Consumer medicine information

CLOPIDOGREL ACTAVIS

Clopidogrel

BRAND INFORMATION

Brand name

Clopidogrel Actavis

Active ingredient

Clopidogrel

Schedule

What Clopidogrel Actavis is used for

Clopidogrel Actavis contains the medicine clopidogrel. Clopidogrel Actavis 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 Actavis 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 Actavis 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).

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

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

Before you take Clopidogrel Actavis

When you must not take Clopidogrel Actavis

You should not take Clopidogrel Actavis if:

you are allergic to clopidogrel or any of the ingredients listed under 'Product Description' 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.
you are breast feeding or intend to breast feed. Clopidogrel Actavis passes into breast milk and, therefore, there is the possibility that the breast fed baby may be affected.
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 Actavis to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

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

Before you start to take Clopidogrel Actavis

You must tell your doctor if:

You are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of taking Clopidogrel Actavis during pregnancy.
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 Clopidogrel Actavis prior to surgery.
If you have or have had any medical conditions, especially the following:
- bleeding disorders or blood clotting 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)
- any form of liver disease

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

Taking other medicines

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

Some medicines and Clopidogrel Actavis may interfere with each other. 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.
phenytoin - a medicine used to treat epilepsy
tolbutamide - a medicine used to treat diabetes
tamoxifen - a medicine used to treat breast cancer
fluvastatin - a medicine used to lower cholesterol.

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

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

If you are unsure about any medicine you are taking you should check with your doctor or pharmacist. They will have more information on medicines to be careful with or avoid while taking Clopidogrel Actavis.

How to take Clopidogrel Actavis

Your doctor will tell you how many tablets to take each day. Take Clopidogrel Actavis 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 Actavis is one 75 mg tablet daily. You can take Clopidogrel Actavis before or after meals. You should swallow the tablet with a glass of water.

Take Clopidogrel Actavis at about 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.

You should take Clopidogrel Actavis for as long as your doctor continues to prescribe it.

If you forget to take it

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

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 Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Clopidogrel Actavis. Do this even if there are no signs of discomfort or poisoning.

While you are taking Clopidogrel Actavis

Things you must do

Take Clopidogrel Actavis exactly as your doctor has prescribed, and have any blood tests promptly if your doctor orders them.
Tell your doctor if you become pregnant while taking Clopidogrel Actavis.
Tell your doctor if you decide to breast feed your baby. Your doctor may want to discuss this and change your medicine.
Tell your doctor that you are taking Clopidogrel Actavis if you are about to start on any new medicine.
Tell all your doctors, dentists, nurses and pharmacists that you are taking Clopidogrel Actavis. Clopidogrel Actavis 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 Actavis and if so, how long before surgery or dental work.
Ask you doctor whether there are any activities you should avoid while taking Clopidogrel Actavis, for example certain sports. 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 Actavis.
It may take longer than usual to stop bleeding while you are taking Clopidogrel Actavis.
Tell your doctor immediately if you notice any of the following:
- abnormal bruising orbleeding 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)

Do not suddenly stop taking Clopidogrel Actavis without telling your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how Clopidogrel Actavis affects you. As with other NSAID medicines, Clopidogrel Actavis may cause dizziness, drowsiness or blurred vision in some people.

Make sure you know how you react to Clopidogrel Actavis before you drive a car, operate machinery, or do anything else that could be dangerous if you are not alert.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Clopidogrel Actavis tablets. Like other medicines Clopidogrel Actavis can cause some side effects. Most are likely to be minor and temporary. However, some may be serious and need medical attention.

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

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

diarrhoea
itching
pain or stiffness in the joints
things taste different.

Tell your doctor immediately if you notice any of the following:

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

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
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
numbness (paralysis) or problems with co-ordination
nausea or vomiting
faintness or dizziness
light-headedness or blurred vision
slurred speech or other difficulty in speaking
headache (severe and continuing)
confusion or hallucinations
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)
red or purple spots visible through your skin
itching, inflamed, cracking or red skin
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.

These could be more serious side effects - you may need urgent medical attention.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of side effects. Most people do not experience any of them.

After taking Clopidogrel Actavis

Storage

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.

Keep Clopidogrel Actavis in a cool, dry place where the temperature stays below 25 degrees C. Heat and dampness can destroy some medicines. Do not leave Clopidogrel Actavis in the car on hot days.

Do not store Clopidogrel Actavis or any other medication in the bathroom or near a sink.

Keep Clopidogrel Actavis 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.

Disposal

If your doctor tells you to stop taking Clopidogrel Actavis, ask your pharmacist what to do with any tablets that are left over.

Product description

What Clopidogrel Actavis looks like

Clopidogrel Actavis comes as pink round biconvex tablets with 'II' engraved on one side.

A box contains 28 tablets.

Active Ingredient:
clopidogrel 75 mg

Other Ingredients:

lactose anhydrous
cellulose-microcrystalline
crospovidone
glyceryl behenate
talc - purified
polyvinyl alcohol, talc-purified, titanium dioxide, macrogol 3350, lecithin, iron oxide red C177491

Supplier

Actavis Australia Pty Ltd
Upper Ground Floor
183 Melbourne Street
North Adelaide SA 5006
Australia
Tel: 1300 881 893

Australian Register Number
75 mg tablets: Bottle: AUST R 164865
Blister: AUST R 164866

This leaflet was prepared in February 2012.

Published by MIMS April 2012

BRAND INFORMATION

Brand name

Clopidogrel Actavis

Active ingredient

Clopidogrel

Schedule

Name of the medicine

Clopidogrel besilate.

Excipients.

Tablet.

Anhydrous lactose, microcrystalline cellulose, crospovidone, glyceryl behenate, purified talc.

Coating.

Polyvinyl alcohol, purified talc, titanium dioxide, macrogol 3350, lecithin, iron oxide red C177491.

Description

Chemical name: (+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine-5-yl-acetic acid methyl ester benzene sulfonate. Molecular formula: C₁₆H₁₆ClNO₂S.C₆H₆O₃S. MW: 479.99. CAS: 744256-69-7. Clopidogrel besilate is a white to almost white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It is freely soluble in methanol, acetonitrile and dichloromethane. It has a specific optical rotation of +47-51 deg.

Pharmacology

Pharmacodynamics.

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 antiplatelet 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.
Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet 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. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxoclopidogrel and subsequent hydrolysis. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet ADP receptors, P2Y12, thus 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.

Pharmacokinetics.

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.
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 (approximately 3 mg/L after repeated 75 mg oral doses) occurred approximately one 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.
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.
Following an oral dose of ¹⁴C-labelled clopidogrel in humans, 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.
Plasma concentrations of the main circulating metabolite were significantly higher in elderly subjects (≥ 75 years) as compared to young healthy volunteers. However, these higher plasma levels were not associated with differences in platelet aggregation and bleeding time.
Plasma levels of the main circulating metabolite were lower in subjects with severe renal disease (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal disease (creatinine clearance from 30 to 60 mL/min) and healthy subjects, after repeated doses of 75 mg/day. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, the prolongation of bleeding was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day.
A bioavailability study was conducted comparing a generic clopidogrel 75 mg tablet product with an originator reference product. Administration of a single oral dose of 75 mg clopidogrel to healthy subjects under fasting conditions a mean peak plasma concentration of clopidogrel of 1.3 nanogram/mL within 0.25 to 5 hours for the generic and within 0.25 to 3.5 hours for the reference. The mean AUC_0-∞ for both products was approximately 2.1 nanogram.hr/mL with an elimination half-life of approximately 4.5 hours for the generic and 4.2 hours for the reference.

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 1. 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 Dosage and Administration).

Special populations.

Pharmacokinetics in the elderly.

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.

Pharmacokinetics in patients with impaired renal function.

After repeated doses of clopidogrel 75 mg 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 clopidogrel 75 mg 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 versus Aspirin in Patients at Risk of Ischaemic 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 Pharmacology, Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

Clinical Trials

The safety and efficacy of clopidogrel in preventing vascular ischaemic events have been evaluated in the CAPRIE study, a double blind clinical trial comparing clopidogrel to aspirin. In addition, three other studies (CURE, CLARITY and COMMIT) have been conducted for unapproved indications.

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 3, clopidogrel was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.78 versus 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.

Pharmacogenetics.

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.
Such studies have included CHARISMA (n = 2428) and TRITON-TIMI 38 (n = 1477), as well as a number of published cohort studies.
In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Guisti), 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 the study by Trenk et al, the *2 allele variant of CYP2C19 was associated with high platelet reactivity in patients on clopidogrel and this high platelet reactivity was in turn associated with increased risks of death and MI in the first year after elective stent replacement.
None of these analyses was adequately sized to detect differences in outcome in poor metabolisers.

Indications

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

Contraindications

Hypersensitivity to clopidogrel or any of the excipients.
Severe liver impairment.
Active pathological bleeding, e.g. peptic ulcer and intracranial haemorrhage.
Breastfeeding (see Precautions, Use in pregnancy and Use in lactation).

Precautions

As with the other antiplatelet 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, as follows.
If a patient is to undergo elective surgery and an antiplatelet 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), the drug should be used with caution in patients who have lesions with a propensity to bleed. Drugs that might induce such lesions (such as aspirin and NSAIDs) should be used with caution in patients taking clopidogrel (see Interactions with Other Medicines).
Patients should be told that it may take longer than usual for bleeding to stop when they take clopidogrel and that they should report any unusual bleeding (site or duration) to their doctor. Patients should inform doctors 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.

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 Adverse Effects).

Cardiovascular.

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).

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 Pharmacology, Pharmacogenetics and Clinical Trials, Pharmacogenetics). 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 Pharmacology, 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 Dosage and Administration, Pharmacogenetics).

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 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 Adverse 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. As with other antiplatelet 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, nonsteroidal 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.

Impaired renal function.

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

Impaired hepatic function.

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.

Carcinogenesis, mutagenesis, impairment of fertility.

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 approx. 18 times the anticipated patient exposure, based on plasma area under the curve (AUC) for the main circulating metabolite in elderly subjects).
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).
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).

Use in pregnancy.

(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 orally, 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.

Use in lactation.

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in breast milk (see Contraindications).

Effect on ability to drive and use machines.

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

Interactions

Aspirin.

A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to increased risk of bleeding.

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.

Antiplatelet 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.

Glycoprotein IIb/IIIa inhibitors.

As a pharmacological interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.

Thrombolytics.

The safety of the concomitant administration of clopidogrel, fibrin or nonfibrin 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 coadministered with aspirin. However, the use of clopidogrel with thrombolytic agents should be undertaken with caution.

Oral anticoagulants (including warfarin).

Clopidogrel inhibits platelet aggregation, so patients receiving both clopidogrel and warfarin may be at an increased risk of bleeding; concomitant administration of warfarin and clopidogrel is not recommended.

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. Consequently, there is a potential increased risk of gastrointestinal bleeding and NSAIDs and clopidogrel should be coadministered with caution (see Precautions).

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 nonsteroidal 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 coadministered with clopidogrel.

Other concomitant therapy.

Since clopidogrel is metabolised to its active metabolite party 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. Concomitant use of drugs that inhibit CYP2C19 (e.g. omeprazole) should be discouraged.
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 coadministered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital (phenobarbitone), cimetidine or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
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, antidiabetic agents (including insulin), antiepileptic agents, GPIIb/IIIa antagonists and hormone replacement therapy without evidence of clinically significant adverse interactions.

Adverse Effects

Clinical studies experience.

Clopidogrel has been evaluated for safety in more than 42,000 patients, including over 9000 patients treated for one year or more. The clinically relevant adverse events observed in CAPRIE 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.
However, when clopidogrel is used concomitantly with aspirin a small but significant increase in 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 2.5% placebo + aspirin) has been observed. 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 intracranial 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.

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 less than or equal to 30 x 10⁹/L have been reported.
Severe neutropenia (< 0.45 x 10⁹/L) was observed in four patients (0.04%) who received clopidogrel and in two patients who 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.
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 two years of treatment. Adverse events occurring in greater than or equal to 2.5% of patients on clopidogrel in the CAPRIE controlled clinical trial are shown in Table 4 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 greater than or equal to 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: greater than or equal to 1/1000 (0.1%) and < 1/100 (1%) and rare: greater than or equal to 1/10,000 (0.01%) and < 1/1000 (0.1%).

Central and peripheral nervous system disorders.

Uncommon: paraesthesia. Rare: vertigo.

Gastrointestinal system disorders.

Uncommon: flatulence, constipation, vomiting, gastric, peptic or duodenal ulcer.

Platelet, bleeding and clotting disorders.

Uncommon: bleeding time increased.

White cell and reticuloendothelial system disorders.

Uncommon: leucopenia and eosinophilia.

Postmarketing experience.

The following have been reported spontaneously from worldwide postmarketing experience.
Very common: ≥ 1/10 (≥ 10%).
Common: ≥1/100 and < 1/10 (≥ 1% and < 10%).
Uncommon: ≥ 1/1,000 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%).

Musculoskeletal, connective and bone.

Very rare: arthralgia, arthritis, myalgia.

Immune system disorders.

Very rare: anaphylactoid reactions, serum sickness.

Vascular disorders.

Very rare: vasculitis, hypotension.

Blood and lymphatic system disorders.

Very rare: serious cases of bleeding, mainly skin, musculoskeletal (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 Interactions with Other Medicines).
Very rare cases of thrombotic thrombocytopenic purpura (TTP) 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 or erythematous rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), eczema, lichen planus.

Psychiatric.

Very rare: confusion, hallucinations.

Nervous system disorders.

Very rare: taste disturbances.

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.

Renal and urinary disorders.

Very rare: glomerulopathy.

Investigations.

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

General disorders and administration site conditions.

Very rare: fever, syncope.

Dosage and 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.
No dosage adjustment is necessary for either elderly patients or patients with renal impairment (see Pharmacology, Pharmacokinetics).

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 Pharmacology, 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.

Overdosage

For advice on the management of overdosage, please contact the Poisons Information Centre on 131 126.
In animals, clopidogrel at single oral doses greater than or equal to 1500 mg/kg caused necrotic haemorrhagic gastritis, oesophagitis and enteritis in mice, rats and baboons. Necrotic tubulopathy and tubulointerstitial 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.

Presentation

Tablets, 75 mg (pink, round, biconvex, film coated, marked II on one side): 7's*, 10's*, 14's*, 20's*, 28's, 30's*, 50's*, 56's*, 60's*, 90's* (blister pack, AUST R 164866); 90's, 112's, 120's (bottle*, AUST R 164865).
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.

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Clopidogrel Actavis Tablets 75 mg