Clopidogrel is indicated in adults for the prevention of atherothrombotic events in:
• Patients suffering from myocardial infarction (from a few days until less than 35 days),
ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial
disease.
For further information please refer to section 5.1.

• Adults and elderly
Clopidogrel should be given as a single daily dose of 75 mg with or without food.
• Pharmacogenetics

CYP2C19 poor metaboliser status is associated with diminished response to clopidogrel. The
optimal dose regimen for poor metabolisers has yet to be determined (see section 5.2).
• Paediatric patients
The safety and efficacy of clopidogrel in children and adolescents have not yet been
established.
• Renal impairment
Therapeutic experience is limited in patients with renal impairment (see section 4.4).
• Hepatic impairment
Therapeutic experience is limited in patients with moderate hepatic disease who may have
bleeding diatheses (see section 4.4).

Bleeding and haematological disorders
Due to the risk of bleeding and haematological adverse reactions, 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 (see section 4.8).
As with other antiplatelet agents, clopidogrel should be used with caution in patients who may
be at risk of increased bleeding from trauma, surgery or other pathological conditions and in
patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal
anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors. Patients should be followed

carefully for any signs of bleeding including occult bleeding, especially during the first weeks
of treatment and/or after invasive cardiac procedures or surgery. The concomitant
administration of clopidogrel with oral anticoagulants is not recommended since it may
increase the intensity of bleedings (see section 4.5).
If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable,
clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians
and dentists that they are taking clopidogrel before any surgery is scheduled and before any
new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with
caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal
and intraocular).
Patients should be told that it might take longer than usual to stop bleeding when they take
clopidogrel (alone or in combination with ASA), and that they should report any unusual
bleeding (site or duration) to their physician.
Thrombotic Thrombocytopenic Purpura (TTP)
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.
Recent ischaemic stroke
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after
acute ischaemic stroke.
Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19
function have lower systemic exposure to the active metabolite of clopidogrel and diminished

antiplatelet responses, and generally exhibit higher cardiovascular event rates following
myocardial infarction than do patients with normal CYP2C19 function (see section 5.2).
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal
products 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. As a precaution concomitant use of medicinal products that inhibit CYP2C19 should
be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).
Renal impairment
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore
clopidogrel should be used with caution in these patients (see section 4.2).
Hepatic impairment
Experience is limited in patients with moderate hepatic disease who may have bleeding
diatheses. Clopidogrel should therefore be used with caution in this population (see section
4.2).
Excipients
Paleta contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose galactose malabsorption should not take this medicinal
product.

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants
is not recommended since it may increase the intensity of bleedings (see section 4.4).
Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who

receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).
Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADPinduced
platelet aggregation, but clopidogrel potentiated the effect of ASA on collageninduced
platelet aggregation. However, concomitant administration of 500 mg of ASA twice
a day for one day did not significantly increase the prolongation of bleeding time induced by
clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic
acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be
undertaken with caution (see section 4.4). However, clopidogrel and ASA have been
administered together for up to one year (see section 5.1).
Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate
modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration
of heparin had no effect on the inhibition of platelet aggregation induced by
clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible,
leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with
caution (see section 4.4).
Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or nonfibrin
specific thrombolytic agents and heparins was assessed in patients with acute
myocardial infarction. The incidence of clinically significant bleeding was similar to that
observed when thrombolytic agents and heparin are co-administered with ASA (see section
4.8)
NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration
of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the
lack of interaction studies with other NSAIDs it is presently unclear whether there is an
increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs
including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see

section 4.4).
Other concomitant therapy:
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of
medicinal products 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. As a precaution concomitant use of medicinal products that inhibit
CYP2C19 should be discouraged (see sections 4.4 and 5.2).
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, 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. 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 (IPA) with 5
μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and
omeprazole were administered together. In another study it was shown that administering
clopidogrel and omeprazole 12 hours apart did not prevent their interaction that is likely to
be driven by the inhibitory effect of omeprazole on CYP2C19. Esomeprazole is expected to
give a similar interaction with clopidogrel.
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. As a precaution, concomitant use of
omeprazole or esomeprozole should be discouraged (see section 4.4). No conclusive data on

the pharmacodynamic interaction of clopidogrel and other PPIs are available.
There is no evidence that other medicinal products that reduce stomach acid such as H2
blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with
antiplatelet activity of clopidogrel.
Other medicinal products:
A number of other clinical studies have been conducted with clopidogrel and other
concomitant medicinal products 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 coadministration of phenobarbital or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration
of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Data from studies with human liver microsomes indicated that the carboxylic acid metabolite
of clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead
to increased plasma levels of medicinal products 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.
Apart from the specific medicinal product interaction information described above,
interaction studies with clopidogrel and some medicinal products commonly administered in
patients with atherothrombotic disease have not been performed. However, patients entered
into clinical trials with clopidogrel received a variety of concomitant medicinal products

including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents,
coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and
GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable
not to use clopidogrel during pregnancy as a precautionary measure.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development (see section 5.3).
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have
shown excretion of clopidogrel in breast milk. As a precautionary measure, breast feeding
should not be continued during treatment with Paleta.

Clopidogrel has no or negligible influence on the ability to drive and use machines.

Clopidogrel has been evaluated for safety in more than 42,000 patients who have participated
in clinical studies, including over 9,000 patients treated for 1 year or more. The clinically
relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies
are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in
CAPRIE regardless of age, gender and race. In addition to clinical studies experience, adverse
reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in
postmarketing experience where it was mostly reported during the first month of treatment.
In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any
bleeding was 9.3%. The incidence of severe cases was 1.4% for clopidogrel and 1.6% for ASA.
In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA
(<100mg: 2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for
placebo+ASA (<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding (lifethreatening,
major, minor, other) decreased during the course of the trial: 01 months
(clopidogrel: 9.6%; placebo: 6.6%), 13 months (clopidogrel: 4.5%; placebo: 2.3%), 36 months
(clopidogrel: 3.8%; placebo: 1.6%), 69 months (clopidogrel: 3.2%; placebo: 1.5%), 912
months (clopidogrel: 1.9%; placebo: 1.0%). There was no excess in major bleeds with
clopidogrel + ASA within 7 days after coronary bypass graft surgery in patients who stopped
therapy more than five days prior to surgery (4.4% clopidogrel+ASA vs. 5.3% placebo+ASA).
In patients who remained on therapy within five days of bypass graft surgery, the event rate
was 9.6% for clopidogrel+ASA, and 6.3% for placebo+ASA.
In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group
(17.4%) vs. the placebo + ASA group (12.9%).The incidence of major bleeding was similar
between groups (1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups,
respectively). This was consistent across subgroups of patients defined by baseline
characteristics, and type of fibrinolytic or heparin therapy.
In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and
similar in both groups (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA
groups, respectively).
Adverse reactions that occurred either during clinical studies or that were spontaneously
reported are presented in the table below. Their frequency is defined using the following

conventions: common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to
<1/1,000); very rare (<1/10,000). Within each system organ class, adverse drug reactions are
presented in order of decreasing seriousness.

Overdose following clopidogrel administration may lead to prolonged bleeding time and
subsequent bleeding complications. Appropriate therapy should be considered if bleedings are
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.

- Anatomical Therapeutical Chemical (ATC): B01AC04.
- Pharmacotherapeutic group:

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation.
Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that
inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the
binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent
ADPmediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet
aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of
their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a
rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP
is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic
or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
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 5 days after treatment was discontinued.
The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving
over 80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE,
CLARITY and COMMIT studies comparing clopidogrel to placebo, both medicinal products
given in combination with ASA and other standard therapy.
Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease
The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent
myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or
established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75
mg/day or ASA 325 mg/day, and were followed for 1 to 3 years.

In the myocardial infarction subgroup, most of the patients received ASA for the first few days
following the acute myocardial infarction.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point
of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the
intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events
with ASA (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p = 0.045), which
corresponds, for every 1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients
being prevented from experiencing a new ischaemic event. Analysis of total mortality as a
secondary endpoint did not show any significant difference between clopidogrel (5.8%) and
ASA (6.0%).
In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and
PAD) the benefit appeared to be strongest (achieving statistical significance at p = 0.003) in
patients enrolled due to PAD (especially those who also had a history of myocardial infarction)
(RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke
patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on
the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not
statistically different from ASA (RRR = -4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a
subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was
less than that observed in patients 75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not
clear whether the differences in relative risk reduction across qualifying conditions are real, or
a result of chance.

Absorption

After repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma
levels of unchanged clopidogrel (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 (inactive) 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.
Biotransformation
Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is
metabolised according to two main metabolic pathways: one mediated by esterases and leading
to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and
one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxoclopidogrel
intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel
intermediate metabolite results in formation of the active metabolite, a thiol derivative of
clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and
CYP2B6. The active thiol metabolite which has been isolated in vitro, binds rapidly and
irreversibly to platelet receptors, thus inhibiting platelet aggregation.
Elimination
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 (inactive) metabolite was 8 hours after single and repeated
administration.

Pharmacogenetics
Several polymorphic CYP450 enzymes activate clopidogrel. 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
correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85%
of reduced function alleles in whites and 99% in Asians. Other alleles associated with reduced
metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general
population. Published frequencies for the common CYP2C19 phenotypes and genotypes are
listed in the table below.
CYP2C19 Phenotype and Genotype Frequency
Frequency (%)

To date, the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of
clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19
metabolism in intermediate and poor metabolisers decreased the Cmax and AUC of the active
metabolite by 30-50% following 300- or 600mg loading doses and 75mg maintenance doses.
Lower active metabolite exposure results in less platelet inhibition or higher residual platelet
reactivity. To date, diminished antiplatelet responses to clopidogrel have been described for
intermediate and poor metabolisers in 21 reported studies involving 4,520 subjects. The
relative difference in antiplatelet response between genotype groups varies across studies
depending on the method used to evaluate response, but is typically greater than 30%. The
association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2
post hoc clinical trial analyses (substudies of CLARITY [n=465] and TRITON-TIMI 38
[n=1,477]) and 5 cohort studies (total n=6,489). In CLARITY and one of the cohort studies
(n=765; Trenk), cardiovascular event rates did not differ significantly by genotype. In
TRITON-TIMI 38 and 3 of the cohort studies (n= 3,516; Collet, Sibbing, Giusti), patients with
an impaired metaboliser status (intermediate and poor combined) had a higher rate of
cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared
to extensive metabolisers. In the fifth cohort study (n=2,208; Simon), the increased event rate
was observed only in poor metabolisers.
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19
activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form the
active metabolite of clopidogrel.
Special populations
The pharmacokinetics of the active metabolite of clopidogrel is not known in these special
populations.

Renal impairment
After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease
(creatinine clearance from 5 to 15 ml/min) compared inhibition of ADP-induced platelet
aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation
of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per
day. In addition, clinical tolerance was good in all patients.
Hepatic impairment
After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic
impairment, inhibition of ADP- induced platelet aggregation was similar to that observed in
healthy subjects. The mean bleeding time prolongation was also similar in the two groups.
Race
The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism
differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in
Asian populations are available to assess the clinical implication of genotyping of this CYP on
clinical outcome events.

During non clinical studies in rat and baboon, the most frequently observed effects were liver
changes. These occurred at doses representing at least 25 times the exposure seen in humans
receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic
metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans
receiving clopidogrel at the therapeutic dose.

At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of
clopidogrel was also reported in rat and baboon.
There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks
to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at
least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).
Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed
no genotoxic activity.
Clopidogrel was found to have no effect on the fertility of male and female rats and was not
teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight
delay in the development of the offspring. Specific pharmacokinetic studies performed with
radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted
in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low
palatability) cannot be excluded.

Cellulose microcrystalline, Spray-dried Mannitol (Mannogem EZ), Hydroxypropylcellulose,
Crospovidone,Citric acid, Polyethylene glycol 6000, Stearic acid (Speziol L2SM), Talc,
OpadryIIPink 32K14834.

Not Applicable.

Store below 30°C.

Blister packed consisting PA/ALL/PVC reel and hard tampered Aluminium Foil lid.

No special requirements.