Consumer medicine information

Clopidogrel Sandoz

Clopidogrel

BRAND INFORMATION

Brand name

Clopidogrel Sandoz

Active ingredient

Clopidogrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Clopidogrel Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

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

What Clopidogrel Sandoz is used for

This medicine is used to reduce blood clots forming and to reduce the risk of heart attack, stroke or death in patients who have previously suffered a heart attack, stroke or have a condition known as peripheral arterial disease (leg pain when walking or at rest).

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

It works by preventing blood clots to form in hardened blood vessels. This process is called atherothrombosis and can lead to events such as stroke, heart attack or death.

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

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

Before you take Clopidogrel Sandoz

When you must not take it

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

  • clopidogrel, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under 'Product description'.

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine if you have or have had:

  • severe liver disease
  • a medical condition that is causing bleeding such as stomach ulcer or bleeding within your head.

Do not breastfeed if you are taking this medicine. The active ingredient in Clopidogrel Sandoz passes into breast milk and there is a possibility that your baby may be affected.

Do not give this medicine to a child under the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established.

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

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

Before you start to take it

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

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

  • bleeding disorders or blood clotting problems
  • any illness or disability that was caused by bleeding such as impaired sight or vision because of bleeding within the eye
  • recent serious injury
  • recent surgery (including dental surgery)
  • liver or kidney problems
  • allergic to other antiplatelet medicines (such as ticlopidine, prasugrel).

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you 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 taking your medicine prior to surgery.

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

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

Taking other medicines

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

Some medicines and Clopidogrel Sandoz may interfere with each other. These include:

  • medicines that thin the blood such as aspirin, heparins and warfarin. There are others, so please check with your doctor.
  • non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen which are used to relieve pain, swelling and other symptoms of inflammation, including arthritis, period pain, aches and pains.
  • medicines used to treat or prevent stomach ulcers or reflux disease (also called heartburn)
  • some medicines used to treat infections (e.g. ciprofloxacin, chloramphenicol, fluconazole and voriconazole)
  • some antidepressant medicines
  • medicines used to treat epilepsy (e.g. carbamazepine, oxcarbazepine and phenytoin)
  • medicines used to treat breast cancer (e.g. tamoxifen, paclitaxel)
  • medicines used to treat diabetes (e.g. tolbutamide, repaglinide)
  • 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.

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

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

How to take Clopidogrel Sandoz

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

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

How much to take

The standard dose for this medicine is one 75 mg tablet daily.

If you are prescribed Clopidogrel Sandoz tablets 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.

Your doctor may have prescribed a different dose.

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

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

How and when to take Clopidogrel Sandoz

Swallow the tablets whole with a glass of water before or after meals.

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

How long to take Clopidogrel Sandoz

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

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

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 that you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Clopidogrel Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Clopidogrel Sandoz

Things you must do

Take your medicine exactly as prescribed by your doctor and have any blood tests done promptly if your doctor orders them.

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

Tell your doctor if you decide to breast feed your baby. Your doctor may want to discuss this and change your medicine.

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

Tell any other doctors, dentists, nurses and pharmacists who treat you that you are taking this medicine. This medicine 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 Sandoz and if so, how long before surgery or dental work.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Ask your doctor whether there are any activities such as certain sports that you should avoid while taking Clopidogrel Sandoz. Sometimes after an injury bleeding may occur inside your body without you knowing about it.

Tell your doctor immediately if you are injured while taking Clopidogrel Sandoz. It may take longer than usual to stop bleeding while you are taking it.

Tell your doctor immediately 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).

Things you must not do

Do not take Clopidogrel Sandoz to treat any other complaints unless your doctor tells you to.

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

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

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. As with other medicines, Clopidogrel Sandoz may cause faintness or dizziness in some people. Make sure you know how you react to this medicine 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.

Side effects

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

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

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

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

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

  • diarrhoea
  • itching
  • pain or stiffness in the joints
  • things taste different
  • hunger
  • trembling
  • flushing
  • a fast, pounding heart beat

These are mild side effects of the medicine.

Tell your doctor as soon as possible if you notice any of the following:

  • itching, inflamed, cracking or red skin, rash or hives
  • bloody or black bowel motions
  • diarrhoea with blood, mucus, stomach pain and fever
  • red or purple spots visible through your skin
  • chest pain
  • abdominal or stomach pain
  • bleeding (including nose bleeds) or bruising more easily than normal
  • unusually heavy or unexpected menstrual bleeding
  • breast enlargement in men
  • nausea or vomiting
  • faintness or dizziness
  • fever or other signs of infection such as a sore throat
  • rash or hives
  • chills, sweating or clammy skin
  • fever, muscle weakness, loss of appetite and fatigue
  • muscle pain
  • weight loss
  • anaemia (being tired and looking pale).

The above list includes serious side effects that may require medical attention.

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

  • vomiting of blood or vomit that looks like coffee grounds
  • coughing up blood
  • blood in the urine
  • blood in the eyes
  • unusually heavy bleeding or oozing from cuts or wounds
  • numbness (paralysis) or problems with co-ordination
  • light-headedness or blurred vision
  • slurred speech or other difficulty in speaking
  • severe and continuing headache
  • confusion or hallucination
  • tightness of the chest, wheezing, coughing or difficulty breathing
  • yellowing of the skin or the whites of the eyes, pale stools and dark urine with vomiting and stomach pain
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.

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

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

After taking Clopidogrel Sandoz

Storage

Keep your medicine in the original container.

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

Keep your medicine in a cool dry place where the temperature stays below 25°C.

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

Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

Clopidogrel Sandoz 75 mg - Pink coloured film-coated round shaped tablets with SZ/75 imprinted on one side and plain on the other side.

Available in blisters of 28 tablets.

Ingredients

Active ingredient:

  • Clopidogrel Sandoz 75 mg - 97.875 mg clopidogrel hydrogen sulfate (equivalent to 75 mg clopidogrel).

Inactive ingredients:

  • mannitol
  • microcrystalline cellulose
  • hyperlose
  • hydrogenated vegetable oil
  • Opadry Pink 03B54942
  • Opacode S-1-27794 Black.

This medicine does not contain lactose, sucrose or gluten.

Suppliers

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park NSW 2113
Australia
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102, Newmarket
Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was revised in May 2020.

Australian Register Number

75mg film-coated tablet: AUST R 155046

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Clopidogrel Sandoz

Active ingredient

Clopidogrel

Schedule

S4

 

1 Name of Medicine

Clopidogrel hydrogen sulfate.

2 Qualitative and Quantitative Composition

Each Clopidogrel Sandoz 75 mg film-coated tablets contains 75 mg clopidogrel hydrogen sulfate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Clopidogrel Sandoz 75 mg film-coated tablets.

Pink coloured film-coated round shaped tablets with SZ/75 imprinted on one side and plain 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.

4.2 Dose and Method of Administration

Dosage.

Adults.

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

Method of administration.

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

Dosage adjustment.

Elderly.

No dosage adjustment is necessary for either elderly patients or patients with renal impairment. (See Section 5.2 Pharmacokinetic Properties.)

Children and adolescents.

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

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, 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.

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, Use in pregnancy, Use in 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) or selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers as follows:
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 the drug 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 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 5.2 Pharmacokinetic Properties, Pharmacogenetics; Section 5.1 Pharmacodynamic Properties, Clinical trials, 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, 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, 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. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Acquired haemophilia.

Acquired haemophilia has been reported following the 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 allergic 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, Dose adjustment, 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. See Section 4.4 Special Warnings and Precautions for Use, General.

Oral anticoagulants (including warfarin).

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

Glycoprotein IIb/IIIa inhibitors.

Clopidogrel 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 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 with thrombolytic agents has not been formally established and should be undertaken with caution.

Acetylsalicylic acid (ASA).

Clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and ASA have been administered together for up to one year.

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.

Nonsteroidal 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 SSRI's 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 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.

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 and a reduction in clinical efficacy. 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, 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, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, ticlopidine 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 micromolar 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 pharmacodynamics 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)/ pharmacodynamics (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, cimetidine, 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 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 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 parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

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.
Please note the following additional information is sourced from 3 studies that have been conducted for unapproved indications.
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%).

Rash.

In CAPRIE, there were significantly more patients with rash in the clopidogrel group (4.2%) compared to the aspirin group (3.5%).

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.
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, diarrhoea. 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: musculo-skeletal bleeding (haemarthrosis), arthralgia, arthritis, myalgia.

Immune system disorders.

Uncommon: cross reactive hypersensitivity amongst thienopyridine (such as ticlopidine, prasugrel) (see Section 4.4 Special Warnings and Precautions for Use). Very rare: anaphylactoid reactions, serum sickness. Not known: insulin autoimmune syndrome, which can lead to severe hypoglycaemia, particularly in patients with HLA DR A4 subtype (more frequent in the Japanese population).

Cardiac disorders.

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

Vascular disorders.

Common: haematoma. Very rare: vasculitis, hypotension.

Blood and lymphatic system disorders.

Uncommon: thrombocytopenia, eosinophilia, leucopenia, decreased neutrophils, decreased platelets, increased bleeding time. Rare: neutropenia (including severe neutropenia). Very rare: serious cases of bleeding, mainly skin, musculo-skeletal (haemarthrosis, haematoma), eye (conjunctival, ocular, retinal), 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), aplastic anaemia, pancytopenia, agranulocytosis, granulocytopenia, anaemia.
Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported. Very rare cases of acquired haemophilia A have been reported.

Skin and subcutaneous tissue disorders.

Common: bruising. Uncommon: rash, pruritus, skin bleeding (purpura). Very rare: maculopapular, exfoliative or erythematous rash, urticaria, 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.

Uncommon: intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness. Very rare: taste disturbances. Not known: ageusia.

Eye disorders.

Very rare: serious cases of eye bleeding (conjunctival, ocular, retinal).

Ear and labyrinth disorders.

Rare: vertigo.

Hepatobiliary disorders.

Very rare: hepatitis, acute liver failure, abnormal liver function test.

Gastrointestinal disorders.

Common: gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia. Uncommon: gastric ulcer and duodenal ulcer, vomiting, gastritis, nausea, constipation, flatulence. Rare: retro-peritoneal haemorrhage. Very rare: gastrointestinal and retroperitoneal haemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.

Respiratory, thoracic and mediastinal disorders.

Common: epistaxis. Very rare: respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.

Renal and urinary disorders.

Uncommon: haematuria. Very rare: glomerulopathy, glomerulonephritis, blood creatinine increased.

Reproductive systems and breast disorders.

Very rare: gynaecomastia.

Investigations.

Uncommon: bleeding time prolonged, neutrophil count decreased, platelet count decreased. Very rare: blood creatinine increase, abnormal liver function tests.

General disorders and administration site conditions.

Common: bleeding at the puncture site. 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 131126 (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 adenosine diphosphate (ADP) to its platelet P2Y12 receptor, and the subsequent ADP mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of 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 double blind clinical trial comparing clopidogrel to aspirin. In addition, three other studies (CURE, CLARITY and COMMIT), 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.

5.2 Pharmacokinetic Properties

Absorption.

After repeated oral doses of 75 mg per day, a single oral dose of clopidogrel is rapidly absorbed. However, plasma concentrations of the parent compound are very low and below the quantification limit (0.00025 mg/L) beyond 2 hours. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution.

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

Metabolism.

Clopidogrel is extensively metabolised by the liver and the main metabolite, which is inactive, is the carboxylic acid derivative which represents about 85% of the circulating compound in plasma. Peak plasma levels of this metabolite (approx. 3 mg/L after repeated 75 mg oral doses) occurred approximately 1 hour after dosing.
The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel.

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. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration.
Administration of a single dose of 75 mg clopidogrel to healthy subjects under fasting conditions achieved a mean peak plasma concentration of clopidogrel of 605.65 picogram/mL within 0.76 hours for Clopidogrel Sandoz and 635.81 picogram/mL within 0.90 hours for a reference clopidogrel film coated tablet product. The mean AUC0-inf was 978.80 picogram.h/mL for Clopidogrel Sandoz and 1067.41 picogram.h/mL for a reference clopidogrel film coated tablet product. The elimination half-life of clopidogrel was 4.5 hours after single administration of Clopidogrel Sandoz.

Pharmacogenetics.

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxoclopidogrel 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 5. 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 6.
The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomized, 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. Such studies have included CHARISMA (n = 2428) and TRITONTIMI 38 (n = 1477), as well as a number of published cohort studies.

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.

Renally impaired patients.

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.

No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. 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, 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, microcrystalline cellulose, hyperlose, hydrogenated vegetable oil, Opadry Pink 03B54942 and Opacode S-1-27794 Black.

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 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Clopidogrel Sandoz 75 mg film-coated tablets are available in Al/Al or PVC/PCTFE (Aclar)/AL blister pack containing 28 tablets.

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.


Chemical name: Methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate sulfate (1:1).
Molecular formula: C16H16ClNO2S.H2SO4.
Molecular weight: 419.9.

CAS number.

120202-66-6 (clopidogrel hydrogen sulfate).
113665-84-2 (clopidogrel base).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes