DuoPlavin

1. NAME OF THE MEDICINAL PRODUCT

DuoPlavin 75 mg/75 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of clopidogrel (as hydrogen sulphate) and 75 mg of

acetylsalicylic acid (ASA).

Excipients:

Each film-coated tablet contains 7 mg of lactose and 3.3 mg of hydrogenated castor oil.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Yellow, oval, slightly biconvex, engraved with «C75» on one side and «A75» on the other side.

4. CLINICAL PARTICULARS

4.1

Therapeutic indications

DuoPlavin is indicated for the prevention of atherothrombotic events in adult patients already taking

both clopidogrel and acetylsalicylic acid (ASA). DuoPlavin is a fixed-dose combination medicinal

product for continuation of therapy in:



Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave

myocardial infarction) including patients undergoing a stent placement following percutaneous

coronary intervention



ST segment elevation acute myocardial infarction in medically treated patients eligible for

thrombolytic therapy

For further information please refer to section 5.1.

4.2 Posology and method of administration

Posology

 Adults and elderly

DuoPlavin should be given as a single daily 75 mg/75 mg dose.

DuoPlavin is used following initiation of therapy with clopidogrel and ASA given separately.

 In patients with non-ST segment elevation acute coronary syndrome (unstable angina or

non-Q-wave myocardial infarction): The optimal duration of treatment has not been formally

established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at

3 months (see section 5.1). If the use of DuoPlavin is discontinued, patients may benefit with

continuation of one antiplatelet medicinal product.

 In patients with ST segment elevation acute myocardial infarction : Therapy should be started as

early as possible after symptoms start and continued for at least four weeks. The benefit of the

combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see

section 5.1). If the use of DuoPlavin is discontinued, patients may benefit with continuation of one

antiplatelet medicinal product.

2

If a dose is missed:

-

Within less than 12 hours after regular scheduled time: patients should take the dose

immediately and then take the next dose at the regular scheduled time.

-

For more than 12 hours: patients should take the next dose at the regular scheduled time and

should not double the dose.



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 population

The safety and efficacy of DuoPlavin in children and adolescents under 18 years old have not

been established. DuoPlavin is not recommended in this population.



Renal impairment

DuoPlavin must not be used in patients with severe renal impairment (see section 4.3).

Therapeutic experience is limited in patients with mild to moderate renal impairment (see

section 4.4). Therefore DuoPlavin should be used with caution in these patients.

 Hepatic impairment

DuoPlavin must not be used in patients with severe hepatic impairment (see section 4.3).

Therapeutic experience is limited in patients with moderate hepatic disease who may have

bleeding diatheses (see section 4.4). Therefore DuoPlavin should be used with caution in these

patients.

Method of administration

For oral use.

It may be given with or without food.

4.3 Contraindications

Due to the presence of both components of the medicinal product, DuoPlavin is contraindicated in case

of:



Hypersensitivity to the active substances or to any of the excipients.



Severe hepatic impairment.



Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

In addition, due to the presence of ASA, its use is also contraindicated in:



Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and syndrome of asthma,

rhinitis, and nasal polyps.



Severe renal impairment.



Third trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

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 a dual antiplatelet

agent, DuoPlavin 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 or thrombolytics. Patients

should be followed carefully for any signs of bleeding including occult bleeding, especially during the

first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant

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administration of DuoPlavin with oral anticoagulants is not recommended since it may increase the

intensity of bleeding (see section 4.5).

Patients should inform physicians and dentists that they are taking DuoPlavin before any surgery is

scheduled and before any new medicinal product is taken. Where elective surgery is being considered,

the need for dual antiplatelet therapy should be reviewed and consideration given to the use of a single

antiplatelet agent. If patients must temporarily stop antiplatelet therapy, DuoPlavin should be

discontinued 7 days prior to surgery.

DuoPlavin 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 also be told that it might take longer than usual to stop bleeding when they take

DuoPlavin, 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 transient ischaemic attack or stroke

In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic

events, the combination of ASA and clopidogrel has been shown to increase major bleeding.

Therefore, such addition should be undertaken with caution outside of clinical situations where the

combination has proven to be beneficial.

Cytochrome P 450 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).

Caution required due to ASA



In patients with a history of asthma or allergic disorders since they are at increased risk of

hypersensitivity reactions



In patients with gout since low doses of ASA increase urate concentrations.



In children under 18 years of age, there is a possible association between ASA and Reye’s

syndrome. Reye’s syndrome is a very rare disease which can be fatal.

Gastrointestinal (GI)

DuoPlavin should be used with caution in patients with a history of peptic ulcer or gastroduodenal

haemorrhage or minor upper GI symptoms as this may be due to gastric ulceration which may lead to

gastric bleeding. GI undesirable effects including stomach pain, heartburn, nausea, vomiting, and GI

bleeding may occur. Although minor upper GI symptoms, such as dyspepsia, are common and can

occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding,

even in the absence of previous GI symptoms. Patients should be told about the signs and symptoms of

GI undesirable effects and what steps to take if they occur.

Excipients

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DuoPlavin contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp

lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product also contains hydrogenated castor oil which may cause stomach upset and

diarrhoea.

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants: the concomitant administration of DuoPlavin with oral anticoagulants is not

recommended since it may increase the intensity of bleeding (see section 4.4).

Glycoprotein IIb/IIIa inhibitors : DuoPlavin should be used with caution in patients who receive

concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

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. Co-administration of heparin had no

effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction

between DuoPlavin 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 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

heparin are co-administered with ASA (see section 4.8). The safety of the concomitant administration

of DuoPlavin with other thrombolytic agents has not been formally established and should be

undertaken with caution (see section 4.4).

NSAIDs : 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 (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet

aggregation when they are dosed concomitantly. However, the limitations of these data and the

uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm

conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be

likely for occasional ibuprofen use (see section 5.1).

Other concomitant therapy with clopidogrel: 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.

5

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 (PK) 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.

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.

Other concomitant therapy with ASA : Interactions with the following medicinal products have been

reported with ASA:

Uricosurics (benzbromarone, probenecid, sulfinpyrazone) : Caution is required because ASA may

inhibit the effect of uricosuric agents through competitive elimination of uric acid.

Methotrexate : Due to the presence of ASA, methotrexate used at doses higher than 20 mg/week should

be used with caution with DuoPlavin as it can inhibit renal clearance of methotrexate, which may lead

to bone marrow toxicity.

Other interactions with ASA : Interactions with the following medicinal products with higher

(anti-inflammatory) doses of ASA have also been reported: angiotensin converting enzyme (ACE)

inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta blockers, diuretics, and

oral hypoglycemic agents.

Other interactions with clopidogrel and ASA: More than 30,000 patients entered into clinical trials

with clopidogrel plus ASA at maintenance doses lower than or equal to 325 mg, and received a variety

of concomitant medicinal products including diuretics, beta blockers, ACE Inhibitors, calcium

antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin),

antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse

interactions.

Apart from the specific medicinal product interaction information described above, interaction studies

with DuoPlavin and some medicinal products commonly administered in patients with

atherothrombotic disease have not been performed.

6

4.6 Fertility, pregnancy and lactation

Pregnancy

No clinical data on exposure to DuoPlavin during pregnancy are available. DuoPlavin should not be

used during the first two trimesters of pregnancy unless the clinical condition of the woman requires

treatment with clopidogrel/ASA.

Due to the presence of ASA, DuoPlavin is contraindicated during the third trimester of pregnancy.

Clopidogrel:

There are no adequate data from the use of clopidogrel in pregnant women. Animal studies do not

indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

ASA:

Low doses (up to 100 mg/day):

Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require

specialised monitoring, appear safe.

Doses of 100-500 mg/day:

There is insufficient clinical experience regarding the use of doses above 100 mg/day up

to 500 mg/day. Therefore, the recommendations below for doses of 500 mg/day and above apply also

for this dose range.

Doses of 500 mg/day and above:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal

development. Data from epidemiological studies suggest an increased risk of miscarriage and of

cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early

pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to

approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals,

administration of a prostaglandin synthesis inhibitor has been shown to result in reproductive toxicity

(see section 5.3). Until the 24 th amenorrhea week (5 th month of pregnancy), acetylsalicylic acid should

not be given unless clearly necessary. If acetylsalicylic acid is used by a woman attempting to

conceive, or until the 24 th amenorrhea week (5 th month of pregnancy), the dose should be kept as low

and duration of treatment as short as possible.

From the beginning of the sixth month of pregnancy, all prostaglandin synthesis inhibitors may

expose:

 the foetus to:

-

cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary

hypertension);

-

renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

 the mother and the neonate, at the end of pregnancy, to:

-

possible prolongation of bleeding time, an anti-aggregating effect which may occur even at

very low doses;

-

inhibition of uterine contractions resulting in delayed or prolonged labour.

Breastfeeding

It is unknown whether clopidogrel is excreted in human milk. ASA is known to be excreted in limited

amounts in human milk. Breastfeeding should be discontinued during treatment with DuoPlavin.

Fertility

There are no fertility data with DuoPlavin. Clopidogrel was not shown to alter fertility in animal

studies. It is unknown whether ASA alters fertility.

4.7 Effects on ability to drive and use machines

7

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

4.8 Undesirable effects

Clopidogrel has been evaluated for safety in more than 42,000 patients who have participated in

clinical studies, including over 30,000 patients treated with clopidogrel plus ASA, and over 9,000

patients treated for 1 year or more. The clinically relevant adverse reactions observed in four major

studies, the CAPRIE study (a study comparing clopidogrel alone to ASA) and the CURE, CLARITY

and COMMIT studies (studies comparing clopidogrel plus ASA to ASA alone) are discussed below.

Overall clopidogrel 75 mg/day was similar 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 the post-marketing

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 similar for clopidogrel and ASA.

In CURE there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary

bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients

who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for

clopidogrel plus ASA, and 6.3% for ASA alone.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the

group taking ASA alone. The incidence of major bleeding was similar between groups. 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.

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), not known (cannot be estimated from the available data). Within each system organ class,

adverse reactions are presented in order of decreasing seriousness.

System Organ

Class

Common

Uncommon

Rare

Very rare, not

known*

Blood and the

lymphatic system

disorders

Thrombocytopenia,

leucopenia,

eosinophilia

Neutropenia,

including

severe

neutropenia

Thrombotic

thrombocytopenic

purpura (TTP) (see

section 4.4), aplastic

anaemia, pancytopenia,

agranulocytosis, severe

thrombocytopenia,

granulocytopenia,

anaemia

Immune system

disorders

Anaphylactic shock*,

serum sickness,

anaphylactoid

reactions, aggravation

of allergic symptoms

of food allergy*

Metabolism and

nutrition disorders

Hypoglycaemia*,

gout* (see section 4.4)

8

System Organ

Class

Common

Uncommon

Rare

Very rare, not

known*

Psychiatric

disorders

Hallucinations,

confusion

Nervous system

disorders

Intracranial

bleeding (some

cases were

reported with fatal

outcome),

headache,

paraesthesia,

dizziness

Taste disturbances

Eye disorders

Eye bleeding

(conjunctival,

ocular, retinal)

Ear and labyrinth

disorders

Vertigo

Hearing loss* or

tinnitus*

Vascular disorders Haematoma

Serious haemorrhage,

haemorrhage of

operative wound,

vasculitis, hypotension

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis

Respiratory tract

bleeding (haemoptysis,

pulmonary

haemorrhage),

bronchospasm,

interstitial pneumonitis

Gastrointestinal

disorders

Gastrointestinal

haemorrhage,

diarrhoea,

abdominal

pain, dyspepsia

Gastric ulcer and

duodenal ulcer,

gastritis, vomiting,

nausea,

constipation,

flatulence

Retroperitoneal

haemorrhage

Gastrointestinal and

retroperitoneal

haemorrhage with fatal

outcome, pancreatitis,

gastro-duodenal

ulcer/perforations*,

colitis (including

ulcerative or

lymphocytic colitis),

upper gastro-intestinal

symptoms* such as

gastralgia (see section

4.4), stomatitis

Hepatobiliary

disorders

Acute liver failure,

hepatitis, abnormal

liver function test

Skin and

subcutaneous tissue

disorders

Bruising

Rash, pruritus, skin

bleeding (purpura)

Bullous dermatitis

(toxic epidermal

necrolysis, Stevens

Johnson Syndrome,

erythema multiforme),

angioedema, rash

erythematous,

urticaria, eczema,

lichen planus

9

System Organ

Class

Common

Uncommon

Rare

Very rare, not

known*

Musculoskeletal

and connective

tissue disorders

Musculo-skeletal

bleeding

(haemarthrosis),

arthritis, arthralgia,

myalgia

Renal and urinary

disorders

Haematuria

Acute renal

impairment (especially

in patients with

existing renal

impairment, heart

decompensation,

nephritic syndrome, or

concomitant treatment

with diuretics)*,

glomerulonephritis,

blood creatinine

increased

General disorders

and administration

site conditions

Bleeding at the

puncture site

Fever

Investigations

Bleeding time

prolonged,

neutrophil count

decreased, platelet

count decreased

* Not known corresponds to information reported in published information for ASA.

4.9

Overdose

There is no information concerning overdose with DuoPlavin.

Clopidogrel: 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.

ASA: The following symptoms are associated with moderate intoxication: dizziness, headache,

tinnitus, confusion and gastrointestinal symptoms (nausea, vomiting and gastric pain).

With severe intoxication, serious disturbances of the acid-base equilibrium occur. Initial

hyperventilation leads to respiratory alkalosis. Subsequently a respiratory acidosis occurs as a result of

a suppressive effect on the respiratory centre. A metabolic acidosis also arises due to the presence of

salicylates. Given that children, infants and toddlers are often only seen at a late stage of intoxication,

they will usually have already reached the acidosis stage.

The following symptoms can also arise: hyperthermia and perspiration, leading to dehydration,

restlessness, convulsions, hallucinations and hypoglycaemia. Depression of the nervous system can

lead to coma, cardiovascular collapse and respiratory arrest. The lethal dose of acetylsalicylic acid is

25-30 g. Plasma salicylate concentrations above 300 mg/l (1.67 mmol/l) suggest intoxication.

If a toxic dose has been ingested then admission to hospital is necessary. With moderate intoxication

an attempt can be made to induce vomiting; if this fails, gastric lavage is indicated. Activated charcoal

(adsorbent) and sodium sulphate (laxative) are then administered. Alkalising of the urine (250 mmol

10

sodium bicarbonate for 3 hours) while monitoring the urine pH is indicated. Haemodialysis is the

preferred treatment for severe intoxication. Treat other signs of intoxication symptomatically.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: platelet aggregation inhibitors excl. Heparin, ATC Code:

B01AC30.

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 P2Y 12 receptor and the subsequent ADP-mediated 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 medicinal products, not all patients will have adequate platelet inhibition.

Repeated doses of clopidogrel 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.

Acetylsalicylic acid inhibits platelet aggregation by irreversible inhibition of prostaglandin

cyclo-oxygenase and thus inhibits the generation of thromboxane A 2 , an inducer of platelet

aggregation and vasoconstriction. This effect lasts for the life of the platelet.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet

aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400 mg

was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81 mg), a

decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However,

the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical

situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically

relevant effect is considered to be likely for occasional ibuprofen use.

The safety and efficacy of clopidogrel plus ASA have been evaluated in three double-blind studies

involving over 61,900 patients: the CURE, CLARITY and COMMIT studies, comparing clopidogrel

plus ASA to ASA alone, both treatments given in combination with other standard therapy.

The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome

(unstable angina or non-Q-wave 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=6,259) plus ASA (75-325 mg once daily) or ASA alone (N=6,303),

(75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In

CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins

were administered in more than 90% of the patients and the relative rate of bleeding between

clopidogrel plus ASA and ASA alone was not significantly affected by the concomitant heparin

therapy.

11

The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial

infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel plus ASA group and 719 (11.4%) in the

ASA group, a 20% relative risk reduction (RRR) (95% CI of 10%-28%; p=0.00009) for the

clopidogrel plus ASA group [17% relative risk reduction when patients were treated conservatively,

29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without

stent and 10% when they underwent coronary artery bypass graft (CABG)]. New cardiovascular

events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32%

(CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1,

1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the

benefit observed in the clopidogrel plus ASA group was not further increased, whereas the risk of

haemorrhage persisted (see section 4.4).

The use of clopidogrel in CURE was associated with a decrease in the need for thrombolytic therapy

(RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%).

The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory

ischaemia) was 1,035 (16.5%) in the clopidogrel plus ASA group and 1,187 (18.8%) in the ASA

group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel plus ASA

group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI

[287 (4.6%) in the clopidogrel plus ASA group and 363 (5.8%) in the ASA group]. There was no

observed effect on the rate of rehospitalisation for unstable angina.

The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave

MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with

the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the

total CURE population) who underwent stent placement (Stent-CURE), the data showed that

clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for

the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second

co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of

clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this

subset are in line with the overall trial results.

In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been

evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation

MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose,

followed by 75 mg/day, n=1,752) plus ASA or ASA alone (n=1,739), (150 to 325 mg as a loading

dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients

were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded

infarct-related artery on the predischarge angiogram, or death or recurrent MI before 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. The patient population included

19.7% women and 29.2% patients ≥65 years. 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.

Fifteen percent (15.0%) of patients in the clopidogrel plus ASA group and 21.7% in the group treated

with ASA alone reached the primary endpoint, representing an absolute reduction of 6.7% and a 36%

odds reduction in favor of clopidogrel (95% CI: 24, 47%; p <0.001), mainly related to a reduction in

occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups

including patients’ age and gender, infarct location, and type of fibrinolytic or heparin used.

The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the

onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST

depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) plus

ASA (162 mg/day), or ASA alone (162 mg/day) (n=22,891), for 28 days or until hospital discharge.

12

The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke

or death. The population included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years) and

54.5% patients who received fibrinolytics.

Clopidogrel plus ASA 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 reduction of 0.5% and 0.9%, respectively. This benefit was

consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

DuoPlavin in all subsets of the paediatric population in the treatment of coronary atherosclerosis. See

4.2 for information on paediatric use.

5.2

Pharmacokinetic properties

Clopidogrel:

Absorption

After single and 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.

Metabolism

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-oxo-clopidogrel 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 14 C-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 Caucasians 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.

13

CYP2C19 phenotype and genotype frequency

Frequency (%)

Caucasian

(n=1356)

Black (n=966) Chinese (n=573)

Extensive metabolism: CYP2C19*1/*1

74

66

38

Intermediate metabolism: CYP2C19*1/*2 or *1/*3

26

29

50

Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3

2

4

14

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 C max and AUC of the active

metabolite by 30-50% following 300- or 600-mg loading doses and 75-mg 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), 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.

14

Acetylsalicylic acid (ASA):

Absorption

Following absorption, the ASA in DuoPlavin is hydrolyzed to salicylic acid with peak plasma levels of

salicylic acid occurring within 1 hour of dosing, such that plasma levels of ASA are essentially

undetectable 1.5-3 hours after dosing.

Distribution

ASA 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 micrograms/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.

Metabolism and Elimination

The ASA in DuoPlavin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 0.3 to

0.4 hours for ASA doses from 75 to 100 mg. Salicylic acid is primarily conjugated in the liver to form

salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites.

Salicylic acid in DuoPlavin has a plasma half-life of approximately 2 hours. 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 doses (1020 g),

the plasma half-life may be increased to over 20 hours. At high ASA 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 active

substance 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.

Based on the pharmacokinetic and metabolic characteristics of both compounds, clinically significant

PK interactions are unlikely

5.3

Preclinical safety data

Clopidogrel : 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.

15

Acetylsalicylic Acid: Single-dose studies have shown that the oral toxicity of ASA is low. Repeat-

dose toxicity studies have shown that levels up to 200 mg/kg/day are well tolerated in rats; dogs

appear to be more sensitive, probably due to the high sensitivity of canines to the ulcerogenic effects

of NSAIDs. No genotoxicity or clastogenicity issues of concern have been found with ASA. Although

no formal carcinogenicity studies have been performed with ASA, it has been shown that it is not a

tumour promoter.

Reproduction toxicity data show that ASA is teratogenic in several laboratory animals.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased

pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of

various malformations, including cardiovascular, have been reported in animals given a prostaglandin

synthesis inhibitor during the organogenetic period.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Mannitol (E421)

Macrogol 6000

Microcrystalline cellulose

Low substituted hydroxypropylcellulose

Maize starch

Hydrogenated castor oil

Stearic acid

Colloidal anhydrous silica

Coating:

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Triacetin (E1518)

Yellow iron oxide (E172)

Polishing agent:

Carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf-life

2 years

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Aluminium blisters in cardboard cartons containing 14, 28, 30 and 84 film-coated tablets.

Aluminium perforated unit-dose blisters in cardboard cartons containing 30x1, 50x1, 90x1 and 100x1

film-coated tablet.

16

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Sanofi Pharma Bristol-Myers Squibb SNC

174 Avenue de France

F-75013 Paris

France

8. MARKETING AUTHORISATION NUMBERS

EU/1/10/619/001 – Cartons of 14 film-coated tablets in aluminium blister packs

EU/1/10/619/002 – Cartons of 28 film-coated tablets in aluminium blister packs

EU/1/10/619/003 – Cartons of 30x1 film-coated tablet in aluminium blister packs

EU/1/10/619/004 – Cartons of 50x1 film-coated tablet in aluminium blister packs

EU/1/10/619/005 – Cartons of 84 film-coated tablets in aluminium blister packs

EU/1/10/619/006 – Cartons of 90x1film-coated tablet in aluminium blister packs

EU/1/10/619/007 – Cartons of 100x1film-coated tablet in aluminium blister packs

EU/1/10/619/015 – Cartons of 30 film-coated tablet in aluminium blister packs

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 March 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the European Medicines Agency

website: http://www.ema.europa.eu/

17

1. NAME OF THE MEDICINAL PRODUCT

DuoPlavin 75 mg/100 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of clopidogrel (as hydrogen sulphate) and 100 mg of

acetylsalicylic acid (ASA).

Excipients:

Each film-coated tablet contains 8 mg of lactose and 3.3 mg of hydrogenated castor oil.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Light pink, oval, slightly biconvex, engraved with «C75» on one side and «A100» on the other side.

4. CLINICAL PARTICULARS

4.1

Therapeutic indications

DuoPlavin is indicated for the prevention of atherothrombotic events in adult patients already taking

both clopidogrel and acetylsalicylic acid (ASA). DuoPlavin is a fixed-dose combination medicinal

product for continuation of therapy in:



Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave

myocardial infarction) including patients undergoing a stent placement following percutaneous

coronary intervention



ST segment elevation acute myocardial infarction in medically treated patients eligible for

thrombolytic therapy

For further information please refer to section 5.1.

4.2 Posology and method of administration

Posology

 Adults and elderly

DuoPlavin should be given as a single daily 75 mg/100 mg dose.

DuoPlavin is used following initiation of therapy with clopidogrel and ASA given separately.

 In patients with non-ST segment elevation acute coronary syndrome (unstable angina or

non-Q-wave myocardial infarction): The optimal duration of treatment has not been formally

established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at

3 months (see section 5.1). If the use of DuoPlavin is discontinued, patients may benefit with

continuation of one antiplatelet medicinal product.

 In patients with ST segment elevation acute myocardial infarction : Therapy should be started as

early as possible after symptoms start and continued for at least four weeks. The benefit of the

combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see

section 5.1). If the use of DuoPlavin is discontinued, patients may benefit with continuation of one

antiplatelet medicinal product.

18