DuoPlavin

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1.  NAME OF THE MEDICINAL PRODUCT 
 
DuoPlavin 75 mg/75 mg film-coated tablets  
DuoPlavin 75 mg/100 mg film-coated tablets 
 
 
2.  QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
DuoPlavin 75 mg/75 mg film-coated tablets  
Each film-coated tablet contains 75 mg of clopidogrel (as hydrogen sulphate) and 75 mg of 
acetylsalicylic acid (ASA).  
 
Excipients with known effect:  
Each film-coated tablet contains 7 mg of lactose and 3.3 mg of hydrogenated castor oil. 
 
DuoPlavin 75 mg/100 mg film-coated tablets 
Each film-coated tablet contains 75 mg of clopidogrel (as hydrogen sulphate) and 100 mg of 
acetylsalicylic acid (ASA). 
 
Excipients with known effect:  
Each film-coated tablet contains 8 mg of lactose and 3.3 mg of hydrogenated castor oil. 
 
For the full list of excipients, see section 6.1. 
 
 
3.  PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet).  
 
DuoPlavin 75 mg/75 mg film-coated tablets  
Yellow, oval, slightly biconvex, engraved with «C75» on one side and «A75» on the other side. 
 
DuoPlavin 75 mg/100 mg film-coated tablets 
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 secondary 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 
 



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DuoPlavin 75 mg/75 mg film-coated tablets  
DuoPlavin should be given as a single daily 75 mg/75 mg dose.  
 
DuoPlavin 75 mg/100 mg film-coated tablets  
DuoPlavin should be given as a single daily 75 mg/100 mg dose.  
 
DuoPlavin fixed-dose combination is used following initiation of therapy with clopidogrel and ASA 
given separately, and replaces the individual clopidogrel and ASA products.  
− 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.  

 
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. 
 

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 listed in section 6.1.  
• 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. 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). 



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• Severe renal impairment (creatinine clearance <30 ml/min). 
• 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, selective serotonin 
reuptake inhibitors (SSRIs), CYP2C19 strong inducers, thrombolytics, or other medicinal products 
associated with bleeding risk such as pentoxifylline (see section 4.5). 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 
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. 
 
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. 
 
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 P450 2C19 (CYP2C19) 
Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended 
doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. 
Tests are available to identify a patient's CYP2C19 genotype.  
 
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, 



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concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for 
a list of CYP2C19 inhibitors, see also section 5.2).  
 
Use of medicinal products 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). 
 
CYP2C8 substrates 
Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate 
medicinal products (see section 4.5).  
 
Cross-reactions among thienopyridines 
Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, 
ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). 
Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or 
haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had 
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 
signs of hypersensitivity in patients with a known allergy to thienopyridines is advised. 
 
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. 
• This medicinal product 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).  

• Alcohol may increase the risk of gastrointestinal injury when taken with ASA. Patients should 
be counseled about the risks of gastrointestinal injury and bleeding while taking clopidogrel plus 
ASA with alcohol, especially if alcohol consumption is chronic or heavy. (See section 4.5.) 

 
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. Minor GI 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 GI symptoms. Patients should be told about the signs and symptoms of GI 
undesirable effects and what steps to take if they occur. (See section 4.8.) 
 
In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an 
increased risk for severe complications such as gastrointestinal ulceration, perforation and 
haemorrhage (see section 4.5). 
 
Excipients 
DuoPlavin contains lactose. Patients with rare hereditary problems of galactose intolerance, total 
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 
 
Medicinal products associated with bleeding risk  



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There is an increased risk of bleeding due to the potential additive effect. The concomitant 
administration of medicinal products associated with bleeding risk should be undertaken with caution 
(see section 4.4).  
 
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). Although the administration of clopidogrel 
75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) 
in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin 
increases the risk of bleeding because of independent effects on hemostasis.  
 
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). 
 
Metamizole 
Metamizole may reduce the effect of ASA on platelet aggregation when taken concomitantly. 
Therefore, this combination should be used with caution in patients taking low dose ASA for 
cardioprotection . 
 
SSRIs 
Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration 
of SSRIs with clopidogrel should be undertaken with caution. 
 
Other concomitant therapy with clopidogrel 
 
Inducers of CYP2C19 
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products 
that induce the activity of this enzyme would be expected to result in increased drug levels of the 
active metabolite of clopidogrel. 
 



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Rifampicin strongly induces CYP2C19 resulting to both an increase 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). 
 
Inhibitors of CYP2C19 
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 strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 
and 5.2). 
 
Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole 
and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, 
carbamazepine, and efavirenz. 
 
Proton Pump Inhibitors (PPI) 
Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours 
between the administrations of the two drugs decreased the exposure of the active metabolite by 45% 
(loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) 
and 21% (maintenance dose) reduction of inhibition of platelet aggregation. 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 esomeprazole should be 
discouraged (see section 4.4). 
 
Less pronounced reductions of metabolite exposure has been observed with pantoprazole or 
lansoprazole. 
The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced 
(maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was 
associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, 
respectively. These results indicate that clopidogrel can be administered with pantoprazole. 
 
There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or 
antacids interfere with antiplatelet activity of clopidogrel. 
 
Boosted anti-retroviral therapy (ART): HIV patients treated with boosted anti-retroviral therapies 
(ART) are at high risk of vascular events. 
 
A significantly reduced platelet inhibition has been shown in HIV patients treated with ritonavir-or 
cobicistat-boosted ART. Although the clinical relevance of these findings is uncertain, there have been 
spontaneous reports of HIV-infected patients treated with ritonavir boosted ART, who have 
experienced re-occlusive events after de-obstruction or have suffered thrombotic events under a 
clopidogrel loading treatment schedule. Average platelet inhibition can be decreased with concomitant 
use of clopidogrel and ritonavir. Therefore, concomitant use of clopidogrel with ART boosted 
therapies should be discouraged. 
 
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. 
 



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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 the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by 
CYP2C9 can be safely co-administered with clopidogrel. 
 
CYP2C8 substrate medicinal products: 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 (see section 4.4). 
 
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.  
 
Tenofovir 
Concomitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the risk of 
renal failure. 
 
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. 
 
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). 
 
Acetazolamide 
Caution is recommended when co-administering salicylates with acetazolamide as there is an increased 
risk of metabolic acidosis. 
 
Nicorandil 
In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an 
increased risk for severe complications such as gastrointestinal ulceration, perforation and 
haemorrhage (see section 4.4). 
 
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, phenytoin, beta blockers, 
diuretics, and oral hypoglycemic agents.  
 
Alcohol 
Alcohol may increase the risk of gastrointestinal injury when taken with ASA. Patients should be 
counseled about the risks of gastrointestinal injury and bleeding while taking clopidogrel plus ASA 
with alcohol, especially if alcohol consumption is chronic or heavy. (See section 4.4.) 
 



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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. 
 
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. 
 
 
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: 
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). 
 
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 24th amenorrhea week (5th 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 24th amenorrhea week (5th 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: 



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• 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.  
 
Breast-feeding 
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown 
excretion of clopidogrel in breast milk. ASA is known to be excreted in limited amounts in human 
milk. Breast-feeding 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 dose in DuoPlavin alters fertility. 
 
4.7  Effects on ability to drive and use machines  
 
DuoPlavin has no or negligible influence on the ability to drive and use machines.  
 
4.8  Undesirable effects 
 
Summary of the safety profile 
 
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 placebo plus ASA. 
 
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. 
 
Tabulated list of adverse reactions 
 



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Adverse reactions that occurred with clopidogrel alone, with ASA alone or with clopidogrel in 
combination with ASA 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), bone 
marrow failure*, 
aplastic anaemia, 
pancytopenia, 
bicytopenia*, 
agranulocytosis, severe 
thrombocytopenia, 
acquired haemophilia 
A, granulocytopenia, 
anaemia, haemolytic 
anaemia in patients 
with 
glucose-6-phosphate 
dehydrogenase (G6PD) 
deficiency* (see 
section 4.4) 

Cardiac disorders    Kounis syndrome 
(vasospastic allergic 
angina / allergic 
myocardial infarction) 
in the context of a 
hypersensitivity 
reaction due to 
acetylsalicylic acid* or 
clopidogrel** 



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System organ 
class 

Common Uncommon Rare Very rare, not known 

Immune system 
disorders 

   Anaphylactic shock*, 
serum sickness, 
anaphylactoid 
reactions, 
cross-reactive drug 
hypersensitivity among 
thienopyridines (such 
as ticlopidine, 
prasugrel) (see section 
4.4)**,insulin 
autoimmune 
syndrome, which can 
lead to severe 
hypoglycemia, 
particularly in patients 
with HLA DRA4 
subtype (more frequent 
in the Japanese 
population)**, 
aggravation of allergic 
symptoms of food 
allergy* 

Metabolism and 
nutrition disorders 

   Hypoglycaemia*, 
gout* (see section 4.4) 

Psychiatric 
disorders 

   Hallucinations, 
confusion 

Nervous system 
disorders 

 Intracranial 
bleeding (some 
cases were 
reported with fatal 
outcome, 
especially in 
elderly), headache, 
paraesthesia, 
dizziness 
 

 Taste disturbances, 
ageusia 

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 (including 
Henoch-Schönlein 
purpura*), hypotension 



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System organ 
class 

Common Uncommon Rare Very rare, not known 

Respiratory, 
thoracic and 
mediastinal 
disorders 

Epistaxis   Respiratory tract 
bleeding (haemoptysis, 
pulmonary 
haemorrhage), 
bronchospasm, 
interstitial 
pneumonitis, 
non-cardiogenic 
pulmonary edema with 
chronic use and in the 
context of a 
hypersensitivity 
reaction due to 
acetylsalicylic acid*, 
eosinophilic 
pneumonia. 



 14 

System organ 
class 

Common Uncommon Rare Very rare, not known 

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. 
Upper gastrointestinal 
disorders 
(oesophagitis, 
oesophageal 
ulceration, perforation, 
erosive gastritis, 
erosive duodenitis; 
gastro-duodenal 
ulcer/perforations)*; 
lower gastrointestinal 
disorders (small 
[jejunum and ileum] 
and large [colon and 
rectum] intestinal 
ulcers, colitis and 
intestinal 
perforation)*; upper 
gastro-intestinal 
symptoms* such as 
gastralgia (see section 
4.4); these ASA-
related GI reactions 
may or may not be 
associated with 
haemorrhage, and may 
occur at any dose of 
acetylsalicylic acid and 
in patients with or 
without warning 
symptoms or a 
previous history of 
serious GI events*. 
Colitis (including 
ulcerative or 
lymphocytic colitis), 
stomatitis, acute 
pancreatitis in the 
context of a 
hypersensitivity 
reaction due to 
acetylsalicylic acid* 



 15 

System organ 
class 

Common Uncommon Rare Very rare, not known 

Hepatobiliary 
disorders 

   Acute liver failure, 
liver injury, mainly 
hepatocellular*, 
hepatitis, elevation of 
hepatic enzymes*, 
abnormal liver 
function test, chronic 
hepatitis* 

Skin and 
subcutaneous tissue 
disorders 

Bruising Rash, pruritus, skin 
bleeding (purpura) 

 Bullous dermatitis 
(toxic epidermal 
necrolysis, Stevens 
Johnson Syndrome, 
erythema multiforme, 
acute generalised 
exanthematous 
pustulosis (AGEP)), 
angioedema, 
drug-induced 
hypersensitivity 
syndrome, drug rash 
with eosinophilia and 
systemic symptoms 
(DRESS), rash 
erythematous or 
exfoliative, urticaria, 
eczema, lichen planus, 
fixed eruption*  

Reproductive 
systems and breast 
disorders 

  Gynaecomastia  

Musculoskeletal 
and connective 
tissue disorders 

   Musculo-skeletal 
bleeding 
(haemarthrosis), 
arthritis, arthralgia, 
myalgia 

Renal and urinary 
disorders 

 Haematuria  Renal failure*, 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, edema*  

Investigations  Bleeding time 
prolonged, 
neutrophil count 
decreased, platelet 
count decreased 

  



 16 

* Information reported in published information for ASA with frequency “not known”. 
** Information related to clopidogrel with frequency “not known”. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation 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 via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose  
 
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.  
 
Overdose with ASA/clopidogrel fixed dose combination may be associated with increased bleeding 
and subsequent bleeding complications due to the pharmacological activity of clopidogrel and ASA.  
 
Non-cardiogenic pulmonary edema can occur with acute and chronic acetylsalicylic acid overdose (see 
section 4.8).  
 
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 
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: Antithrombotic agents, platelet aggregation inhibitors excl. Heparin, ATC 
Code: B01AC30.  
 
Mechanism of action 
 
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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 17 

diphosphate (ADP) to its platelet P2Y12 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. 
 
Pharmacodynamic effects 
 
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 A2, 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. 
 
Clinical efficacy and safety 
 
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.  
 
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 



 18 

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. 
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. 
 



 19 

De-escalation of P2Y12 Inhibitor Agents in ACS  
Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin after 
acute phase in ACS has been evaluated in two randomized investigator-sponsored studies (ISS) – 
TOPIC and TROPICAL-ACS – with clinical outcome data. 
 
The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in their 
pivotal studies is related to a significant reduction in recurrent ischaemic events (including acute and 
subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although 
the ischaemic benefit was consistent throughout the first year, greater reduction in ischaemic 
recurrence after ACS was observed during the initial days following the treatment initiation.  In 
contrast, post-hoc analyses demonstrated statistically significant increases in the bleeding risk with the 
more potent P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first 
month post-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding 
events while maintaining efficacy. 
 
TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome) 
This randomized, open-label trial included ACS patients requiring PCI. Patients on aspirin and a more 
potent P2Y12 blocker and without adverse event at one month were assigned to switch to fixed-dose 
aspirin plus clopidogrel (de-escalated dual antiplatelet therapy (DAPT)) or continuation of their drug 
regimen (unchanged DAPT).   
 
Overall, 645 of 646 patients with STEMI or NSTEMI or unstable angina were analyzed (de-escalated 
DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients 
(98.1%) in the de-escalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. 
The median follow-up for both groups was 359 days. The characteristics of the studied cohort were 
similar in the 2 groups. 
 
The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and 
BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in 
43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged 
DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding 
events, with no difference reported in ischaemic endpoints (p=0.36), while BARC ≥2 bleeding 
occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9%  in the unchanged 
DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the 
de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01). 
 
TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment 
for Acute Coronary Syndromes) 
This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful 
PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1306), or 
prasugrel 5 or 10 mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1304), in 
combination with ASA (<100 mg/day).  At Day 14, platelet function testing (PFT) was performed. 
The prasugrel-only patients were continued on prasugrel for 11.5 months.   
 
The de-escalated patients underwent high platelet reactivity (HPR) testing.  If HPR≥46 units, the 
patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients 
continued on clopidogrel 75 mg/d for 11.5 months.  Therefore, the guided de-escalation arm had 
patients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and 
were followed for one year.  
 
The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 
at 12 months) was met showing non-inferiority. Ninety five patients (7%) in the guided de-escalation 
group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided 
de-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-
escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary 
endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group 



 20 

(p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events) 
in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14). 
 
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 
section 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. 
 
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-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. The active metabolite is formed mostly by 
CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and 
CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to 
platelet receptors, thus inhibiting platelet aggregation. 
 
The Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose 
as it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after 
dosing.  
 
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 
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 nonfunctional metabolism. 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 the 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.  
 



 21 

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, 
extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg 
followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). 
No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation 
(IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor 
metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive 
metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor 
metabolisers with mean IPA (5 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. 
 
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 been a number of 
retrospective analyses, however, 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. 
 
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 
 
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.  
 



 22 

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. 
 
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.  
 
Biotransformation 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 



 23 

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. 
 
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 

 
DuoPlavin 75 mg/75 mg film-coated tablets  
Coating 
Lactose monohydrate 
Hypromellose (E464) 
Titanium dioxide (E171) 
Triacetin (E1518) 
Yellow iron oxide (E172)  
 
DuoPlavin 75 mg/100 mg film-coated tablets 
Coating 
Lactose monohydrate 
Hypromellose (E464) 
Titanium dioxide (E171) 
Triacetin (E1518) 
Red iron oxide (E172)  
 
Polishing agent 
Carnauba wax 

 
6.2  Incompatibilities  
 
Not applicable.  
 



 24 

6.3  Shelf-life  
 
2 years 
 
6.4  Special precautions for storage  
 
Store below 25°C.  
 
6.5  Nature and contents of container  
 
DuoPlavin 75 mg/75 mg film-coated tablets  
Aluminium blisters in cardboard cartons containing 14, 28, 30 and 84 film-coated tablets. 
 
DuoPlavin 75 mg/100 mg film-coated tablets 
Aluminium blisters in cardboard cartons containing 14, 28 and 84 film-coated tablets. 
 
Aluminium unit-dose blisters in cardboard cartons containing 30x1, 50x1, 90x1 and 100x1 film-coated 
tablet. 
 
Not all pack sizes may be marketed. 
 
6.6  Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7.  MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe  
54, rue La Boétie 
F-75008 Paris 
France 
 
 
8.  MARKETING AUTHORISATION NUMBERS  
 
DuoPlavin 75 mg/75 mg film-coated tablets  
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  
 
DuoPlavin 75 mg/100 mg film-coated tablets 
EU/1/10/619/008 – Cartons of 14 film-coated tablets in aluminium blister packs  
EU/1/10/619/009 – Cartons of 28 film-coated tablets in aluminium blister packs  
EU/1/10/619/010 – Cartons of 30x1 film-coated tablet in aluminium blister packs  
EU/1/10/619/011 – Cartons of 50x1 film-coated tablet in aluminium blister packs  
EU/1/10/619/012 – Cartons of 84 film-coated tablets in aluminium blister packs  
EU/1/10/619/013 – Cartons of 90x1 film-coated tablet in aluminium blister packs  
EU/1/10/619/014 – Cartons of 100x1 film-coated tablet in aluminium blister packs  
 
 



 25 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
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/  

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


 26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



 27 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release  
 
Sanofi Winthrop Industrie 
1 rue de la Vierge 
Ambarès et Lagrave 
F-33565 Carbon Blanc Cedex  
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP)  
 
Not applicable 



 28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX III  

 
LABELLING AND PACKAGE LEAFLET  

 



 29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

A. LABELLING 



 30 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
DuoPlavin 75 mg/75 mg film-coated tablets 
clopidogrel/acetylsalicylic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S)  
 
Each tablet contains: 75 mg of clopidogrel (as hydrogen sulphate) and 75 mg of acetylsalicylic acid.  
 
 
3. LIST OF EXCIPIENTS  
 
It also contains: lactose and hydrogenated castor oil. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS  
 
14 film-coated tablets 
28 film-coated tablets 
30x1 film-coated tablet 
50x1 film-coated tablet 
84 film-coated tablets 
90x1film-coated tablet 
100x1 film-coated tablet 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION  
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN  
 
Keep out of the sight and reach of children.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY  
 
 
8. EXPIRY DATE  
 
EXP 
 
 



 31 

9. SPECIAL STORAGE CONDITIONS  
 
Store below 25°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  

 
Refer to local requirements for disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  
 
sanofi-aventis groupe  
54, rue La Boétie 
F-75008 Paris 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/619/001 14 film-coated tablets  
EU/1/10/619/002 28 film-coated tablets  
EU/1/10/619/003 30x1 film-coated tablet 
EU/1/10/619/004 50x1 film-coated tablet 
EU/1/10/619/005 84 film-coated tablets  
EU/1/10/619/006 90x1 film-coated tablet 
EU/1/10/619/007 100x1 film-coated tablet 
EU/1/10/619/015 30 film-coated tablets 
 
 
13. BATCH NUMBER  
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY  
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE  
 
 
16. INFORMATION IN BRAILLE  
 
DuoPlavin 75 mg/75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



 32 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



 33 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER / 14, 28 and 84 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DuoPlavin 75 mg/75 mg tablet 
clopidogrel/acetylsalicylic acid  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 
 



 34 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER / 30, 30x1, 50x1, 90x1 and 100x1 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DuoPlavin 75 mg/75 mg tablets 
clopidogrel/acetylsalicylic acid  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
 



 35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
DuoPlavin 75 mg/100 mg film-coated tablets 
clopidogrel/acetylsalicylic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S)  
 
Each tablet contains: 75 mg of clopidogrel (as hydrogen sulphate) and 100 mg of acetylsalicylic acid. 
 
 
3. LIST OF EXCIPIENTS  
 
It also contains: lactose and hydrogenated castor oil. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS  
 
14 film-coated tablets 
28 film-coated tablets 
30x1 film-coated tablet 
50x1 film-coated tablet 
84 film-coated tablets 
90x1film-coated tablet 
100x1 film-coated tablet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION  
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN  
 
Keep out of the sight and reach of children.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY  
 
 
8. EXPIRY DATE  
 
EXP 
 
 



 36 

9. SPECIAL STORAGE CONDITIONS  
 
Store below 25°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE  
 
Refer to local requirements for disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER  
 
sanofi-aventis groupe  
54, rue La Boétie 
F-75008 Paris 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/619/008 14 film-coated tablets  
EU/1/10/619/009 28 film-coated tablets  
EU/1/10/619/010 30x1 film-coated tablet 
EU/1/10/619/011 50x1 film-coated tablet 
EU/1/10/619/012 84 film-coated tablets  
EU/1/10/619/013 90x1 film-coated tablet 
EU/1/10/619/014 100x1 film-coated tablet 
 
 
13. BATCH NUMBER  
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY  
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE  
 
 
16. INFORMATION IN BRAILLE  
 
DuoPlavin 75 mg/100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



 37 

 
PC:  
SN:  
NN:  
 
 



 38 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER / 14, 28 and 84 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DuoPlavin 75 mg/100 mg tablets 
clopidogrel/acetylsalicylic acid  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 
 



 39 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER / 30x1, 50x1, 90x1 and 100x1 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
DuoPlavin 75 mg/100 mg tablet 
clopidogrel/acetylsalicylic acid  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. OTHER 
 
 



 40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 41 

Package leaflet: Information for the user 
 

DuoPlavin 75 mg/75 mg film-coated tablets 
DuoPlavin 75 mg/100 mg film-coated tablets  

clopidogrel/acetylsalicylic acid 
 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What DuoPlavin is and what it is used for 
2. What you need to know before you take DuoPlavin 
3. How to take DuoPlavin 
4. Possible side effects 
5 How to store DuoPlavin 
6. Contents of the pack and other information 
 
 
1.  What DuoPlavin is and what it is used for 
 
DuoPlavin contains clopidogrel and acetylsalicylic acid (ASA) and belongs to a group of medicines 
called antiplatelet medicinal products. Platelets are very small structures in the blood which clump 
together during blood clotting. By preventing this clumping in some types of blood vessels (called 
arteries), antiplatelet medicinal products reduce the chances of blood clots forming (a process called 
atherothrombosis). 
 
DuoPlavin is taken by adults to prevent blood clots forming in hardened arteries which can lead to 
atherothrombotic events (such as stroke, heart attack, or death).  
 
You have been prescribed DuoPlavin in place of the two separate medicines, clopidogrel and ASA, to 
help prevent blood clots because you have experienced a severe type of chest pain known as ‘unstable 
angina’ or heart attack (myocardial infarction). For the treatment of this condition your doctor may 
have placed a stent in the blocked or narrowed artery to restore effective blood flow. 
 
2.  What you need to know before you take DuoPlavin 
 
Do not take DuoPlavin  
• if you are allergic to clopidogrel, acetylsalicylic acid (ASA) or any of the other ingredients of 

this medicine (listed in section 6).  
• if you are allergic to other products called non-steroidal anti-inflammatory products usually used 

to treat painful and/or inflammatory conditions of muscles or joints. 
• if you have a medical condition that includes the combination of asthma, nasal discharge (runny 

nose) and polyps (a type of growth in the nose). 
• if you have a medical condition that is currently causing bleeding such as a stomach ulcer or 

bleeding within the brain. 
• if you suffer from severe liver disease. 
• if you suffer from severe kidney disease. 
• if you are in your last trimester of pregnancy.  



 42 

 
Warnings and precautions 
 
If any of the situations mentioned below apply to you, you should tell your doctor before taking 
DuoPlavin: 
• if you have a risk of bleeding such as:  

- a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer). 
- a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, 

organs or joints of your body). 
- a recent serious injury. 
- a recent surgery (including dental). 
- a planned surgery (including dental) in the next seven days. 

• if you have had a clot in an artery of your brain (ischaemic stroke) which occurred in the last 
seven days. 

• if you have kidney or liver disease. 
• if you have a history of asthma or allergic reactions including allergy to any medicine used to 

treat your disease.  
• if you have gout.  
• if you drink alcohol, because of the increased risk of bleeding or gastrointestinal injury.  
• if you have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency 

because of the risk of a particular form of anaemia (low number of red blood cells). 
 

While you are taking DuoPlavin: 
• You should tell your doctor 

- if a surgery (including dental) is planned. 
- if you have any stomach or abdominal pain or bleeding in the stomach or bowels (red 

stools or black stools). 
• You should also tell your doctor immediately if you develop a medical condition known as 

Thrombotic Thrombocytopenic Purpura or TTP that includes fever and bruising under the skin 
that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, 
yellowing of the skin or eyes (jaundice) (see section 4). 

• If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to 
the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and 
injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are 
concerned by your bleeding, you should contact your doctor straightaway (see section 4 
‘Possible side effects’). 

• Your doctor may order blood tests. 
 
Children and adolescents 
DuoPlavin is not intended for use in children or adolescents less than 18 years of age. There is a 
possible association between acetylsalicylic acid (ASA) and Reye’s Syndrome when products 
containing ASA are given to children or adolescents with a viral infection. Reye’s Syndrome is a very 
rare disease which can be fatal. 
 
Other medicines and DuoPlavin 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
Some other medicines may influence the use of DuoPlavin or vice versa. 
 
You should specifically tell your doctor if you take 
• medicines that may increase your risk of bleeding such as: 

- oral anticoagulants, medicines used to reduce blood clotting,  
- ASA or another non-steroidal anti-inflammatory medicine usually used to treat painful 

and/or inflammatory conditions of muscle or joints, 
- heparin or any other injectable medicine used to reduce blood clotting, 
- ticlopidine, other antiplatelet agent, 



 43 

- a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or 
fluvoxamine), medicines usually used to treat depression, 

- rifampicin (used to treat severe infections) 
• omeprazole or esomeprazole, medicines to treat upset stomach, 
• methotrexate, a medicine used to treat severe joint disease (rheumatoid arthritis) or skin disease 

(psoriasis),  
• acetazolamide, a medicine used to treat glaucoma (increased ocular pressure) or epilepsy or to 

increase urine flow, 
• probenecid, benzbromarone, or sulfinpyrazone, medicines used to treat gout, 
• fluconazole or voriconazole, medicines to treat fungal infections,  
• efavirenz or tenofovir, or other anti-retroviral medicines (used to treat HIV infections), 
• valproic acid, valproate or carbamazepine, medicines to treat some forms of epilepsy, 
• the varicella vaccine, a medicine used to prevent chickenpox or shingles, within 6 weeks of 

taking DuoPlavin, or if you have active chickenpox or shingles infection (see section 2 
‘Children and adolescents’), 

• moclobemide, medicine to treat depression, 
• repaglinide, medicine to treat diabetes,  
• paclitaxel, medicine to treat cancer, 
• nicorandil, medicine to treat cardiac chest pain, 
• opioids: while you are treated with clopidogrel, you should inform your doctor before being 

prescribed any opioids (used to treat severe pain). 
 
You should stop other clopidogrel treatment while you are taking DuoPlavin. 
 
An occasional use of ASA (no more than 1,000 mg in any 24-hour period) should generally not cause 
a problem, but prolonged use of ASA in other circumstances should be discussed with your doctor or 
pharmacist. 
 
Pregnancy and breast-feeding  
Do not take DuoPlavin during third trimester of pregnancy. 
It is preferable not to take this medicine during first and second trimesters of pregnancy. 
 
If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist 
before taking DuoPlavin. If you become pregnant while taking DuoPlavin, consult your doctor 
immediately as it is recommended not to take DuoPlavin while you are pregnant.  
 
You should not breast-feed while using this medicine. 
If you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines  
DuoPlavin should not affect your ability to drive or to use machines. 
 
DuoPlavin contains lactose  
If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact 
your doctor before taking this medicine.  
 
DuoPlavin contains hydrogenated castor oil  
This may cause stomach upset or diarrhoea.  
 
 



 44 

3.  How to take DuoPlavin  
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose is one tablet of DuoPlavin per day to be taken orally with a glass of water, 
with or without food. 
 
You should take your medicine at the same time each day. 
 
Depending on your condition, your doctor will determine the length of time for which you need to take 
DuoPlavin. If you have had a heart attack, it should be prescribed for at least four weeks. In any case, 
you should take it for as long as your doctor continues to prescribe it.  
 
If you take more DuoPlavin than you should 
Contact your doctor or the nearest hospital emergency department because of the increased risk of 
bleeding. 
 
If you forget to take DuoPlavin 
If you forget to take a dose of DuoPlavin, but remember within 12 hours of your usual time, take your 
tablet straightaway and then take your next tablet at the usual time.  
 
If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a 
double dose to make up for a forgotten tablet.  
 
For the 14, 28 and 84 tablets pack sizes you can check the day on which you last took a tablet of 
DuoPlavin by referring to the calendar printed on the blister. 
 
If you stop taking DuoPlavin 
Do not stop the treatment unless your doctor tells you so. Contact your doctor before stopping or 
restarting your treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Contact your doctor immediately if you experience: 
• fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood 

cells.  
• signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not 

associated with bleeding which appears under the skin as red pinpoint dots, and/or confusion 
(see section 2 ‘Warnings and precautions’). 

• swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. These 
may be the signs of an allergic reaction. 

 
The most common side effect which has been seen with DuoPlavin is bleeding. Bleeding may 
occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under 
the skin), nose bleed, blood in the urine. In a small number of cases, bleeding in the eye, inside the 
head (especially in elderly), the lung or the joints has also been reported. 
 
If you experience prolonged bleeding when taking DuoPlavin 
If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the 
way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries 



 45 

e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your 
bleeding, you should contact your doctor straightaway (see section 2 ‘Warnings and precautions’). 
 
Other side effects include: 
Common side effects (may affect up to 1 in 10 people):  
Diarrhoea, abdominal pain, indigestion or heartburn. 
 
Uncommon side effects (may affect up to 1 in 100 people):  
Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, 
rashes, itching, dizziness, sensation of tingling and numbness. 
 
Rare side effect (may affect up to 1 in 1000 people):  
Vertigo, enlarged breasts in males. 
 
Very rare side effects (may affect up to 1 in 10,000 people):  
Jaundice (yellowing of skin and/or eyes); burning in stomach and/or esophagus (gullet); severe 
abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with 
cough; generalised allergic reactions (for example, overall sensation of heat with sudden general 
discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore mouth 
(stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes 
in taste or loss of taste of foods, inflammation of small vessels.  
 
Side effects with frequency not known (frequency cannot be estimated from the available data):  
Ulcer perforation, ringing in the ears, hearing loss, sudden life-threatening allergic or hypersensitivity 
reactions with chest or abdominal pain, kidney disease, low blood sugar, gout (a condition of painful, 
swollen joints caused by uric acid crystals) and worsening of food allergies, a particular form of 
anaemia (low number of red blood cells) (see section 2 ‘Warnings and precautions’), swelling. 
 
In addition, your doctor may identify changes in your blood or urine tests. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store DuoPlavin 
 
Keep this medicine out of the sight and reach of children.  
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister, after 
EXP. The expiry date refers to the last day of that month. 
 
Store below 25°C.  
 
Do not use this medicine if you notice any visible sign of deterioration. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What DuoPlavin contains  
 
DuoPlavin 75 mg/75 mg film-coated tablets 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 46 

The active substances are clopidogrel and acetylsalicylic acid (ASA). Each tablet contains 75 mg of 
clopidogrel (as hydrogen sulphate) and 75 mg of acetylsalicylic acid. 
 
The other ingredients are: 
- Tablet core: mannitol (E421), macrogol 6000, microcrystalline cellulose, low substituted 

hydroxypropylcellulose, maize starch, hydrogenated castor oil (see section 2 ‘DuoPlavin 
contains hydrogenated castor oil’), stearic acid and colloidal anhydrous silica 

- Tablet coating: lactose monohydrate (see section 2 ‘DuoPlavin contains lactose’), hypromellose 
(E464), titanium dioxide (E171), triacetin (E1518), yellow iron oxide (E172) 

- Polishing agent: carnauba wax 
 
DuoPlavin 75 mg/100 mg film-coated tablets 
The active substances are clopidogrel and acetylsalicylic acid (ASA). Each tablet contains 75 mg of 
clopidogrel (as hydrogen sulphate) and 100 mg of acetylsalicylic acid. 
 
The other ingredients are: 
- Tablet core: mannitol (E421), macrogol 6000, microcrystalline cellulose, low substituted 

hydroxypropylcellulose, maize starch, hydrogenated castor oil (see section 2 ‘DuoPlavin 
contains hydrogenated castor oil’), stearic acid and colloidal anhydrous silica 

- Tablet coating: lactose monohydrate (see section 2 ‘DuoPlavin contains lactose’), hypromellose 
(E464), titanium dioxide (E171), triacetin (E1518), red iron oxide (E172) 

- Polishing agent: carnauba wax 
 
What DuoPlavin looks like and contents of the pack 
 
DuoPlavin 75 mg/75 mg film-coated tablets 
DuoPlavin 75 mg/75 mg film-coated tablets (tablets) are oval, slightly biconvex, yellow, engraved on 
one side with ‘C75’ and ‘A75’on the other side. DuoPlavin is supplied in cardboard cartons 
containing: 
- 14, 28, 30 and 84 tablets in all-aluminium blisters 
- 30x1, 50x1, 90x1 and 100x1 tablet in all-aluminium unit-dose blisters. 
 
DuoPlavin 75 mg/100 mg film-coated tablets 
DuoPlavin 75 mg/100 mg film-coated tablets (tablets) are oval, slightly biconvex, light pink, engraved 
on one side with ‘C75’ and ‘A100’on the other side. DuoPlavin is supplied in cardboard cartons 
containing: 
- 14, 28 and 84 tablets in all-aluminium blisters 
- 30x1, 50x1, 90x1 and 100x1 tablet in all-aluminium unit-dose blisters. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder:  
sanofi-aventis groupe  
54, rue La Boétie 
F-75008 Paris 
France 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1, rue de la Vierge, Ambarès & Lagrave, F-33565 Carbon Blanc cedex, France 
 



 47 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:  
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB «SANOFI-AVENTIS LIETUVA» 
Tel: +370 5 2755224 
 

България 
SANOFI BULGARIA EOOD 
Тел: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt.  
Tel.: +36 1 505 0050 
 

Danmark 
Sanofi  A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.r.l. 
Tel: +39 02 39394275 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel.: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 
 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 3488 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel: +48 22 280 00 00 
 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.r.l. 
Tel: 800 536 389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 



 48 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
 
This leaflet was last revised in <Month YYYY>. 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/  
 

  
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET