discontinuation due to adverse events occurred in approximately 13% of patients after 2 years of treatment. Adverse events occurring in ≥ 2.5% of patients on clopidogrel in the CAPRIE controlled clinical trial are shown in Table 3 regardless of relationship to clopidogrel. The median duration of therapy was 20 months, with a maximum of 3 years.
In CURE, the overall incidence of discontinuation due to adverse events was greater in the clopidogrel group than in the placebo group (366 [5.8%] and 247 [3.9%] patients, respectively), with the main differences being in events in the platelet, bleeding and clotting disorders (1.1% versus 0.7%) and skin disorders (0.7% versus 0.3%). The increase in the rate of study drug discontinuation due to non-haemorrhagic adverse events was primarily due to the increase in rash seen in the clopidogrel group. There was no apparent difference between the 2 treatment groups in the rates of discontinuations due to other adverse events.
In CLARITY, the overall incidence of discontinuation due to adverse events was greater in the placebo group compared with the clopidogrel group (6.9% for clopidogrel treated patients compared to 8.6% for placebo treated patients).
In COMMIT, the overall incidence of discontinuation due to adverse events was similar in each treatment group (2.4% for clopidogrel treated patients compared to 2.2% for placebo treated patients).
Clinically relevant adverse reactions not listed above pooled from CAPRIE, CURE, CLARITY and COMMIT studies with an incidence of ≥ 0.1% as well as all serious and clinically relevant adverse reactions are listed below according to the World Health Organisation classification.
Their frequency is defined using the following conventions: common: > 1/100 (1%) and < 1/10 (10%); uncommon: ≥ 1/1000 (0.1%) and < 1/100 (1%); and rare: ≥ 1/10,000 (0.01%) and < 1/1000 (0.1%).

Central and peripheral nervous system disorders.

Uncommon: paraesthesia, headache, dizziness. Rare: vertigo.

Gastrointestinal system disorders.

Common: dyspepsia, abdominal pain, diarrhea. Uncommon: flatulence, nausea, gastritis, constipation, vomiting, gastric, peptic or duodenal ulcer.

Platelet, bleeding and clotting disorders.

Uncommon: bleeding time increased, platelets decreased.

Skin and appendages disorders.

Uncommon: rash, pruritus.

White cell and RES disorders.

Uncommon: leucopenia, neutrophils decreased and eosinophilia.

Post-marketing experience.

The following have been reported spontaneously from worldwide post-marketing experience.
Note: very common: ≥ 1/10 (≥ 10%); common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%); uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1.0%); rare: ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%); very rare: < 1/10,000 (< 0.01%); not known: cannot be estimated from available data.

Musculoskeletal, connective and bone.

Very rare: arthralgia, arthritis, myalgia.

Immune system disorders.

Very rare: anaphylactoid reactions, serum sickness. Uncommon: cross-reactive hypersensitivity among thienopyridine (such as ticlopidine, prasugrel) (see Section 4.4 Special Warnings and Precautions for Use). Not known: insulin autoimmune syndrome, which can lead to severe hypoglycaemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population).

Cardiac disorders.

Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel.

Vascular disorders.

Very rare: vasculitis, hypotension.

Blood and lymphatic system disorders.

Very rare: serious cases of bleeding, mainly skin, musculo-skeletal (haemarthrosis, haematoma), eye (conjunctival, ocular, retinal) and respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), epistaxis, haematuria and haemorrhage of operative wound. Fatal haemorrhage, including intracranial, gastrointestinal and retroperitoneal haemorrhage. Cases of serious haemorrhage have been reported in patients taking clopidogrel concomitantly with aspirin or clopidogrel with aspirin and heparin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Very rare cases of thrombotic thrombocytopenic purpura (TTP), have been reported.
Very rare cases of acquired haemophilia A have been reported.
Very rare: aplastic anaemia, neutropenia, pancytopenia, agranulocytosis, granulocytopenia, anaemia. Uncommon: eosinophilia, leucopenia, decreased neutrophils, decreased platelets, increased bleeding time.

Skin and subcutaneous tissue disorders.

Very rare: maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis (AGEP)), drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, lichen planus.

Psychiatric.

Very rare: confusion, hallucinations.

Nervous system disorders.

Very rare: taste disturbances. Not known: ageusia.

Hepatobiliary disorders.

Very rare: hepatitis, acute liver failure.

Gastrointestinal disorders.

Very rare: colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.

Respiratory, thoracic and mediastinal disorders.

Very rare: bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

Renal and urinary disorders.

Very rare: glomerulopathy.

Reproductive systems and breast disorders.

Very rare: gynaecomastia.

Investigations.

Very rare: blood creatinine increase, abnormal liver function tests.

General disorders and administration site conditions.

Very rare: fever, syncope.

Reporting suspected adverse effects.

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

4.9 Overdose

In animals, clopidogrel at single oral doses ≥ 1500 mg/kg caused necrotic-haemorrhagic gastritis, oesophagitis and enteritis in mice, rats and baboons. Necrotic tubulopathy and tubulo-interstitial nephritis were also noted in mice.
Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleeding is observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Clopidogrel is a specific and potent inhibitor of platelet aggregation. Platelets have an established role in the pathophysiology of atherosclerotic disease and thrombotic events. Long-term use of anti-platelet drugs has shown consistent benefit in the prevention of ischaemic stroke, myocardial infarction and vascular death in patients at increased risk of such outcomes, including those with established atherosclerosis or a history of atherothrombosis.

Mechanism of action.

The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxoclopidogrel and subsequent hydrolysis. The active metabolite of clopidogrel selectively inhibits the binding of ADP to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover (approximately 7 days).
Statistically significant and dose-dependent inhibition of platelet aggregation was noted 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between day 3 and day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 7 days after treatment was discontinued.

Clinical trials.

The safety and efficacy of clopidogrel in preventing vascular ischaemic events has been evaluated in four double-blind studies: the CAPRIE study, a comparison of clopidogrel to aspirin, and the CURE, CLARITY and COMMIT studies, which compared clopidogrel in combination with aspirin, to placebo with aspirin.

Myocardial infarction or stroke, or established peripheral arterial disease.

The CAPRIE study included 19,185 patients with established atherosclerosis or history of atherothrombosis as manifested by myocardial infarction, ischaemic stroke or peripheral arterial disease. Patients were randomised to clopidogrel 75 mg/day or aspirin 325 mg/day, and were followed for 1 to 3 years.
The trial's primary outcome was the time to first occurrence of new ischaemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.
As shown in Table 4, clopidogrel was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.78% vs. 10.64%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischaemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the clopidogrel group.
The curves showing the overall event rate are shown in Figure 1. The event curves separated early and continued to diverge over the 3-year follow-up period.

Acute coronary syndrome.

The CURE study included 12,562 patients with acute coronary syndrome (unstable angina or non-ST-elevation myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, n = 6244) or placebo (n = 6287), both given in combination with aspirin (75-325 mg once daily) and other standard therapies (oral anti-coagulants and long term NSAIDs were not permitted). Patients were treated for up to one year.
The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p = 0.00009) for the clopidogrel-treated group. The benefits of clopidogrel were seen within a few hours and maintained throughout the course of the study (up to 12 months). The primary outcome was reduced to a similar extent within the first 30 days (relative risk reduction of 22%), from 30 days to one year (relative risk reduction of 19%), and for the entire one year study (relative risk reduction of 20%).
The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1035 (16.5%) in the clopidogrel-treated group and 1187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p = 0.0005) for the clopidogrel-treated group, a benefit which was consistent for each component, indicating that clopidogrel reduced a range of atherothrombotic events.
In the course of the study, patients who underwent cardiac revascularisation (surgical or percutaneous coronary intervention with or without coronary stent implantation), received similar benefit from clopidogrel + aspirin (including standard therapies) as those who did not have a cardiac revascularisation.
The results obtained in populations with different characteristics (e.g. unstable angina or non-ST-elevation MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis.
The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering drugs, beta-blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of aspirin (75-325 mg once daily).
In patients with ST-segment elevation acute myocardial infarction, safety and efficacy of clopidogrel have been evaluated in two randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.
The randomised, double-blind, placebo-controlled CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation myocardial infarction and planned for thrombolytic therapy. Patients were randomised to receive either clopidogrel (300 mg loading dose, followed by 75 mg/day; n = 1752) or placebo (n = 1739), together with aspirin (150 to 325 mg loading dose followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin for 48 hours. The patients were followed for 30 days.
The primary endpoint was the occurrence of the composite of an occluded infarct-related artery (defined as TIMI Flow grade 0 or 1) on the predischarge angiogram, or death or recurrent myocardial infarction by the time of the start of coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by day 8 or by hospital discharge, if prior to day 8.
The patient population was mostly Caucasian (89.5%) and included 19.7% women and 29.2% were 65 years or over. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors and 63% statins.
The number of patients who reached the primary endpoint was 262 (15.0%) in the clopidogrel-treated group and 377 (21.7%) in the placebo group, representing an absolute reduction of 6.7% and a 36% reduction in the odds of the endpoint in favour of treatment with clopidogrel (95% CI: 0.53, 0.76; p < 0.001), as shown in Table 5, mainly related to a reduction in occluded infarct-related arteries.
The benefit of clopidogrel on the primary endpoint was consistent across all prespecified subgroups, including patients' age, gender, infarct location and type of fibrinolytic or heparin used.
The randomised, double-blind, placebo-controlled, 2 x 2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected myocardial infarction with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle branch block). Patients were randomised to receive clopidogrel (75 mg/day) or placebo, in combination with aspirin (162 mg/day), for 28 days or until hospital discharge, whichever came first.
The coprimary endpoints were death from any cause and the first occurrence of reinfarction, stroke or death. The patient population included 27.8% women, 58.4% 60 years or over (26% 70 years or over) and 54.5% patients who received fibrinolytics, 68% who received ACE-inhibitors and 10.9% who received non-trial beta-blockers (as well as half of the patients who received metoprolol as study medication).
As shown in Table 6 and Figure 2 and Figure 3, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029) and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002), representing an absolute risk reduction of 5 and 9 patients per 1000 treated (0.5 and 0.9%), respectively.
The benefit associated with clopidogrel on the combined endpoint was consistent across age, gender and with or without fibrinolytics and was observed as early as 24 hours.

5.2 Pharmacokinetic Properties

Absorption.

After single and repeated oral doses of 75 mg/day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 nanogram/mL after a single 75 mg oral dose) occurred approximately 45 minutes after dosing. The increase in area under the curve (AUC) in the range of 75 to 300 mg is dose proportional, while the Cmax increases by 3-fold for a 4-fold increase in dose. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Metabolism.

Clopidogrel is extensively metabolised by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes including CYP3A4, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing.

Distribution.

Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro over a wide concentration range.

Excretion.

Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120 hour interval after dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half life of the active metabolite is about 30 minutes.

Pharmacogenetics.

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite.
The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and *3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function alleles in white (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent, and include, but are not limited to, CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as defined above. Published frequencies for poor CYP2C19 metaboliser genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese and are listed in Table 7. Tests are available to determine a patient's CYP2C19 genotype.
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 microM ADP) of 24% (24 hours) and 37% (day 5) as compared to IPA of 39% (24 hours) and 58% (day 5) in the extensive metabolisers and 37% (24 hours) and 60% (day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (day 5), which were greater than in poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials (see Section 4.2 Dose and Method of Administration). (See Table 8.)
Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 microM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.
The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have, however, been a number of retrospective analyses to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n = 2721), CHARISMA (n = 2428), CLARITY-TIMI 28 (n = 227), and TRITON-TIMI 38 (n = 1477) and ACTIVE-A (n = 601), as well as a number of published cohort studies.
In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.
In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.
In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.
None of these analyses were adequately sized to detect differences in outcome in poor metabolisers.

Special populations.

The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.

Geriatric patients.

Plasma concentrations of the main circulating metabolite are significantly higher in the elderly (≥ 75 years) compared to young healthy volunteers but these higher plasma levels were not associated with differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.

Renal impairment.

After repeated doses of 75 mg clopidogrel per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, the prolongation of bleeding time was similar in healthy volunteers receiving 75 mg of clopidogrel per day. No dosage adjustment is needed in renally impaired patients. However, experience with clopidogrel is limited in patients with severe renal impairment. Therefore clopidogrel should be used with caution in this population.

Gender.

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.

Ethnicity.

The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Section 5.2 Pharmacokinetic Properties, Excretion, Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

5.3 Preclinical Safety Data

Genotoxicity.

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by the oral route in mice).

Carcinogenicity.

There was no evidence of carcinogenic effects when clopidogrel was given in the diet for 78 weeks to mice and 104 weeks to rats at doses up to 77 mg/kg per day (representing an exposure ≈ 18 times the anticipated patient exposure, based on plasma AUC for the main circulating metabolite in elderly subjects).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains mannitol, macrogol 6000, microcrystalline cellulose, hydrogenated castor oil, hyprolose, carnauba wax, Opadry II complete film coating system 32K14834 Pink (coating contains lactose monohydrate).

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, 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.

6.5 Nature and Contents of Container

Clopidogrel Winthrop 75 mg is available in blister packs (PVC/PVDC/Al) containing 28 tablets.
Clopidogrel Winthrop is a registered trademark of Sanofi-Aventis.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Clopidogrel hydrogen sulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It is freely soluble in methanol, sparingly soluble in methylene chloride and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.

Chemical structure.

Clopidogrel hydrogen sulfate has the following chemical structure:
Molecular Formula: C16H16ClNO2S.H2SO4.
Molecular Weight: 419.9.
Chemical Name: methyl (+)-(S)- α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5(4H)-acetate sulfate (1:1).

CAS number.

120202-66-6 (clopidogrel hydrogen sulfate), 113 665-84-2 (clopidogrel base).

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes