CoPlavix PI

AUSTRALIAN PRODUCT INFORMATION – COPLAVIX®
(CLOPIDOGREL (AS HYDROGEN SULFATE)/ ASPIRIN) FILM

COATED TABLET
1 NAME OF THE MEDICINE

Clopidogrel (as hydrogen sulfate) and aspirin.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Coplavix tablet contains clopidogrel 75 mg (as clopidogrel hydrogen sulfate) and
aspirin 100 mg.
Excipient with known effect: lactose
For the full list of excipients, see Section 6.1 LIST OF EXCIPIENTS.
3 PHARMACEUTICAL FORM
Coplavix tablets are light pink, oval, slightly biconvex, film-coated, engraved with “C75” on
one side and “A100” on the other side.
4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
CoPlavix is a fixed-dose combination product.
CoPlavix is intended as continuation of therapy in patients with acute coronary syndrome

already initiated with separate clopidogrel and aspirin products:
• 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). CoPlavix 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, CoPlavix has been shown to reduce the
rate of death from any cause and the rate of a combined endpoint of death, re-
infarction or stroke in medically treated patients eligible for thrombolytic therapy.
coplavix-ccdsv23-24-piv20-03feb23
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4.2 DOSE AND METHOD OF ADMINISTRATION
Adults
CoPlavix is given as a single tablet (75mg/100mg) once a day taken with adequate water.
Acute Coronary Syndrome
CoPlavix is used following an initial loading dose of 300 mg clopidogrel in combination with
aspirin in patients with acute coronary syndrome:
• Unstable angina or non-ST-elevation myocardial infarction:
- Treatment should be initiated with a single 300 mg loading dose of clopidogrel
plus aspirin (75 mg to 325 mg).
- Long-term daily treatment should be continued with one CoPlavix tablet
(75mg/100mg) once a day taken with adequate water.
• ST-segment elevation acute myocardial infarction:
- Treatment should be initiated with or without a 300 mg loading dose of
clopidogrel in combination with aspirin and with or without thrombolytics as soon
as possible after symptoms start. 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.
- Daily treatment should continue with one CoPlavix tablet (75mg/100mg) once a
day with adequate water. 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.
Should doses of aspirin greater than 100 mg be required for daily maintenance therapy,
clopidogrel and aspirin products should be administered separately.
Pharmacogenetics
CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to

clopidogrel. A higher dose of clopidogrel (600 mg loading dose followed by 150 mg once
daily) in poor metabolisers increases antiplatelet response (see Section 5.2
PHARMACOKINETIC PROPERTIES, Pharmacogenetics). Consider the use of higher
clopidogrel doses in patients who are poor CYP2C19 metabolisers. An appropriate dose
regimen for this patient population has not been established in clinical outcome trials.
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Renal Impairment
Experience is limited in patients with mild to moderate renal impairment (see Section 4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE). CoPlavix should not be used in
patients with severe renal impairment (see Section 4.3 CONTRAINDICATIONS).
Hepatic Impairment
Experience is limited in patients with moderate hepatic disease who may have bleeding
diatheses (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
CoPlavix should not be used in patients with severe hepatic impairment (see Section 4.3
CONTRAINDICATIONS).
Elderly
No dosage adjustment is necessary for elderly patients (see Section 5

PHARMACOLOGICAL PROPERTIES, SPECIAL POPULATIONS).
Children and Adolescents
Safety and efficacy in subjects below the age of 18 have not been established.
There is a possible association between aspirin and Reye’s syndrome when aspirin is given to
children. Reye’s syndrome is a very rare disease which can be fatal.
4.3 CONTRAINDICATIONS
Due to the presence of both components of the product, CoPlavix is contraindicated in case
of:
• Hypersensitivity to clopidogrel, salicylates or any of the excipients.
• Severe liver impairment.
• Active pathological bleeding such as haemophilia, intracranial haemorrhage or
gastrointestinal bleeding.
• Peptic ulcer or erosive gastritis
• Breast-feeding (see Section 4.6 FERTILITY, PREGNANCY AND LACTATION -
Use in lactation).
In addition, due to the presence of aspirin, its use is also contraindicated in case of:
• Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and in patients
with the syndrome of asthma with rhinitis and/or nasal polyps. Patients with pre-
existing mastocytosis, in whom the use of acetylsalicylic acid may induce severe
hypersensitivity reactions (including circulatory shock with flushing, hypotension,
tachycardia and vomiting).
• Severe renal impairment.
• Third trimester of pregnancy (see Section 4.6 FERTILITY, PREGNANCY AND
LACTATION - Use in pregnancy).
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4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
General
Clopidogrel and aspirin prolong 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 anti-platelet effect is not desired,
CoPlavix should be discontinued 7 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.
• CoPlavix 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 NSAIDs) are not recommended in
patients taking CoPlavix (see Section 4.5 INTERACTIONS WITH OTHER
MEDICINES AND OTHER FORMS OF INTERACTIONS).
• CoPlavix should be used with caution in patients with a history of peptic ulcer or
gastroduodenal haemorrhage or minor upper gastrointestinal symptoms, as this may
be due to gastric ulceration which may lead to gastric bleeding.
• Due to the increased risk of haemorrhage, triple antiplatelet therapy (clopidogrel +
aspirin + dipyridamole) for stroke secondary prevention is not recommended in
patients with acute non-cardioembolic ischemic stroke or TIA (see Section 4.5
INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS).
• Gastrointestinal side effects, including stomach pain, heartburn, nausea, vomiting and
gastrointestinal bleeding, may occur. Minor gastrointestinal symptoms, such as
dyspepsia, are common and can occur anytime during therapy. Physicians should
remain alert for signs of GI ulceration and bleeding, even in the absence of previous
gastrointestinal symptoms (see Section 4.8 ADVERSE EFFECTS (UNDESIRABLE
EFFECTS)).
• Patients should be told about the signs and symptoms of gastrointestinal side effects
and what steps to take if they occur. Patients should be told that it may take longer
than usual for bleeding to stop when they take CoPlavix, and that they should report
any unusual bleeding (site or duration) to their physician. Patients should inform
physicians and dentists that they are taking CoPlavix 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, use of the combination of clopidogrel
and aspirin should be undertaken with caution outside of clinical situations where the
combination has proven to be beneficial.
• To prevent gastric irritation due to aspirin, CoPlavix should be taken with or after
food.
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• Due to the presence of aspirin, caution is required in patients with a history of asthma
or allergic disorders (as they are at increased risk of hypersensitivity reactions) or
with gout (as low doses of aspirin increase urate concentrations).
• In patients concomitantly receiving nicorandil and NSAIDS including aspirin, there is
an increased risk for severe complications such as gastrointestinal ulceration,
perforation and haemorrhage (see Section 4.5 INTERACTIONS WITH OTHER
MEDICINES AND OTHER FORMS OF INTERACTIONS).
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
• CoPlavix must be administered under close medical supervision in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency due to risk of haemolysis (see
Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)).
• The hypoglycaemic effect of chlorpropamide may be enhanced by the concurrent
administration of aspirin. Large doses of aspirin may have intrinsic hypoglycaemic
activity when given to diabetic patients, but the effects on carbohydrate metabolism
are complex and it may cause hyperglycaemia
• Alcohol - Due to the presence of aspirin:
- alcohol may increase the risk of gastrointestinal injury when taken with aspirin.
Therefore, alcohol should be used with caution in patients taking aspirin (see
Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER
FORMS OF INTERACTIONS)
- patients should be counselled about the bleeding risks involved with chronic,
heavy alcohol use while taking clopidogrel plus aspirin.
• Concomitant treatment with levothyroxine and salicylates should be avoided (see
Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS
OF INTERACTIONS).
• Tinnitus is a premonitory sign of salicylism but may not be detected in patients with
hearing loss
• This medicinal product also contains hydrogenated castor oil which may cause
stomach upset and diarrhoea.
• CoPlavix is to be used under medical supervision only.
• Clopidogrel plus aspirin should not be used during the first two trimesters of
pregnancy unless the clinical condition of the woman requires treatment with
clopidogrel plus aspirin (see Section 4.6 FERTILITY, PREGNANCY AND
LACTATION).
Coronary Artery Bypass Surgery
When coronary artery bypass surgery is to be performed, clopidogrel and aspirin should be
suspended at least 7 days before surgery to reduce the risk of bleeding (see Section 4.8
ADVERSE EFFECTS (UNDESIRABLE EFFECTS)).
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PHARMACOGENETICS
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is mainly due to an

active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by
genetic variations in CYP2C19 and by concomitant medications that interfere with
CYP2C19. Genetic variants of other CYP450 enzymes may also affect the formation of
clopidogrel’s active metabolite. In patients who are CYP2C19 poor metabolisers clopidogrel
at recommended doses forms less of the active metabolite of clopidogrel and has a smaller
effect on platelet function. Poor metabolisers with acute coronary syndrome or undergoing
percutaneous coronary intervention treated with clopidogrel at recommended doses may
exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function
(see Section 5 PHARMACOLOGICAL PROPERTIES and Section 5.2
PHARMACOKINETIC PROPERTIES, Pharmacogenetics).
Use of drugs that induce the activity of CYP2C19 would be expected to result in increased
drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As
a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see
Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS).
Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an
aid in determining therapeutic strategy. Although a higher dose regimen in poor metabolisers
increases antiplatelet response (see Section 5 PHARMACOLOGICAL PROPERTIES,
PHARMACOGENETICS), an appropriate dose regimen for this patient population has not
been established in clinical outcome trials. Consider alternative treatment strategies in
patients identified as CYP2C19 poor metabolisers (see Section 4.2 DOSE AND METHOD
OF ADMINISTRATION, Pharmacogenetics).
CYP2C19 Metabolism
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs
that inhibit the activity of this enzyme would be expected to result in reduced drug levels of
the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain.
Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole) should be
discouraged (See Section 5 PHARMACOLOGICAL PROPERTIES, Pharmacogenetics and
Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). If a proton pump
inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19
inhibitory activity, such as pantoprazole.
Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole,

fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin,
cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Ischaemic Stroke
In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke
(less than 7 days).
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Haematological
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the
use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia
and microangiopathic haemolytic anaemia associated with either neurological findings, renal
dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment,
including plasmapheresis (plasma exchange).
Thrombocytopenia, neutropenia, aplastic anaemia and pancytopenia have also been reported
very rarely in patients taking clopidogrel (see Section 4.8 ADVERSE EFFECTS
(UNDESIRABLE EFFECTS)).
Due to the risk of bleeding and haematological undesirable effects, blood cell count
determination and/or other appropriate testing should be promptly considered whenever
clinical symptoms suggestive of bleeding arise during the course of treatment. The
concomitant administration of CoPlavix with warfarin is not recommended since it may
increase the intensity of bleeding (see Section 4.5 INTERACTIONS WITH OTHER
MEDICINES AND OTHER FORMS OF INTERACTIONS). With chronic administration,
occult blood loss may lead to iron deficiency anaemia. As a dual anti-platelet agent, CoPlavix
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
other NSAIDs including Cox-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective
serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers discouraged
or thrombolytics. Patients should be followed carefully for any signs of bleeding including
occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac
procedures or surgery.
Acquired Haemophilia
Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed
isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without
bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of
acquired haemophilia should be managed and treated by specialists and clopidogrel should be
discontinued.
Cross-reactivity among Thienopyridines
Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as

ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see
Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)). Thienopyridines may
cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions
such as thrombocytopenia and neutropenia. Patients who have developed a previous allergic
reaction and/or haematological reaction to one thienopyridine may have an increased risk of
developing the same or another reaction to another thienopyridine. Monitoring for cross-
reactivity is advised.
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Use in hepatic impairment
Experience is limited in patients with moderate hepatic disease who may have bleeding
diatheses. CoPlavix should therefore be used with caution in this population. See also Section
4.3 CONTRAINDICATIONS for severe hepatic impairment.
Use in renal impairment
Experience with clopidogrel plus aspirin is limited in patients with mild to moderate renal
impairment. Therefore CoPlavix should be used with caution in this population. Patients
should be observed closely for signs of salicylism. See also Section 4.3
CONTRAINDICATIONS for severe renal impairment.
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in
patients taking NSAIDs such as aspirin. Some of these events have been fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash,
lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis,
nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of
DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this
disorder is variable in its presentation, other organ systems not noted here may be involved. It
is important to note that early manifestations of hypersensitivity, such as fever or
lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms
are present, discontinue aspirin and evaluate the patient immediately (see Section 4.8
ADVERSE EFFECTS (UNDESIRABLE EFFECTS)).
Use in the elderly
No data available
Paediatric use
See Section 4.2 DOSE AND METHOD OF ADMINISTRATION, Children and Adolescents.
Effects on laboratory tests
No data available
Alcohol
The effect of alcohol on the safety and efficacy of the combination of clopidogrel and aspirin
has not been investigated in clinical trials. Concurrent ingestion of alcohol and aspirin may
enhance occult blood loss and gastric irritation. In prolonged aspirin administration, occult
blood loss may lead to iron deficiency anaemia. Aspirin inhibits ethanol dehydrogenase, a
major enzyme in the first pass elimination of alcohol.
In vitro, the metabolism of clopidogrel has been shown to be altered in the presence of
ethanol, such that clopidogrel is hydrolysed (inactivated) more slowly, and ethyl clopidogrel
formed; the toxicity of ethyl clopidogrel has not been fully investigated. See Section 4.5
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INTERACTIONS – Interaction with alcohol.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS
Aspirin
A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to

increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.
However, clopidogrel and aspirin have been administered together for up to one year. See
also Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE - General
CoPlavix should not be administered simultaneously with other salicylate containing

preparations, uricosuric agents or NSAIDs.
Drugs associated with bleeding risk:
There is an increased risk of bleeding due to the potential additive effect. The concomitant
administration of drugs associated with bleeding risk should be undertaken with caution (see
Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Oral Anticoagulants (including warfarin)
The concomitant administration of CoPlavix with oral anticoagulants, including warfarin, is

not recommended since it may increase the intensity of bleeding (see Section 4.4 SPECIAL
WARNINGS AND PRECAUTIONS FOR USE).
Glycoprotein IIb/IIIa Inhibitors
CoPlavix 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 (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR
USE). As a pharmacodynamic interaction between CoPlavix and glycoprotein IIb/IIIa
inhibitors is possible, concomitant use should be undertaken with caution.
Injectable Anticoagulants
A pharmacodynamic interaction between CoPlavix and heparin is possible, leading to

increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.
Anti-platelet Agents (such as eptifibatide, ticlopidine, tirofiban)
The effects of CoPlavix and other drugs which inhibit platelet aggregation may be additive,
leading to an increased risk of bleeding.
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Thrombolytics
The safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific

thrombolytic agents and heparins was assessed in patients with acute myocardial infarction.
The incidence of clinically significant bleeding was similar to that observed when
thrombolytic agents and heparins are co-administered with aspirin. The safety of concomitant
administration of CoPlavix with thrombolytic agents has not been formally established and
should be undertaken with caution.
Nicorandil
In patients concomitantly receiving nicorandil and NSAIDS, including aspirin, there is an

increased risk for severe complications such as gastrointestinal ulceration, perforation and
haemorrhage (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Methotrexate
Due to the presence of aspirin, methotrexate and CoPlavix should be used together with
caution, as aspirin can inhibit renal clearance of methotrexate, which may lead to bone
marrow toxicity. Salicylates can also displace methotrexate from albumin.
Acetazolamide
Caution is recommended when co-administering salicylates with acetazolamide as there is an

increased risk of metabolic acidosis.
Non Steroidal Anti-inflammatory Drugs (NSAIDs)
Aspirin may increase the risk of gastrointestinal side effects, including bleeding, when
administered with NSAIDs. Aspirin displaces diclofenac from its binding sites, reducing
diclofenac effectiveness.
Ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are
dosed concomitantly and may limit the beneficial cardiovascular effects of aspirin in patients
with increased cardiovascular risk.
In a clinical study conducted in healthy volunteers, the concomitant administration of

clopidogrel and naproxen increased occult gastrointestinal blood loss. Consequently, the
concomitant use of NSAIDs including Cox-2 inhibitors is not recommended with CoPlavix
(see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Selective Serotonin Reuptake Inhibitors (SSRIs)
Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant
administration of SSRIs with clopidogrel should be undertaken with caution.
Uricosuric Agents (e.g. probenecid)
Caution is required because aspirin may inhibit the effect of uricosuric agents through
competitive elimination of uric acid.
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Varicella vaccine
It is recommended that patients not be given salicylates for an interval of six weeks after
receiving the varicella vaccine. Cases of Reye’s syndrome have occurred following the use of
salicylates during varicella infections (See Section 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE.)
Levothyroxine
Salicylates, specifically at doses greater than 2.0 g/day, may inhibit binding of thyroid
hormones to carrier proteins and thereby lead to an initial transient increase in free thyroid
hormones, followed by an overall decrease in total thyroid hormone levels. Thyroid hormone
levels should be monitored. (See Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS
FOR USE.)
Valproic acid
The concomitant administration of salicylates and valproic acid may result in decreased
valproic acid protein binding and inhibition of valproic acid metabolism resulting in
increased serum levels of total and free valproic acid.
Tenofovir
Concomitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the
risk of renal failure.
Drugs Metabolised by Cytochrome P450 2C9
At high concentrations in vitro, clopidogrel inhibits cytochrome P450 (2C9) and at lower
concentrations inhibits CYP2B6 and CYP2C19. Accordingly, CoPlavix may interfere with
the metabolism of bupropion, lansoprazole, omeprazole, pantoprazole, diazepam, phenytoin,
tamoxifen, tolbutamide, warfarin, fluvastatin, and many NSAIDs, but there are no data with
which to predict the magnitude of these interactions. Caution should be used when any of
these drugs is co-administered with CoPlavix.
Other Concomitant Therapy
Inducers of CYP2C19
that induce the activity of this enzyme would be expected to result in increased drug levels of
the active metabolite of clopidogrel.
Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel

active metabolite and platelet inhibition, which in particular might potentiate the risk of
bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be
discouraged (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
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Inhibitors of CYP2C19
that inhibit the activity of this enzyme would be expected to result in reduced drug levels of
the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain.
Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole) should be

discouraged (see Section 5 PHARMACOLOGICAL PROPERTIES, Pharmacogenetics and
Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). If a proton pump
inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19
inhibitory activity, such as pantoprazole.
Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole,

fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin,
cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.
Proton Pump Inhibitors (PPI): In a crossover clinical study (N=72 healthy subjects),
clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80
mg at the same time as clopidogrel) were administered for 5 days. Mean maximal platelet
aggregation intensity % (MAI) was the primary pharmacodynamic endpoint of the clinical
study and was used in the calculation of the mean inhibition of platelet aggregation % (IPA).
Similar trends in results were seen across both the MAI% and IPA%. The exposure to the
active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when
clopidogrel and omeprazole were administered together. Mean inhibition of platelet
aggregation with 5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when
clopidogrel and omeprazole were administered together. The same results were observed
when omeprazole 80mg was administered 12 hours apart.
In a crossover clinical study (N=66), healthy subjects were administered clopidogrel (300-mg
loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as
clopidogrel) for 5 days. Mean maximal platelet aggregation intensity % was the primary
pharmacodynamic endpoint of the clinical study and was used in the calculation of the mean
inhibition of platelet aggregation %. Similar trends in results were seen across both the
MAI% and IPA%. The exposure to the active metabolite of clopidogrel was decreased by
20% (Day 1) and 14% (Day 5) when clopidogrel and pantoprazole were administered
together. Mean inhibition of platelet aggregation was diminished by 15% (24 hours) and 11%
(Day 5) when clopidogrel and pantoprazole were administered together. These results
indicate that clopidogrel can be administered with pantoprazole.
Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic

(PD) interaction in terms of major cardiovascular events have been reported from both
observational and clinical studies.
Care should be observed when coadministering aspirin and methotrexate, chlorpropamide,

corticosteroids, sulfinpyrazone, probenecid and spironolactone. The hypoglycaemic effect of
chlorpropamide may be enhanced by the concurrent administration of aspirin
Hydrocortisone may increase the renal clearance of salicylate and when hydrocortisone is
discontinued, serum salicylate levels may rise significantly. Aspirin may antagonise the
diuretic effect of spironolactone. The rate and extent of aspirin absorption is increased by
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caffeine. The rate of excretion is increased by urinary alkalinisers. Aspirin at high doses
reduces the uricosuric effects of probenecid and sulfinpyrazone.
A number of other clinical studies have been conducted with clopidogrel and other
concomitant medications to investigate the potential for pharmacodynamic and
pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were
observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol
and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not
significantly influenced by the co-administration of phenobarbital or oestrogen.
In a study comparing administration of warfarin with either clopidogrel (N=20) or placebo

(N=23) the administration of clopidogrel 75 mg/day for 8 days did not modify the
pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term
warfarin therapy (at least 2 months). Coadministration of clopidogrel with warfarin increases
the risk of bleeding because of independent effects on haemostasis. However, at high
concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel interferes
with the metabolism of drugs such as phenytoin and tolbutamide and the NSAIDs, which are
metabolised by cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin
and tolbutamide can be safely co-administered with clopidogrel.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration

of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
CYP2C8 substrate drugs:
Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro
studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by
the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations,
concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8
metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution.
Rosuvastatin
Rosuvastatin: Clopidogrel has been shown to increase rosuvastatin exposure in patients by

1.4-fold (AUC) without effect on Cmax, after repeated administration of a 75 mg clopidogrel
dose.
Combination use of ACE Inhibitors or Angiotensin Receptor Antagonists, Anti-

inflammatory Drugs and Thiazide Diuretics
Concomitant use of a renin-angiotensin system inhibiting drug (angiotensin converting

enzyme (ACE) inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug
(NSAID, including aspirin or COX-2 inhibitors) and a thiazide diuretic may increase the risk
of renal impairment. This includes use in fixed-combination products containing more than
one class of drug. The combination of these agents should be administered with caution,
especially in the elderly and in patients with pre-existing renal impairment. Renal function
(serum creatinine) should be monitored after initiation of concomitant therapy and
periodically thereafter.
13
Interactions with Higher Dose Aspirin
Interactions with the following medicines with higher (anti-inflammatory) doses of aspirin
have been reported: alendronate, ACE inhibitors, acetazolamide, anticonvulsants (phenytoin
and valproic acid), beta blockers, systemic corticosteroids, diuretics, selective serotonin
reuptake inhibitors (SSRIs), spironolactone, verapamil, hypoglycaemic agents and
zafirlukast.
Other interactions with clopidogrel and aspirin
More than 30,000 patients entered into clinical trials with clopidogrel plus aspirin at
maintenance doses lower than or equal to 325 mg, received a variety of concomitant
medications, including diuretics, beta blockers, ACE inhibitors, calcium channel antagonists,
cholesterol lowering agents, coronary vasodilators, anti-diabetic agents (including insulin),
anti-epileptic agents, hormone replacement therapy and GPIIb/IIIa antagonists, without
evidence of clinically significant adverse interactions.
As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to
delay and reduce the absorption of clopidogrel presumably because of slowed gastric
emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet
agent in acute coronary syndrome patients requiring co-administration of morphine or other
opioid agonists.
Interactions with alcohol
Alcohol may increase the risk of gastrointestinal injury when taken with aspirin. Therefore,
alcohol should be used with caution in patients taking aspirin. See Section 4.4 SPECIAL
WARNINGS AND PRECAUTIONS FOR USE – Alcohol.
4.6 FERTILITY, PREGNANCY AND LACTATION
Effects on fertility
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up
to 400 mg/kg per day.
Aspirin had antispermatogenic effects by inhibiting prostaglandin formation in Long Evans

rats at 250 mg/kg/day PO, but did not affect the fertility of male Wistar rats at 300 mg/kg/day
IP. The clinical relevance of these observations is unknown.
For Aspirin in doses > 500 mg/day; there is some evidence that drugs which inhibit cyclo-
oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on
ovulation. This is reversible on withdrawal of treatment.
Use in pregnancy
Pregnancy Category C
No clinical data on exposure to clopidogrel plus aspirin during pregnancy are available.
Clopidogrel plus aspirin should not be used during the first two trimesters of pregnancy
14
unless the clinical condition of the woman requires treatment with clopidogrel in combination
with aspirin (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including clopidogrel plus aspirin at about 20 weeks gestation or later in
pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases,
neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks
of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours
after NSAID initiation.
Oligohydramnios is often, but not always, reversible with treatment discontinuation.

Complications of prolonged oligohydramnios may, for example, include limb contractures
and delayed lung maturation. In some postmarketing cases of impaired neonatal renal
function, invasive procedures such as exchange transfusion or dialysis were required.
Due to the risk of oligohydramnios, if clopidogrel plus aspirin treatment is necessary from
about 20 weeks gestation to the end of the second trimester, it should be managed under
medical supervision and use limited to the lowest effective dose and shortest duration
possible. Consider ultrasound monitoring of amniotic fluid. Discontinue clopidogrel plus
aspirin if oligohydramnios occurs and follow up according to clinical practice.
Due to the presence of aspirin clopidogrel plus aspirin is contraindicated during the third
trimester of pregnancy (see Section 4.3 CONTRAINDICATIONS).
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.
Reproduction toxicity data show that aspirin is teratogenic in several laboratory animals.
Aspirin inhibits prostaglandin synthesis. When given late in pregnancy, it may cause
premature closure of the foetal ductus arteriosus, prolong labour and delay birth. Aspirin
increases bleeding time both in the newborn infant and in the mother because of its anti-
platelet effects.
CoPlavix should not be used in women during pregnancy unless the potential benefits
outweigh the risks.
Use in lactation
Breast-feeding is contraindicated during treatment with CoPlavix (see Section 4.3

CONTRAINDICATIONS). Studies in rats have shown that clopidogrel and/or its metabolites
are excreted in breast milk. Salicylates are excreted in breast milk. Chronic high doses of
aspirin can cause adverse effects in the infant.
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
CoPlavix has no or negligible influence on the ability to drive and use machines.
15
4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)
Clopidogrel
Clinical Studies Experience
Clopidogrel has been evaluated for safety in more than 44,000 patients, including over 30,000
patients treated with clopidogrel plus aspirin, and over 12,000 patients treated for 1 year or
more. The clinically relevant adverse events observed in CURE, CLARITY, COMMIT,
CHARISMA, ACTIVE-A and ACTIVE-W are discussed below.
CURE, CLARITY AND COMMIT
Haemorrhagic Disorders
In CURE, there was a significant difference between the two treatment groups for non life-
threatening major bleeds (1.6% clopidogrel + aspirin vs. 1.0% placebo + aspirin), primarily
gastrointestinal and at arterial 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%; >200mg: 4.9%) as was the
major bleeding event rate for placebo + aspirin (<100 mg: 2.0%; 100-200 mg: 2.3%; >200
mg: 4.0%).
The administration of clopidogrel + aspirin as compared to placebo + aspirin, was not

associated with an increase in life-threatening or fatal bleeds (event rates 2.2% vs. 1.8% and
0.2% vs. 0.2%, respectively). The incidence of intra-cranial bleeding was 0.1% in both
groups.
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in
patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel + aspirin
vs. 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass
graft surgery, the event rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo +
aspirin.
In CLARITY, there was an overall increase in bleeding in the clopidogrel + aspirin group
(17.4%) versus the placebo + aspirin group (12.9%), with the incidence of major bleeding
(defined as intracranial bleeding or bleeding associated with a fall in haemoglobin > 5 g/dL)
being similar between groups (1.3% versus 1.1% in the clopidogrel + aspirin and the placebo
+ aspirin groups, respectively). This was consistent across subgroups of patients defined by
baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal
bleeding (0.8% versus 0.6% in the clopidogrel + aspirin and in the placebo + aspirin groups,
respectively) and intracranial haemorrhage (0.5% versus 0.7%, respectively) was low and
similar in both groups.
The overall rate of non-cerebral major bleeding or cerebral bleeding in COMMIT was low
and similar in both groups, as shown in Table 1.
16
Table 1 - Number of patients with bleeding events in COMMIT
Type of bleeding Clopidogrel Placebo p-value

+ aspirin + aspirin
(n = 22,961) (n = 22,891)
Major * non-cerebral or cerebral bleeding 134 (0.6%) 125 (0.5%) 0.59
Major non-cerebral 82 (0.4%) 73 (0.3%) 0.48
Fatal 36 (0.2%) 37 (0.2%) 0.90
Haemorrhagic stroke 55 (0.2%) 56 (0.2%) 0.91
Fatal 39 (0.2%) 41 (0.2%) 0.81
Other non-cerebral bleeding (non major) 831 (3.6%) 721 (3.1%) 0.005
Any non-cerebral bleeding 896 (3.9%) 777 (3.4%) 0.004
*Major bleeds are cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion
Haematological Disorders
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 CURE, there was no significant difference in the incidence of non-haemorrhagic

gastrointestinal effects in the clopidogrel or placebo groups.
In CLARITY, the incidence of gastrointestinal adverse events was 6.9% for clopidogrel
treated patients, compared to 7.2% in placebo treated patients.
In COMMIT, 2 patients reported gastrointestinal adverse events in the clopidogrel treated

group, compared to one in the placebo treated group.
Rash
In 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 CURE, the overall incidence of discontinuation due to adverse events was greater in the
clopidogrel group than in the placebo group (366 [5.8%] and 247 [3.9%] patients,
respectively), with the main differences being in events in the platelet, bleeding and clotting
disorders (1.1% versus 0.7%) and skin disorders (0.7% versus 0.3%). The increase in the rate
of study drug discontinuation due to non-haemorrhagic adverse events was primarily due to
the increase in rash seen in the clopidogrel group. There was no apparent difference between
the 2 treatment groups in the rates of discontinuations due to other adverse events.
17
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).
ACTIVE Studies
The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included
patients with atrial fibrillation (AF) who had at least one risk factor for vascular events.
Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were
candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study
included patients who could not receive VKA therapy because they were unable or unwilling
to receive the treatment.
The ACTIVE-W study demonstrated that treatment with VKA was more effective than the
combination of clopidogrel and aspirin. The rate of major bleeding episodes was higher in the
clopidogrel + aspirin group than in the VKA group: 101 (3.03%) subjects compared with 93
(2.76%).
The ACTIVE-A study demonstrated when preventing atherothrombotic and thromboembolic

events including stroke, the rate of major bleeding was greater in the clopidogrel + aspirin
group 251 (6.7%) than in the placebo + aspirin group 162 (4.3%).
CAPRIE & CHARISMA
The following safety data is extracted from clinical studies for different indications of
clopidogrel.
Haemorrhagic Disorders
In CAPRIE a study conducted in 19,185 patients with established atherosclerosis or history of

atherothrombosis as manifested by myocardial infarction, ischaemic stroke or peripheral
arterial disease, who randomised to clopidogrel 75 mg/day or aspirin 325 mg/day, and
followed for 1 to 3 years, 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.
The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%)
compared to aspirin (6.5%). However, the incidence of severe events was similar in both
treatment groups (0.6% vs. 0.4%). The most frequent events reported were purpura/bruising
and epistaxis. Other less frequently reported events were haematoma, haematuria and eye
bleeding (mainly conjunctival).
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.
18
In CHARISMA, a study conducted in patients with 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 (see Table 2). This represented a number needed to treat, to harm, of 84
in 23 months of follow-up.
Table 2 - Number of patients with bleeding events in CHARISMA
Number (%) with event

Type of bleeding (GUSTO) Clopidogrel + aspirin Placebo + aspirin Difference Clopidogrel – Placebo (%) (95% CI)
(N=7802) (N=7801)
Any 2827 (36.2) 1616 (20.7) 15.52 (14.12, 16.91)
Severe/moderate 290 (3.7) 197 (2.5) 1.19 (0.65, 1.74)
Haematological Disorders
In CAPRIE, 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.
One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopaenia (<80 G/L) was 0.2% on clopidogrel and 0.1% on
aspirin; very rare cases of platelet count ≤30 G/L have been reported.
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%).
19
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 and CURE
controlled clinical trials are shown in Table 3 regardless of relationship to clopidogrel.
Table 3 Adverse events occurring in ≥2.5% of patients receiving clopidogrel in CAPRIE and
CURE
CAPRIE CURE
% Incidence % Incidence
(% discontinuation) (% discontinuation)
Clopidogrel Aspirin Clopidogrel + aspirin Placebo + aspirin
BODY SYSTEM/EVENT n = 9599 n = 9586 n = 6259 n= 6303
Body as a Whole - general disorders
Chest pain 8.3 (0.2) 8.3 (0.3) 2.7 (0.02) 2.8 (0.0)
Accidental/inflicted injury 7.9 (0.1) 7.3 (0.1) 1.1 (0.06) 1.2 (0.03)
Influenza like symptoms 7.5 (<0.1) 7.0 (<0.1) 1.1 (0.0) 1.1 (0.0)
Pain 6.4 (0.1) 6.3 (0.1) 1.3 (0.02) 1.4 (0.0)
Fatigue 3.3 (0.1) 3.4 (0.1) 1.5* (0.02) 1.0 (0.0)
Cardiovascular disorders - general
Hypertension 4.3 (<0.1) 5.1* (<0.1) 0.9 (0.0) 0.9 (0.0)
Central and peripheral nervous system disorders
Headache 7.6 (0.3) 7.2 (0.2) 3.1 (0.08) 3.2 (0.10)
Dizziness 6.2 (0.2) 6.7 (0.3) 2.4 (0.08) 2.0 (0.02)
Gastrointestinal
Abdominal pain 5.6 (0.7) 7.1* (1.0) 2.3 (0.26) 2.8 (0.27)
Dyspepsia 5.2 (0.6) 6.1* (0.7) 2.0 (0.08) 1.9 (0.02)
Diarrhoea 4.5* (0.4) 3.4 (0.3) 2.1 (0.11) 2.2 (0.13)
Nausea 3.4 (0.5) 3.8 (0.4) 1.9 (0.18) 2.3 (0.08)
Metabolic and nutritional disorders
Hypercholesterolaemia 4.0 (0) 4.4 (<0.1) 0.1 (0.0) 0.2 (0.0)
Musculoskeletal system disorders
Arthralgia 6.3 (0.1) 6.2 (0.1) 0.9 (0.0) 0.9 (0.0)
Back pain 5.8 (0.1) 5.3 (<0.1) 1.0 (0.03) 1.2 (0.0)
Myo-, endo-, pericardial and valve disorders
Angina pectoris 10.1 (0.6) 10.7 (0.4) 0.1 (0.0) 0.1 (0.0)
Coronary artery disorder 6.2 (0.3) 5.6 (0.3) 0.03 (0.0) 0.06 (0.0)
Platelet, bleeding and clotting disorders
Purpura 5.3* (0.3) 3.7 (0.1) 0.3 (0.0) 0.1 (0.0)
Epistaxis 2.9 (0.2) 2.5 (0.1) 0.2 (0.08) 0.1 (0.02)
Psychiatric disorders
Depression 3.6 (0.1) 3.9 (0.2) 0.7 (0.02) 0.7 (0.0)
20
CAPRIE CURE
% Incidence % Incidence
(% discontinuation) (% discontinuation)
Clopidogrel Aspirin Clopidogrel + aspirin Placebo + aspirin
BODY SYSTEM/EVENT n = 9599 n = 9586 n = 6259 n= 6303
Resistance mechanism disorders
Infection 4.7 (<0.1) 4.2 (0.1) 1.3 (0.0) 1.2 (0.0)
Respiratory system disorders
Upper respiratory tract infection 8.7 (<0.1) 8.3 (<0.1) 1.1 (0.0) 1.0 (0.0)
Dyspnoea 4.5 (0.1) 4.2. (0.1) 1.9 (0.0) 1.9 (0.02)
Rhinitis 4.2 (0.1) 4.2 (<0.1) 0.2 (0.0) 0.1 (0.0)
Bronchitis 3.7 (0.1) 3.7 (0) 1.1 (0.0) 1.5 (0.0)
Coughing 3.1 (<0.1) 2.7 (<0.1) 1.3 (0.0) 1.2 (0.0)
Skin and appendage disorders
Rash 4.2* (0.5) 3.5 (0.2) 1.3 (0.29) 1.1 (0.14)
Pruritis 3.3* (0.3) 1.6 (0.1) 0.5 (0.11) 0.5 (0.05)
Urinary system disorders
Urinary tract infection 3.1 (0) 3.5 (0.1) 1.5 (0.0) 1.4 (0.0)
Vascular (extracardiac) disorders
Claudication intermittent 3.8 (0.2) 3.8 (0.2) 0.1 (0.02) 0.1 (0.0)
Peripheral ischaemia 3.2 (0.2) 3.4 (0.2) 0.4 (0.03) 0.3 (0.0)
Cerebrovascular disorder 2.6 (0.3) 2.9 (0.3) 0.3 (0.03) 0.4 (0.03)
* indicates statistical significance (p≤0.05)
Incidence of discontinuation, regardless of relationship to therapy is shown in parentheses.
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%)
rare: ≥ 1/10000 (0.01%) and < 1/1000 (0.1%)
Central and peripheral nervous system disorders
uncommon: Headache, dizziness, paraesthesia,

rare: Vertigo
Gastrointestinal system disorders
common: Dyspepsia, abdominal pain, diarrhea

uncommon: Nausea, gastritis, flatulence, constipation, vomiting, gastric, peptic or duodenal
ulcer
21
Platelet, bleeding and clotting disorders
uncommon: Bleeding time increased, decreased platelets
Skin and appendages disorders
uncommon: Rash, pruritus
White cell and RES disorders
uncommon: Leucopenia, decreased neutrophils, eosinophilia
Post-Marketing Experience
In addition to clinical study experience with clopidogrel either alone or in combination with
aspirin, the following is a list of adverse reactions reported with clopidogrel or aspirin.
Bleeding is the most common reaction reported in the post-marketing experience with
clopidogrel or aspirin.
The following have been reported spontaneously from worldwide post-marketing experience
with clopidogrel:
Note very common ≥ 1/10 (≥ 10%)

common ≥ 1/100 and < 1/10 (≥ 1% and < 10%)
uncommon ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1.0%)
rare ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%)
very rare < 1/10,000 (< 0.01%)
Not known cannot be estimated from available data
Musculoskeletal, connective and bone
very rare: Arthralgia, arthritis, myalgia
Immune system disorders
very rare: Anaphylactoid reactions, serum sickness

unknown: Cross-reactive hypersensitivity among thienopyridine (such as ticlopidine,
prasugrel) (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE)
Not known: Insulin autoimmune syndrome, which can lead to severe hypoglycaemia,
particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population)
Vascular disorders
very rare: Vasculitis, hypotension
22
Blood and lymphatic system disorders
very rare: Serious cases of bleeding, mainly skin, musculo-skeletal (haemarthrosis,

haematoma), eye (conjunctival, ocular, retinal) and respiratory tract bleeding (haemoptysis,
pulmonary haemorrhage), epistaxis, haematuria and haemorrhage of operative wound. Fatal
haemorrhage, especially intracranial, gastrointestinal and retroperitoneal haemorrhage.
Cases of serious haemorrhage have been reported in patients taking clopidogrel

concomitantly with aspirin or clopidogrel with aspirin and heparin (see Section 4.5
INTERACTIONS).
Very rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported.
Aplastic anaemia, neutropenia, pancytopenia, bicytopenia, agranulocytosis, granulocytopenia,

anaemia, bone marrow failure.
Very rare cases of acquired haemophilia A have been reported.
uncommon: Eosinophilia, leucopenia, decreased neutrophils, decreased platelets, increased

bleeding time
Cardiac disorders:
Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) in the context

of a hypersensitivity reaction.
Skin and subcutaneous tissue disorders
very rare: Maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema,

bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal
necrolysis, acute generalised exanthematous pustulosis (AGEP)), drug-induced
hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)
(see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE), eczema, lichen
planus.
Psychiatric
very rare: Confusion, hallucinations
Nervous system disorders
very rare: Taste disturbances

Not known: Ageusia
Hepatobiliary disorders
very rare: Hepatitis, acute liver failure
23
Gastrointestinal disorders
very rare: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis
Respiratory, thoracic and mediastinal disorders
very rare: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia
Renal and urinary disorders
very rare: Glomerulopathy, renal failure
Reproductive systems and breast disorders
very rare: Gynaecomastia
Investigations
very rare: Blood creatinine increase, abnormal liver function tests
General disorders and administration site conditions
very rare: Fever, syncope
Aspirin
In addition to some of the adverse reactions listed above, aspirin is associated with the
following adverse effects.
Aspirin produces a prolongation of the bleeding time and may produce epigastric distress,
nausea and vomiting, gastric or duodenal ulcers and erosive gastritis which may lead to
serious gastrointestinal bleeding. These side effects are more likely to occur when higher
doses are administered, although they may also occur when low doses are used.
Oesophagitis, oesophageal ulceration, perforation. Erosive gastritis, erosive duodenitis,

gastro-duodenal ulcer/perforations, upper gastro-intestinal symptoms such as gastralgia (see
Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Small (jejunum and
ileum) and large (colon and rectum) intestinal ulcers, colitis and intestinal perforation. These
reactions may or may not be associated with haemorrhage, and may occur at any dose of
acetylsalicylic acid and in patient with or without warning symptoms or a previous history or
serious GI events.
Iron deficiency anaemia may develop as a result of occult gastrointestinal bleeding when
aspirin is used for long periods of time.
Aspirin may cause intracranial haemorrhage that may be fatal, especially in the elderly.
Aspirin may cause haemolysis, thrombocytopenia or haemolytic anaemia in patients with

glucose-6-phosphate dehydrogenase (G6PD) deficiency. Cases of pancytopenia, bicytopenia,
24
aplastic anaemia, bone marrow failure, agranulocytosis, neutropenia and leukopenia have
also been reported.
Vasculitis, including Henoch-Schönlein purpura has been reported.
Aspirin may cause tinnitus, dizziness, vertigo or hearing loss.
Aspirin sensitivity is most commonly manifested by asthma, vasomotor rhinitis, urticaria,

angioneurotic oedema and allergic dermatological reactions, hypoglycaemia, gout. As well
as anaphylactic shock, aggravation of allergic symptoms of food allergy.
Aspirin may cause an elevation of hepatic enzymes, liver injury, mainly hepatocellular,
chronic hepatitis.
Low doses of aspirin have been reported to cause retention of uric acid, whereas high dosage
may increase excretion.
Aspirin may cause renal failure, acute renal impairment (especially in patients with existing
renal impairment, heart decompensation, nephritic syndrome, or concomitant treatment with
diuretics).
Aspirin may cause fixed eruption.
Oedema has been reported with higher (anti-inflammatory) doses of aspirin.
Respiratory, thoracic and mediastinal disorder; non-cardiogenic pulmonary oedema with

chronic use and in the context of a hypersensitivity reaction due to acetylsalicylic acid.
Hypersensitivity to aspirin may cause cardiac disorders (Kounis Syndrome) and acute
pancreatitis.
Reporting suspected adverse effects
Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions at
www.tga.gov.au/reporting-problems.
4.9 OVERDOSE
In animals, clopidogrel at single oral doses ≥1500 mg/kg caused necrotic-haemorrhagic

gastritis, oesophagitis and enteritis in mice, rats and baboons. Necrotic tubulopathy and
tubulo-interstitial nephritis were also noted in mice.
Overdose following clopidogrel administration may lead to prolonged bleeding time and
subsequent bleeding complications. Appropriate therapy should be considered if bleeding is
observed. No antidote to the pharmacological activity of clopidogrel has been found. If
prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the
effects of clopidogrel.
Aspirin overdosage is manifested by the following symptoms:
25
Moderate overdosage: tinnitus, hearing loss, dizziness, headaches, vertigo, confusion and
gastrointestinal symptoms (nausea, vomiting and gastric pain).
Severe overdosage: fever, hyperventilation, ketosis, respiratory alkalosis, metabolic acidosis,

coma, cardiovascular collapse, respiratory failure, severe hypoglycaemia, haemorrhage
In case of severe aspirin overdose, the following actions should be undertaken: admission to
hospital is necessary, control of acid-base balance, possibility of haemodialysis or peritoneal
dialysis if necessary.
Apart from general measures, treatment of aspirin overdosage consists chiefly of measures to
accelerate the excretion (forced alkaline diuresis) and to restore the acid-base and electrolyte
balance. Infusions of sodium bicarbonate and potassium chloride solutions may be given.
Overdosage with salicylates, particularly in young children, can result in severe

hypoglycaemia and potentially fatal poisoning.
Non-cardiogenic pulmonary oedema can occur with acute and chronic acetylsalicylic acid
overdose (see Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)).
For information on the management of overdose, contact the Poisons Information Centre on
131126 (Australia).
5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Mechanism of action
Clopidogrel
Clopidogrel is a specific and potent inhibitor of platelet aggregation. Platelets have an

established role in the pathophysiology of atherosclerotic disease and thrombotic events.
Long term use of anti-platelet drugs has shown consistent benefit in the prevention of
ischaemic stroke, myocardial infarction and vascular death in patients at increased risk of
such outcomes, including those with established atherosclerosis or a history of
atherothrombosis.
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).
26
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.
Aspirin
Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclo-oxygenase and
the production of thromboxane A2, an inducer of platelet aggregation and vasoconstriction.
This effect lasts for the life of the platelet.
Clinical trials
The safety and efficacy of clopidogrel and aspirin has been evaluated in patients in three
double-blind studies: the CURE, CLARITY, and COMMIT studies, which compared
clopidogrel to placebo, both given in combination with aspirin and other standard therapy.
The CURE study included 12,562 patients with acute coronary syndrome (unstable angina or
non-ST-elevation myocardial infarction), and presenting within 24 hours of onset of the most
recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to
have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or
troponin I or T to at least twice the upper limit of normal. Patients were randomised to
clopidogrel (300 mg loading dose followed by 75 mg/day, n = 6244) or placebo (n = 6287),
both given in combination with aspirin (75-325 mg once daily) and other standard therapies
(oral anti-coagulants and long term NSAIDs were not permitted). Patients were treated for up
to one year.
The number of patients experiencing the primary endpoint [cardiovascular (CV) death,
myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and
719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-
28%; p = 0.00009) for the clopidogrel-treated group. The benefits of clopidogrel were seen
within a few hours and maintained throughout the course of the study (up to 12 months). The
primary outcome was reduced to a similar extent within the first 30 days (relative risk
reduction of 22 %), from 30 days to one year (relative risk reduction of 19%), and for the
entire one year study (relative risk reduction of 20%).
The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or
refractory ischaemia) was 1035 (16.5%) in the clopidogrel-treated group and 1187 (18.8%) in
the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p = 0.0005) for
the clopidogrel-treated group, a benefit which was consistent for each component, indicating
that clopidogrel reduced a range of atherothrombotic events.
In the course of the study, patients who underwent cardiac revascularisation (surgical or
percutaneous coronary intervention with or without coronary stent implantation), received
similar benefit from clopidogrel + aspirin (including standard therapies) as those who did not
have a cardiac revascularisation.
27
The results obtained in populations with different characteristics (e.g. unstable angina or non-
ST-elevation MI, low to high risk levels, diabetes, need for revascularisation, age, gender,
etc.) were consistent with the results of the primary analysis.
The benefits observed with clopidogrel were independent of other acute and long-term
cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering
drugs, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed
independently of the dose of aspirin (75-325 mg once daily).
In patients with ST-segment elevation acute myocardial infarction, safety and efficacy of
clopidogrel have been evaluated in two randomised, placebo-controlled, double-blind studies,
CLARITY and COMMIT.
The randomised, double-blind, placebo-controlled CLARITY trial included 3,491 patients

presenting within 12 hours of the onset of a ST elevation myocardial infarction and planned
for thrombolytic therapy. Patients were randomised to receive either clopidogrel (300 mg
loading dose, followed by 75 mg/day; n = 1752) or placebo (n = 1739), together with aspirin
(150 to 325 mg loading dose followed by 75 to 162 mg/day), a fibrinolytic agent and, when
appropriate, heparin for 48 hours. The patients were followed for 30 days.
The primary endpoint was the occurrence of the composite of an occluded infarct-related
artery (defined as TIMI Flow Grade 0 or 1) on the predischarge angiogram, or death or
recurrent myocardial infarction by the time of the start of coronary angiography. For patients
who did not undergo angiography, the primary endpoint was death or recurrent myocardial
infarction by Day 8 or by hospital discharge, if prior to Day 8.
The patient population was mostly Caucasian (89.5%) and included 19.7% women and
29.2% were 65 years or over. A total of 99.7% of patients received fibrinolytics (fibrin
specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7%
ACE inhibitors and 63% statins.
The number of patients who reached the primary endpoint was 262 (15.0%) in the
clopidogrel-treated group and 377 (21.7%) in the placebo group, representing an absolute
reduction of 6.7% and a 36% reduction in the odds of the endpoint in favour of treatment
with clopidogrel (95% CI: 0.53, 0.76; p<0.001), as shown in Table 4, 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.
28
Table 4 - Event rates for the primary composite endpoint in the CLARITY study
Clopidogrel + aspirin Placebo + OR 95% CI

N = 1753 aspirin
N = 1739
Number (%) of patients reporting the composite 262 (15.0%) 377 (21.7%) 0.64 0.53, 0.76
endpoint
Occluded IRA
N (subjects undergoing angiography) 1640 1634
n (%) patients reporting endpoint 192 (11.7%) 301 (18.4%) 0.59 0.48, 0.72
Death
Recurrent MI
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, 2x2 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 co-primary endpoints were death from any cause and the first occurrence of re-infarction,
stroke or death. The patient population included 27.8% women, 58.4% 60 years or over (26%
70 years or over) and 54.5% patients who received fibrinolytics, 68% who received ACE-
inhibitors and 10.9% who received non-trial beta-blockers (as well as half of the patients who
received metoprolol as study medication).
As shown in Table 5, Figure 1and Figure 2 below, clopidogrel significantly reduced the
relative risk of death from any cause by 7% (p = 0.029) and the relative risk of the
combination of re-infarction, stroke or death by 9% (p = 0.002), representing an absolute risk
reduction of 5 and 9 patients per 1000 treated (0.5 and 0.9%), respectively.
Table 5 - Outcome events in the COMMIT analysis
Event Clopidogrel Placebo Odds ratio p-value

+aspirin +aspirin (95% CI)
n = 22961 n = 22891
Composite endpoint:
Death, MI or Stroke 2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0.002
Death 1726 (7.5%) 1845 (8.1%) 0.93 (0.87, 0.99) 0.029
Non-fatal MI 270 (1.2%) 330 (1.4%) 0.81 (0.69, 0.95) 0.011
Non-fatal Stroke 127 (0.6%) 142 (0.6%) 0.89 (0.70, 1.13) 0.33
Note: 9 patients (2 clopidogrel and 7 placebo) suffered from both a non-fatal stroke and a non-fatal MI, hence the apparent disparity
between composite endpoint and the sum of death, non-fatal MI and non-fatal stroke. Values for non-fatal MI and non-fatal stroke
exclude patients who died of any cause.
29
Figure 1 - Cumulative event rates for death in the COMMIT study*
* All treated patients received aspirin.
Figure 2 - Cumulative event rates for the combined endpoint re-infarction, stroke or death in
the COMMIT study*
* All treated patients received aspirin
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.
30
The bioequivalence of CoPlavix to reference clopidogrel and aspirin tablets has been
demonstrated in three open-label, randomised, single-dose, 2-sequence, 2-period, 2-treatment
crossover studies. One study was performed with CoPlavix 75 mg/75 mg (BDR4659) and
two with CoPlavix 75 mg/100 mg (BDR5000 and BEQ10600). Study BEQ10600 (CoPlavix
75 mg/100 mg) evaluated bioequivalence in 121 young healthy subjects based on clopidogrel
and its inactive carboxylic acid metabolite (Table 6), and aspirin and salicylic acid (Table 7).
Studies BDR4659 (CoPlavix 75 mg/75 mg) and BDR5000 (CoPlavix 75 mg/100 mg)
evaluated bioequivalence in 40 young healthy subjects based on clopidogrel inactive
carboxylic acid metabolite, and aspirin and salicylic acid.
CoPlavix 75 mg/75 mg and 75/100 mg were demonstrated to be bioequivalent to the

clopidogrel 75 mg tablets in terms of clopidogrel Cmax and AUC, and/or carboxylic acid
metabolite. For aspirin, CoPlavix 75 mg/75 mg and 75/100 mg were demonstrated to be
bioequivalent to aspirin 75 mg and 100 mg, respectively, in terms of aspirin AUC, and
salicylic acid Cmax and AUC. The 90% CIs for these parameters were entirely within the
bioequivalence interval [0.80 1.25].
In terms of Cmax, aspirin was not bioequivalent in the 3 studies, with the Cmax being 1.3 to 1.6
fold higher for CoPlavix than for the aspirin tablets. However, considering the large number
of aspirin formulations on the market and the clinical studies evaluating the benefit/risk of
clopidogrel in combination with aspirin (see above), a slight difference in aspirin Cmax is not
considered to be clinically significant.
Table 6 - Mean (coefficient of variation %) exposure of clopidogrel and its inactive carboxylic
acid metabolite after a single oral dose of CoPlavix 75mg/75mg or 75mg/100mg and Plavix
75mg
CoPlavix
CoPlavix 75 mg/100 mg
75 mg/75 mg
PK
Compound
parameter BDR4659 BDR5000 BEQ10600
CoPlav
CoPlavix Plavix 90%CI CoPlavix Plavix 90%CI Plavix 90%CI
ix
2.49 2.23 0.94;
Clopidogrel Cmax (ng/mL) Not assessed Not assessed
(306) (255) 1.23
AUC 2.74 2.72 0.92;
Not assessed Not assessed
(ng.h/mL) (210)a (189)a 1.15
Carboxylic acid 3319 3105 0.99; 3042 2810 0.98; 3640 3590 0.96;
Cmax (ng/mL)
metabolite (26) (27) 1.17 (25) (26) 1.20 (30) (30) 1.06
AUC 9215 8947 0.98; 8059 8004 0.98; 9830 9860 0.98;
(ng.h/mL) (29) (27) 1.07 (19) (26)a 1.07 (25) (27) 1.02
an=39; bn=110, cn=1116
31
Table 7 - Mean (coefficient of variation %) exposure of aspirin and salicylic acid after a single
oral dose of CoPlavix 75mg/75mg or 75mg/100mg and aspirin 75mg or 100mg
CoPlavix 75 mg/75 mg CoPlavix 75 mg/100 mg

PK
Compound BDR4659 BDR5000 BEQ10600
parameter
CoPlavix Aspirin 90%CI CoPlavix Aspirin 90%CI CoPlavix Aspirin 90%CI
Cmax 1207 738 1.51; 1492 964 1.41; 1580 1230 1.22;
Aspirin
(ng/mL) (25) (26) 1.78 (26) (23) 1.69 (31) (35) 1.39
AUC 936 826 1.10; 1131 1007 1.08; 1440 1300 1.07;
(ng.h/mL) (17) (22)a 1.20 (16)a (21)b 1.19 (24)c (22)d 1.13
Cmax 3533 3094 1.10; 4878 4189 1.12; 5390 5030 1.04;
Salicylic acid
(ng/mL) (16) (17) 1.20 (14) (16) 1.22 (22) (21) 1.10
AUC 12217 11778 1.00; 17791 17225 1.01; 21700 20900 1.02;
(ng.h/mL) (21)a (19) 1.06 (32)a (30) 1.05 (29)c (28) 1.04
an=39; bn=37; cn=116; dn=111
5.2 PHARMACOKINETIC PROPERTIES
Clopidogrel
Absorption
Clopidogrel: after single and repeated oral doses of 75 mg per day, clopidogrel is rapidly
absorbed. Clopidogrel mean peak plasma levels (approximately 2.2 - 2.5 ng/ml after a single
75 mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%,
based on urinary excretion of clopidogrel metabolites.
Distribution
Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma
proteins (98% and 94% respectively). The binding is non saturable in vitro over a wide
concentration range.
Metabolism and Elimination
Clopidogrel is a prodrug which is extensively hydrolysed in the liver by HCEl (human

carboxylesterase1). In vitro and in vivo, clopidogrel is metabolised according to two main
metabolic pathways:
• One mediated by esterases and leading to hydrolysis into its carboxylic acid
derivative, which is inactive and is the main circulating metabolite (about 85% of the
circulating compound in plasma). Mean peak plasma levels of this metabolite
(approx. 3600 ng/ml after single 75 mg oral dose) occurred approximately 45 minutes
after dosing. In vitro in the presence of ethyl alcohol, the rate of clopidogrel
hydrolysis was decreased, and some of the clopidogrel was converted to ethyl
clopidogrel.
• One mediated by multiple cytochromes P450 in the gastrointestinal tract and liver
leading to the active metabolite(s) of clopidogrel, a thiol derivative, which is
generated through formation of 2 oxo clopidogrel. The active metabolite is formed
32
mostly by CYP2C19 with contributions from several other CYP enzymes including
CYP3A4, CYP3A5, CYP1A2, CYP2C9, CYP2E1 and CYP2B6. The active thio CYP
l metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet
receptors, thus inhibiting platelet aggregation. Clinical studies have indicated that
individuals with loss of function variants of CYP2C9 and CYP2C19 are more likely
to have lower concentrations of the active metabolite and higher residual platelet
activity; clopidogrel is therefore less likely to be efficacious in these poor
metabolisers.
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.
Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted
in the urine and approximately 46% in the faeces in the 120 hour interval after dosing. After a
single oral dose of 75 mg, clopidogrel has a half life of approximately 6 hours. The
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.
Aspirin
Absorption
Following absorption, the aspirin in CoPlavix is hydrolysed to salicylic acid, with peak
plasma levels of salicylic acid occurring within 1 hour of dosing, such that plasma levels of
aspirin are essentially undetectable 1.5 to 4 hours after dosing. Administration of aspirin with
meals did not significantly modify its bioavailability.
Distribution
Based on available data, aspirin is poorly bound to plasma proteins and its apparent volume
of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins,
but its binding is concentration dependent (nonlinear). At low concentrations (<100 μg/mL),
approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed
to all tissues and fluids in the body, including the central nervous system, breast milk and
foetal tissues.
33
Metabolism and Elimination
The aspirin in CoPlavix is rapidly hydrolysed by HCE2 (human carboxylesterase 2) in the

intestine and the liver to salicylic acid, with a half-life of 0.3 to 0. 4 hours for aspirin doses
from 75 to 100 mg. This salicylic acid has a plasma half-life of approximately 2 hours.
Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic
glucuronide, an acyl glucuronide and a number of minor metabolites. Salicylate metabolism
is saturable and total body clearance decreases at higher serum concentrations, due to the
limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following
toxic aspirin doses (10 to 20 g), the plasma half-life may be increased to over 20 hours. At
high aspirin doses, the elimination of salicylic acid follows zero-order kinetics (i.e. the rate of
elimination is constant in relation to plasma concentration), with an apparent half-life of 6
hours or higher. Renal excretion of unchanged drug depends upon urinary pH. As urinary pH
rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Following
therapeutic doses, approximately 10% is found excreted in the urine as salicylic acid, 75% as
salicyluric acid, 10% phenolic- and 5% acyl-glucuronides of salicylic acid.
Clopidogrel/Aspirin Bioequivalence
CoPlavix 75 mg/75 mg and 75/100 mg were demonstrated to be bioequivalent to the

clopidogrel 75 mg tablets in terms of clopidogrel Cmax and AUC, and/or carboxylic acid
metabolite. For aspirin, CoPlavix 75 mg/75 mg and 75/100 mg were demonstrated to be
bioequivalent to aspirin 75 mg and 100 mg, respectively, in terms of aspirin AUC, and
salicylic acid Cmax and AUC. In terms of Cmax, aspirin was not bioequivalent with the Cmax
being 1.3 to 1.6 fold higher for CoPlavix than for the aspirin tablets. However, a slight
difference in aspirin Cmax is not considered to be clinically significant (See Section 5.1
PHARMACODYNAMIC PROPERTIES - Clinical trials).
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.
The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2
and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account
for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor
metabolisers. Other alleles associated with absent or reduced metabolism are less frequent
and include 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 Caucasians, 4% for Blacks and
14% for Chinese. 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). As shown in Table 8, 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
34
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 μM 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 the poor
metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19
metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for
this patient population has not been established in clinical outcome trials (see Section 4.2
DOSE AND METHOD OF ADMINISTRATION).
Table 8 - Active metabolite pharmacokinetics and antiplatelet responses by CYP2C19 metaboliser status
Dose Ultrarapid Extensive Intermediate Poor

(n=10) (n=10) (n=10)
(n=10)
AUClast (ng.h/mL) 300 mg (Day 1) 33 (11) 39 (24) 31 (14) 14 (6)
600 mg (Day 1) 56 (22) 70 (46) 56 (27) 23 (7)
75 mg (Day 5) 11 (5) 12 (6) 9.9 (4) 3.2 (1)
150 mg (Day 5) 18 (8) 19 (8) 16 (7) 7 (2)
IPA (%)a 300 mg (24 h) 40 (21) 39 (28) 37 (21) 24 (26)

600 mg (24 h) 51 (28) 49 (23) 56 (22) 32 (25)
75 mg (Day 5) 56 (13) 58 (19) 60 (18) 37 (23)
150 mg (Day 5) 68 (18) 73 (9) 74 (14) 61 (14)
Values are mean (SD)
a Inhibition of platelet aggregation with 5μM ADP; larger value indicates greater platelet inhibition
Consistent with the above results, in a meta analysis including 6 studies of 335 clopidogrel
treated subjects at steady state, it was shown that active metabolite exposure was decreased
by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet
aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and
21.4%, respectively, when compared to extensive metabolisers.
The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel
has not been evaluated in prospective, randomised, controlled trials. There have, however,
been a number of retrospective analyses to evaluate this effect in patients treated with
clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428),
CLARITY TIMI 28 (n=227), TRITON TIMI 38 (n=1477) and ACTIVE-A (n=601), as well
as a number of published cohort studies.
In TRITON TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group
of patients with either intermediate or poor metaboliser status had a higher rate of
cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared
to extensive metabolisers.
In CHARISMA and one cohort study (Simon), an increased event rate was observed only in
poor metabolisers when compared to extensive metabolisers.
35
In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event
rate was observed based on metaboliser status.
None of these analyses were adequately sized to detect differences in outcome in poor
metabolisers.
Special Populations
Geriatric Patients
Plasma concentrations of the main circulating metabolite of clopidogrel 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
CoPlavix is contraindicated in severe renal impairment. After repeated doses of 75 mg

clopidogrel per day, plasma levels of the main circulating metabolite were lower in patients
with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to
subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy
subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that
observed in healthy volunteers, the prolongation of bleeding time was similar in healthy
volunteers receiving 75 mg of clopidogrel per day. Experience with clopidogrel plus aspirin
is limited in patients with mild to moderate renal impairment. Therefore CoPlavix should be
used with caution in this population (see Section 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE).
Patients with Hepatic Impairment
CoPlavix is contraindicated in severe hepatic impairment. Experience is limited in patients

with moderate hepatic disease who may have bleeding diatheses. CoPlavix should therefore
be used with caution in this population (see Section 4.4 SPECIAL WARNINGS AND
PRECAUTIONS FOR USE).
CYP2C9 and CYP2C19 Poor Metabolisers
Clinical studies have indicated that individuals with loss of function variants of CYP2C9 and
CYP2C19 are more likely to have lower concentrations of the active metabolite and higher
residual platelet activity; clopidogrel is therefore less likely to be efficacious in these poor
metabolisers.
Gender
No significant difference was observed in the plasma levels of the main circulating
metabolite of clopidogrel between males and females. In a small study comparing men and
women, less inhibition of ADP-induced platelet aggregation was observed in women, but
there was no difference in prolongation of bleeding time. In the large, controlled clinical
study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the
36
incidence of clinical outcome events, other adverse clinical events, and abnormal clinical
laboratory parameters was similar in men and women.
Ethnicity
The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19
metabolism differs according to race/ethnicity (see Section 5 PHARMACOLOGICAL
PROPERTIES, Pharmacogenetics). From literature, limited data in Asian populations are
available to assess the clinical implication of genotyping of this CYP on clinical outcome
events.
5.3 PRECLINICAL SAFETY DATA
Genotoxicity
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat
hepatocytes, gene mutation assay in Chinese hamster fibroblasts and metaphase chromosome
analysis of human lymphocytes) and in one in vivo test (micronucleus test by the oral route in
mice).
Aspirin was not genotoxic in bacterial reverse mutation assays or in a recessive lethal
mutation assay in Drosophila. However, there are conflicting results on the clastogenicity of
aspirin in mammalian cells.
Carcinogenicity
There was no evidence of carcinogenic effects when clopidogrel was given in the diet for 78
weeks to mice and 104 weeks to rats at doses up to 77 mg/kg per day (representing an
exposure approx. 18 times the anticipated patient exposure, based on plasma AUC for the
main circulating metabolite in elderly subjects).
Carcinogenicity studies have not been conducted with aspirin.
6 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS

Coplavix tablets are film coated and each tablet contains mannitol, carnauba wax, macrogol
6000, microcrystalline cellulose, hydrogenated castor oil, hyprolose, maize starch, stearic acid,
colloidal anhydrous silica and OPADRY II complete film coating system 32K24375 Pink
(ARTG PI No: 12607).
6.2 INCOMPATIBILITIES
Incompatibilities were either not assessed or not identified as part of the registration of this
medicine.
37
6.3 SHELF LIFE
In Australia, information on the shelf life can be found on the public summary of the
Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the
packaging.
6.4 SPECIAL PRECAUTIONS FOR STORAGE
Store below 25°C
6.5 NATURE AND CONTENTS OF CONTAINER
Coplavix tablets are registered in PA/Al/PVC/Al blister packs containing 30 tablets.

Coplavix is a registered trademark of sanofi-aventis.
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL
In Australia, any unused medicine or waste material should be disposed of by taking to your
local pharmacy.
6.7 PHYSICOCHEMICAL PROPERTIES
Clopidogrel
Clopidogrel hydrogen sulfate is a white to off-white powder. It is practically insoluble in

water at neutral pH but freely soluble at pH 1. It is freely soluble in methanol, sparingly
soluble in methylene chloride and is practically insoluble in ethyl ether. It has a specific
optical rotation of about + 56°.
Aspirin
Aspirin is a white crystalline powder or colourless crystals, odourless or almost odourless,

slightly soluble in water, freely soluble in alcohol, soluble in chloroform and in ether. It
melts at about 135°C.
Chemical structure
Clopidogrel
Clopidogrel hydrogen sulfate has the following chemical structure:

O
C OCH3
H Cl
N
,H2SO4
S
38
Molecular Formula: C16H16ClNO2S.H2SO4
Molecular Weight: 419.9
Chemical Name: methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-
acetate sulfate (1:1).
CAS number:
120202-66-6 (Clopidogrel hydrogen sulfate), 113 665-84-2 (Clopidogrel base).
Aspirin
Aspirin has the following chemical structure:
Molecular Formula: C9H8O4

Molecular Weight: 180.2
Chemical Name: 2-acetoxybenzoic acid.
CAS number:
50-78-2
7 MEDICINE SCHEDULE (POISONS STANDARD)

Schedule 4 (Prescription only medicine).
8 SPONSOR
sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Toll Free Number (medical information): 1800 818 806
Email: [email protected]
9 DATE OF FIRST APPROVAL

24 September 2009
39
10 DATE OF REVISION
03 February 2023
SUMMARY TABLE OF CHANGES
Section Changed Summary of new information

Addition of drug reaction with eosinophilia systemic symptoms (DRESS). Revisions to
4.4
precautions for triple anti-platelet therapy and pregnancy
4.5, 4.6, 5.1 and 6.5 Editorial changes.
4.6 Addition of oligohydramnios/neonatal impairment
4.8 Revision of AE relating to drug reaction with eosinophilia systemic symptoms (DRESS).
40

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AUSTRALIAN PRODUCT INFORMATION – COPLAVIX®

(CLOPIDOGREL (AS HYDROGEN SULFATE)/ ASPIRIN) FILM

1 NAME OF THE MEDICINE

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

4.1 THERAPEUTIC INDICATIONS

CoPlavix is a fixed-dose combination product.

CoPlavix is intended as continuation of therapy in patients with acute coronary syndrome

Acute Coronary Syndrome

CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to

No dosage adjustment is necessary for elderly patients (see Section 5

Children and Adolescents

Coronary Artery Bypass Surgery

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is mainly due to an

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole,

Cross-reactivity among Thienopyridines

Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as

Use in renal impairment

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Use in the elderly

Effects on laboratory tests

4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to

CoPlavix should not be administered simultaneously with other salicylate containing

Drugs associated with bleeding risk:

Oral Anticoagulants (including warfarin)

The concomitant administration of CoPlavix with oral anticoagulants, including warfarin, is

Glycoprotein IIb/IIIa Inhibitors

A pharmacodynamic interaction between CoPlavix and heparin is possible, leading to

Anti-platelet Agents (such as eptifibatide, ticlopidine, tirofiban)

The safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific

In patients concomitantly receiving nicorandil and NSAIDS, including aspirin, there is an

Caution is recommended when co-administering salicylates with acetazolamide as there is an

Non Steroidal Anti-inflammatory Drugs (NSAIDs)

In a clinical study conducted in healthy volunteers, the concomitant administration of

Selective Serotonin Reuptake Inhibitors (SSRIs)

Uricosuric Agents (e.g. probenecid)

Drugs Metabolised by Cytochrome P450 2C9

Other Concomitant Therapy

Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel

Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole) should be

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole,

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic

Care should be observed when coadministering aspirin and methotrexate, chlorpropamide,

In a study comparing administration of warfarin with either clopidogrel (N=20) or placebo

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration

CYP2C8 substrate drugs:

Rosuvastatin: Clopidogrel has been shown to increase rosuvastatin exposure in patients by

Combination use of ACE Inhibitors or Angiotensin Receptor Antagonists, Anti-

Concomitant use of a renin-angiotensin system inhibiting drug (angiotensin converting

Other interactions with clopidogrel and aspirin

Interactions with alcohol

4.6 FERTILITY, PREGNANCY AND LACTATION

Aspirin had antispermatogenic effects by inhibiting prostaglandin formation in Long Evans

Oligohydramnios/Neonatal Renal Impairment

Oligohydramnios is often, but not always, reversible with treatment discontinuation.

Breast-feeding is contraindicated during treatment with CoPlavix (see Section 4.3

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Clinical Studies Experience

CURE, CLARITY AND COMMIT