Consumer medicine information

Clovix 75 Tablets

Clopidogrel

BRAND INFORMATION

Brand name

Clovix

Active ingredient

Clopidogrel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clovix 75 Tablets.

What is in this leaflet

This leaflet answers some common questions about CLOVIX 75.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking CLOVIX 75 against the benefits they expect it will have for you.

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

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

What CLOVIX 75 is used for

CLOVIX 75 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).

CLOVIX 75 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 CLOVIX 75 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.

CLOVIX 75 is only available on a doctor's prescription.

Before you take CLOVIX 75

When you must not take it

You should not take CLOVIX 75 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. CLOVIX 75 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 CLOVIX 75 to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

CLOVIX 75 is not recommended for children as its safety and effectiveness in children have not been established.

Before you start to take it

You must tell your doctor if:

  • you have allergies to any other medicines, foods, preservatives or dyes.
  • you are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of taking CLOVIX 75 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 CLOVIX 75 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 them before you start taking CLOVIX 75.

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 CLOVIX 75 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.
  • medicines used to treat stomach ulcers or reflux disease (also called heartburn)
  • 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 CLOVIX 75 or affect how well CLOVIX 75 works.

You may need different amounts of your medicines, or you may need to take different medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking CLOVIX 75.

How to take CLOVIX 75

How to take it

Take CLOVIX 75 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 CLOVIX 75 is one 75mg tablet daily.

Your doctor may have prescribed a different dose.

You can take CLOVIX 75 before or after meals. You should swallow the tablet with a glass of water.

Take CLOVIX 75 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 CLOVIX 75 for as long as your doctor continues to prescribe it.

If you forget to take CLOVIX 75

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 the Poisons Information Centre (telephone 13  11  26), or go to the Emergency Department at your nearest hospital, if you think that you or anyone else may have taken too much CLOVIX 75. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking CLOVIX 75

Things you must do

  • Take CLOVIX 75 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 CLOVIX 75.
  • 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 CLOVIX 75 if you are about to start on any new medicine.
  • Tell all your doctors, dentists, nurses and pharmacists that you are taking CLOVIX 75. CLOVIX 75 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 CLOVIX 75 and if so, how long before surgery or dental work.
  • Ask you doctor whether there are any activities you should avoid while taking CLOVIX 75, 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 CLOVIX 75. .
It may take longer than usual to stop bleeding while you are taking CLOVIX 75.
  • 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)

Do not suddenly stop taking CLOVIX 75 without telling your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how CLOVIX 75 affects you.

As with other medicines, CLOVIX 75 may cause faintness or dizziness in some people. Make sure you know how you react to CLOVIX 75 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 CLOVIX 75 tablets.

Like other medicines CLOVIX 75 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:

  • 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 using CLOVIX 75

Storage

Keep CLOVIX 75 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.

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of their packaging they may not keep well.

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

Do not store CLOVIX 75 or any other medicine in the bathroom or near a sink.

Do not leave CLOVIX 75 in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking CLOVIX 75, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

CLOVIX 75 comes as pink round biconvex film-coated tablet with “II” on one side.

Available in blister packs containing 28 tablets.

Ingredients

The active ingredient in CLOVIX 75 is clopidogrel. Each tablet contains 75 mg clopidogrel.

The tablet also contains:

  • lactose anhydrous
  • microcrystalline cellulose
  • crospovidone
  • glyceryl behenate
  • talc
  • polyvinyl alcohol
  • titanium dioxide
  • macrogol 3350
  • lecithin
  • iron oxide red

Sponsor

Spirit Pharmaceuticals Pty. Limited
117 Harrington Street
The Rocks, Sydney NSW 2000
Australia
1800 065 772

Distributor

Sigma Pharmaceuticals (Australia) Pty Ltd
96 Merrindale Drive
Croydon VIC 3136
Australia

Australian registration numbers:
CLOVIX 75 - AUST R 155942

Date of preparation:
January 2010

™Trade Mark

Published by MIMS September 2010

BRAND INFORMATION

Brand name

Clovix

Active ingredient

Clopidogrel

Schedule

S4

 

Name of the medicine

Clopidogrel besilate.

Excipients.

Anhydrous lactose, microcrystalline cellulose, crospovidone, glyceryl behenate and talc. The coating contains talc, polyvinyl alcohol, titanium dioxide, macrogol 3350, lecithin and iron oxide red.

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: C16H16CINO2S.C6H6O3S. MW: 479.99. CAS: 744256-69-7. Clopidogrel besilate is a white to almost white powder. It is practically insoluble in water. It is very soluble in methanol, acetonitrile and dichloromethane.

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 (i.e. Tmax) of this metabolite 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.
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 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.
After administration of a single dose of two 75 mg (150 mg) clopidogrel to healthy subjects under fasting conditions, a mean peak plasma concentration of clopidogrel of 3307.1 pg/mL within 1 hour for Clovix 75 and 3357.4 pg/mL within 0.84 hours for the reference clopidogrel product was achieved. The mean AUC0-∞ was 6557.9 pg.hr/mL for Clovix 75 and 6730.7 pg.hr/mL for the reference clopidogrel product. The mean elimination half-life of clopidogrel was 6.8 hours after single dose of two 75 mg (150 mg) Clovix 75 tablets.

Pharmacogenetics.

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite.

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.

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. 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 has been evaluated in four double blind studies: the CAPRIE study, a comparison of clopidogrel to aspirin, and the CURE, CLARITY and COMMIT studies, which compared clopidogrel in combination with aspirin, to placebo with aspirin.

Myocardial infarction or stroke, or established peripheral arterial disease.

The CAPRIE study included 19,185 patients with established atherosclerosis or history of atherothrombosis as manifested by myocardial infarction, ischaemic stroke or peripheral arterial disease. Patients were randomised to clopidogrel 75 mg/day or aspirin 325 mg/day, and were followed for 1 to 3 years.
The trial's primary outcome was the time to first occurrence of new ischaemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.
As shown in Table 1, 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.

Acute coronary syndrome.

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

Indications

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

Acute coronary syndrome.

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

Contraindications

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

Precautions

General.

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 prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Drugs that might induce such lesions (such as aspirin and nonsteroidal anti-inflammatory drugs) 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 (alone or in combination with aspirin), and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of aspirin and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.

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).

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 and Clinical Trials). 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).

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 Pharmacology and Precautions). 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.

Renal impairment.

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

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).

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 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. Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution. 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.

Carcinogenicity, mutagenicity and 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 ≈ 18 times the anticipated patient exposure, based on plasma 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 PO, respectively, revealed no evidence of embryotoxicity or teratogenicity. There are no adequate and well controlled studies in pregnant women. As 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).

Effects 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. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and aspirin have been administered together for up to one year. See also Precautions, General.

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.

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.

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. The safety of concomitant administration of clopidogrel with thrombolytic agents has not been formally established and 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 since it may increase the intensity of bleeding.

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.

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 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 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. Concomitant use of drugs that inhibit CYP2C19 (e.g. omeprazole) should be discouraged. 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.
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, 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.
Coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on haemostasis.
In addition to the above specific interaction studies, patients entered into clinical trials with clopidogrel (including CAPRIE, CURE, CLARITY and COMMIT) received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, 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 9,000 patients treated for 1 year or more. The clinically relevant adverse events observed in CAPRIE, CURE, CLARITY and COMMIT are discussed below.
Clopidogrel was well tolerated compared to aspirin in a large controlled clinical trial (CAPRIE). The overall tolerability of clopidogrel in this study was similar to aspirin, regardless of age, gender and race.

Haemorrhagic disorders.

In CAPRIE, the overall incidence of any bleeding in patients treated with either clopidogrel or aspirin was similar (9.3%). The incidence of severe bleeds was 1.4% in the clopidogrel group and 1.6% in the aspirin group.
Gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) compared to aspirin (2.66%). The incidence of intracranial haemorrhage was 0.35% for clopidogrel compared to 0.49% for aspirin.
In CURE, there was a significant difference between the two treatment groups for nonlife threatening major bleeds (1.6% clopidogrel + aspirin vs. 1.0% placebo + aspirin), primarily gastrointestinal and at puncture sites, and minor bleeds (5.1% clopidogrel + aspirin vs. 2.4% placebo + aspirin). The major bleeding event rate for clopidogrel + aspirin was dose dependent on aspirin (< 100 mg: 2.6%; 100-200 mg: 3.5%; > 200 mg: 4.9%) as was the major bleeding event rate for placebo + aspirin (< 100 mg: 2.0%; 100-200 mg: 2.3%; > 200 mg: 4.0%).
The administration of clopidogrel + aspirin as compared to placebo + aspirin, was not associated with an increase in life threatening or fatal bleeds (event rates 2.2% vs. 1.8% and 0.2% vs. 0.2%, respectively). The incidence of 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.
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 show in Table 4.
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.

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.
Severe neutropenia (< 0.45 x 109/L) was observed in four patients (0.04%) that received clopidogrel and in two patients that received aspirin. Two of the 9599 patients who received clopidogrel and none of the patients who received aspirin had a neutrophil count of zero. One of the clopidogrel treated patients was receiving cytostatic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with clopidogrel.
In CURE and CLARITY, the numbers of patients with thrombocytopenia or neutropenia were similar in both groups.
Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other signs of infection.

Gastrointestinal.

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

Rash.

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

Treatment discontinuation.

In the clopidogrel and aspirin treatment groups of the CAPRIE study, discontinuation due to adverse events occurred in approximately 13% of patients after 2 years of treatment. Adverse events occurring in ≥ 2.5% of patients on clopidogrel in the CAPRIE controlled clinical trial are shown in Table 6 regardless of relationship to clopidogrel. The median duration of therapy was 20 months, with a maximum of 3 years.
In CURE, the overall incidence of discontinuation due to adverse events was greater in the clopidogrel group than in the placebo group (366 [5.8%] and 247 [3.9%] patients, respectively), with the main differences being in events in the platelet, bleeding and clotting disorders (1.1% versus 0.7%) and skin disorders (0.7% versus 0.3%). The increase in the rate of study drug discontinuation due to nonhaemorrhagic adverse events was primarily due to the increase in rash seen in the clopidogrel group. There was no apparent difference between the 2 treatment groups in the rates of discontinuations due to other adverse events.
In CLARITY, the overall incidence of discontinuation due to adverse events was greater in the placebo group compared with the clopidogrel group (6.9% for clopidogrel treated patients compared to 8.6% for placebo treated patients).
In COMMIT, the overall incidence of discontinuation due to adverse events was similar in each treatment group (2.4% for clopidogrel treated patients compared to 2.2% for placebo treated patients).
Clinically relevant adverse reactions not listed above pooled from CAPRIE, CURE, CLARITY and COMMIT studies with an incidence of ≥ 0.1% as well as all serious and clinically relevant adverse reactions are listed below according to the World Health Organisation classification. Their frequency is defined using the following conventions: common: > 1/100 (1%) and < 1/10 (10%); uncommon: ≥ 1/1000 (0.1%) and < 1/100 (1%); and rare: ≥ 1/10,000 (0.01%) and < 1/1000 (0.1%).

Central and peripheral nervous system disorders.

Uncommon: paraesthesia. 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 RES disorders.

Uncommon: leucopenia and eosinophilia.

Postmarketing experience.

The following have been reported spontaneously from worldwide postmarketing 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%).

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.
In patients with acute coronary syndrome.

Unstable angina or non-ST elevation myocardial infarction.

Clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued long-term at 75 mg once a day (with aspirin 75 mg-325 mg daily).

ST segment elevation acute myocardial infarction.

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

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 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.
For advice on the management of overdosage, please contact the Poisons Information Centre on 131 126.

Presentation

Tablets, clopidogrel (as besilate) 75 mg (pink, round, biconvex, film coated, marked II on one side): 28's (blister pack, bottle*).
*Not currently marketed in Australia.

Storage

Store below 25°C.

Poison Schedule

S4.