Clopidogrel Acino Pharma

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel Acino Pharma 75 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 75 mg of clopidogrel (as besilate). 
Excipients: each film-coatedtablet contains 3.80 mg of hydrogenated castor oil. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
White to off-white, marbled, round and biconvex film-coated tablets.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: 
 

 Patients suffering from myocardial infarction (from a few days until less than 35 days), 
ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial 
disease. 

 
For further information please refer to section 5.1. 
 
4.2 Posology and method of administration 
 
Posology 
 Adults and elderly 
 Clopidogrel should be given as a single daily dose of 75 mg. 
 
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 
 Clopidogrel should not be used in children because of efficacy concerns (see section 5.1). 
 
 Renal impairment 
 Therapeutic experience is limited in patients with renal impairment (see section 4.4). 
 
 Hepatic impairment 
 Therapeutic experience is limited in patients with moderate hepatic disease who may have 
 bleeding diatheses (see section 4.4). 
 

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Method of administration 
For oral use 
It may be given with or without food. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substance or to any of the excipients. 
 Severe hepatic impairment. 
 Active pathological bleeding such as peptic ulcer or intracranial haemorrhage. 
 
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 with other antiplatelet 
agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding 
from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, 
heparin, glycoprotein IIb/IIIa inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) including 
Cox-2 inhibitors. Patients should be followed carefully for any signs of bleeding including occult 
bleeding,especially during the first weeks of treatment and/or after invasive cardiac procedures or 
surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended 
since it may increase the intensity of bleedings (see section 4.5). 
 
If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, 
clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and 
dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal 
product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who 
have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). 
 
Patients should be told that it might take longer than usual to stop bleeding when they take 
clopidogrel, and that they should report any unusual bleeding (site or duration) to their physician.  
 
Thrombotic Thrombocytopenic Purpura (TTP) 
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of 
clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and 
microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction 
or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.  
 
Recent ischaemic stroke 
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute 
ischaemic stroke. 
 
Cytochrome P450 2C19 (CYP2C19) 
Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended 
doses forms less of the active metabolite of clopidogrel  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 
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).  
 
Renal impairment 
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore 
clopidogrel should be used with caution in these patients (see section 4.2). 

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Hepatic impairment 
Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. 
Clopidogrel should therefore be used with caution in this population (see section 4.2). 
 
Excipients  
Clopidogrel Acino Pharma contains hydrogenated castor oil which may cause stomach upset and 
diarrhoea.  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not 
recommended since it may increase the intensity of bleedings (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: clopidogrel should be used with caution in patients who receive 
concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4). 
 
Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced 
platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet 
aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not 
significantly increase the prolongation of bleeding time induced by clopidogrel intake. A 
pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to 
increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 
4.4).  
 
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 clopidogrel and heparin is possible, leading to increased risk of bleeding. 
Therefore, concomitant use should be undertaken with caution (see section 4.4). 
 
Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or 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) 
 
NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of 
clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of 
interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of 
gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and 
clopidogrel should be co-administered with caution (see section 4.4). 
 
Other concomitant therapy:  
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal 
products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of 
the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a 
precaution concomitant use strong or moderate CYP2C19 inhibitors should be discouraged (see 
sections 4.4 and 5.2). 
 
Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, 
fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, 
carbamazepine, oxcarbazepine and chloramphenicol. 
 

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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 
(except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of 
clopidogrel. 
 
Other medicinal products: 
A number of other clinical studies have been conducted with clopidogrel and other concomitant 
medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic 
interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel 
was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the 
pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of 
phenobarbital or oestrogen. 
 
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of 
clopidogrel. Antacids did not modify the extent of clopidogrel absorption. 
 
Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by 
CYP2C9 can be safely co-administered with clopidogrel. 
 
Apart from the specific medicinal products interaction information described above, interaction studies 
with clopidogrel and some medicinal products commonly administered in patients with 
atherothrombotic disease have not been performed. However, patients entered into clinical trials with 
clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, 
ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents 
(including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically 
significant adverse interactions. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
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).  
 

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Breastfeeding 
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown 
excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be 
continued during treatment with clopidogrel. 
 
Fertility 
Clopidogrel was not shown to alter fertility in animal studies. 
 
4.7 Effects on ability to drive and use machines 
 
Clopidogrel has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Clopidogrel has been evaluated for safety for 1 year or more. The clinically relevant adverse reactions 
observed in the CAPRIE study are discussed below. Overall, clopidogrel 75 mg/day was comparable 
to ASA 325 mg/day in CAPRIE regardless of age, gender and race. In addition to clinical studies 
experience, adverse reactions have been spontaneously reported. 
 
Bleeding is the most common reaction reported both in clinical studies as well as in 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 1.6% for ASA. 
 
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are 
presented in the table below. Their frequency is defined using the following conventions: common 
(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare 
(< 1/10,000). Within each system organ class, adverse reactions are presented in order of decreasing 
seriousness. 
 

System Organ 
Class  

Common  Uncommon  Rare  Very rare  

Blood and the 
lymphatic 
system disorders  

 Thrombocytopenia, 
leucopenia, 
eosinophilia  

Neutropenia, 
including severe 
neutropenia  

Thrombotic 
thrombocytopenic 
purpura (TTP) (see 
section 4.4), aplastic 
anaemia, 
pancytopenia, 
agranulocytosis, 
severe 
thrombocytopenia, 
granulocytopenia, 
anaemia  

Immune system 
disorders  

   Serum sickness, 
anaphylactoid 
reactions  

Psychiatric 
disorders  

   Hallucinations, 
confusion  

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Nervous system 
disorders  

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

 Taste disturbances  

Eye disorders   Eye bleeding 
(conjunctival, 
ocular, retinal)  

  

Ear and 
labyrinth 
disorders  

  Vertigo   

Vascular 
disorders  

Haematoma    Serious 
haemorrhage, 
haemorrhage of 
operative wound, 
vasculitis, 
hypotension  

Respiratory, 
thoracic and 
mediastinal 
disorders  

Epistaxis    Respiratory tract 
bleeding 
(haemoptysis, 
pulmonary 
haemorrhage), 
bronchospasm, 
interstitial 
pneumonitis  

Gastrointestinal 
disorders  

Gastrointestinal 
haemorrhage, 
diarrhoea, 
abdominal pain, 
dyspepsia  

Gastric ulcer and 
duodenal ulcer, 
gastritis, vomiting, 
nausea, constipation, 
flatulence  

Retroperitoneal 
haemorrhage  

Gastrointestinal and 
retroperitoneal 
haemorrhage with 
fatal outcome, 
pancreatitis, colitis 
(including ulcerative 
or lymphocytic 
colitis), stomatitis  

Hepato-biliary 
disorders  

   Acute liver failure, 
hepatitis, abnormal 
liver function test  

Skin and 
subcutaneous 
tissue disorders  

Bruising  Rash, pruritus, skin 
bleeding (purpura)  

 Bullous dermatitis 
(toxic epidermal 
necrolysis, Stevens 
Johnson Syndrome, 
erythema 
multiforme), 
angioedema, rash 
erythematous, 
urticaria, eczema, 
lichen planus  

Musculoskeletal
, connective 
tissue and bone 
disorders  

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

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Renal and 
urinary 
disorders  

 Haematuria   Glomerulonephritis, 
blood creatinine 
increased  

General 
disorders and 
administration 
site conditions  

Bleeding at 
puncture site  

  Fever  

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

  

 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin,  
ATC Code: B01AC-04.  
 
Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel 
must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet 
aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine 
diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the 
glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible 
binding, platelets exposed are affected for the remainder of their lifespan (approximately 7 - 10 days) 
and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet 
aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of 
platelet activation by released ADP. 
 
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or 
subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition. 
 
Repeated doses of 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.  
 
Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease 
 
The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent 
myocardial infarction (< 35 days), recent ischaemic stroke (between 7 days and 6 months) or 
established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or 
ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of 
the patients received ASA for the first few days following the acute myocardial infarction.  
 

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Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of 
myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention 
to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA 
(relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every 
1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from 
experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show 
any significant difference between clopidogrel (5.8%) and ASA (6.0%).  
 
In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the 
benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due 
to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 
36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 
18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial 
infarction, clopidogrel was numerically inferior, but not statistically different from ASA 
(RRR = -4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the 
benefit of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.  
 
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear 
whether the differences in relative risk reduction across qualifying conditions are real, or a result of 
chance. 
 
Paediatric population 
 
In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis 
(PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and 
infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition 
of 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking 
Plavix 75 mg/day. 
 
In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates 
and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial 
shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with 
concomitant background therapy up to the time of second stage surgery. The mean time between shunt 
palliation and first administration of study medicinal product was 20 days. Approximately 88% of 
patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference 
between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related 
intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] 
for the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the 
most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was 
no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this 
study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months 
of age. No new safety concerns were noted during this long-term follow-up. 
 
The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In 
a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent 
and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the 
authorised tablet. 
 
5.2 Pharmacokinetic properties 
 
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. 
 

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Distribution 
Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma 
proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration 
range. 
 
Metabolism 
Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised 
according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into 
its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple 
cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. 
Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the 
active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by 
CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated in 
vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.  
 
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 are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the 
majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other 
alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, 
*6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as 
defined above. Published frequencies for 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.  
 
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. 
 

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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. 
 
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. 
 
5.3 Preclinical safety data 
 
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. 

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There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to 
mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times 
the exposure seen in humans receiving the clinical dose of 75 mg/day). 
 
Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no 
genotoxic activity. 
 
Clopidogrel was found to have no effect on the fertility of male and female rats and was not 
teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in 
the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled 
clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. 
Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be 
excluded. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Macrogol 6000 
Cellulose, microcrystalline (E460) 
Crospovidone type A 
Castor oil, hydrogenated 
 
Film-coating: 
Macrogol 6000 
Ethylcellulose (E462) 
Titanium dioxide (E 171) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Store in the original blister in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Alu/Alu blisters containing 14, 28, 30, 50, 84, 90 and 100 film-coated tablets packed in cardboard 
cartons. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements 
 
 

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7. MARKETING AUTHORISATION HOLDER 
 
Acino Pharma GmbH 
Am Windfeld 35 
83714 Miesbach  
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/549/001-007 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
21.09.2009 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency: http://www.ema.europa.eu/ 

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ANNEX II 
 

A. MANUFACTURING AUTHORISATION HOLDER 
RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 

 

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A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH 

RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Acino AG 
Am Windfeld 35 
83714 Miesbach 
Germany 
 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 
 CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription. 
 
 CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
 OTHER CONDITIONS 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the 
Marketing Authorisation, is in place and functioning before and whilst the product is on the market. 
 
Risk Management Plan 
Not applicable. 
The application is based on a reference medicinal product for which no safety concerns requiring 
additional risk minimisation activities have been identified. 
 
PSURs 
The PSUR submission schedule should follow the PSUR schedule for the reference product. 
 
 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel Acino Pharma 75 mg film-coated tablets  
Clopidogrel 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 75 mg of clopidogrel (as besilate). 
 
3. LIST OF EXCIPIENTS 
 
It also contains hydrogenated castor oil. See leaflet for further information. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
84 film-coated tablets 
90 film-coated tablets 
100 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 REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children.  
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original blister in order to protect from moisture. 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

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19 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Acino Pharma GmbH 
Am Windfeld 35 
83714 Miesbach 
Germany 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/549/001 
EU/1/09/549/002 
EU/1/09/549/003 
EU/1/09/549/004 
EU/1/09/549/005 
EU/1/09/549/006 
EU/1/09/549/007 
 
 
13. BATCH NUMBER 
 
Batch 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
  
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Clopidogrel Acino Pharma 75 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Clopidogrel Acino Pharma 75 mg film-coated tablets 
 
Clopidogrel 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Acino Pharma GmbH 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Batch 
 
5. OTHER 
 

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B. PACKAGE LEAFLET 
 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 

 
Clopidogrel Acino Pharma 75 mg film-coated tablets 

Clopidogrel  
 
Read all of this leaflet carefully before you start taking this medicine. 
- 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. Do not pass it on to others. It may harm them, 

even if their symptoms are the same as yours. 
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist, 
 
In this leaflet:  
1. What Clopidogrel Acino Pharma is and what it is used for 
2. Before you take Clopidogrel Acino Pharma 
3. How to take Clopidogrel Acino Pharma 
4. Possible side effects 
5. How to store Clopidogrel Acino Pharma 
6. Further information 
 
 
1. WHAT CLOPIDOGREL ACINO PHARMA IS AND WHAT IT IS USED FOR 
 
Clopidogrel Acino Pharma contains the active ingredient Clopidogrel which belongs to a group of 
medicines called antiplatelet medicinal products. Platelets (so-called thrombocytes) are very small 
structures, which clump together during blood clotting. By preventing this clumping, antiplatelet 
medicinal products reduce the chances of blood clots forming (a process called thrombosis). 
  
Clopidogrel Acino Pharma is taken to prevent blood clots (thrombi) forming in hardened blood vessels 
(arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as 
stroke, heart attack, or death). 
 
You have been prescribed Clopidogrel Acino Pharma to help prevent blood clots and reduce the risk 
of these severe events because: 
- You have a condition of hardening of arteries (also known as atherosclerosis), and  
- You have previously experienced a heart attack, stroke or have a condition known as 

peripheral arterial disease (disturbed blood flow in arms or legs caused by vascular 
occlusions) 

 
 
2. BEFORE YOU TAKE CLOPIDOGREL ACINO PHARMA 
 
Do not take Clopidogrel Acino Pharma: 
 If you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of 

Clopidogrel Acino Pharma; 
 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 think any of these apply to you, or if you are in any doubt at all, consult your doctor before 
taking Clopidogrel Acino Pharma. 
 

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Take special care with Clopidogrel Acino Pharma: 
If any of the situations mentioned below apply to you, you should tell your doctor before taking 
Clopidogrel Acino Pharma: 
 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 within the 

last seven days 
 if you have kidney or liver disease 
 
While you are taking Clopidogrel Acino Pharma: 
 You should tell your doctor if a surgery (including dental) is planned. 
 You should also tell your doctor immediately if you develop a medical condition (also 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 ‘POSSIBLE SIDE 
EFFECTS’). 

 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 
Clopidogrel Acino Pharma is not intended for use in children or adolescents. 
 
Taking other medicines 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription.  
Some other medicines may influence the use of Clopidogrel Acino Pharma or vice versa.  
 
You should specifically tell your doctor if you take 
- oral anticoagulants, medicines used to reduce blood clotting, 
- a 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 
- omeprazole, esomeprazole or cimetidine, medicines to treat upset stomach 
- fluconazole, voriconazole, ciprofloxacin, or chloramphenicol, medicines to treat bacterial and 

fungal infections 
- fluoxetine, fluvoxamine, or moclobemide, medicines to treat depression 
- carbamazepine, or oxcarbazepine, medicines to treat some forms of epilepsy 
- ticlopidine, other antiplatelet agent. 
 
Acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever: An 
occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally 
not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. 
 
Taking Clopidogrel Acino Pharma with food and drink 
Clopidogrel Acino Pharma may be taken with or without food. 
 

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Pregnancy and breast-feeding 
It is preferable not to take this product during pregnancy. 
 
If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist 
before taking Clopidogrel Acino Pharma. If you become pregnant while taking Clopidogrel Acino 
Pharma, consult your doctor immediately as it is recommended not to take clopidogrel while you are 
pregnant. 
 
You should not breastfeed while taking this medicine. 
If you are breastfeeding or planning to breastfeed, talk to your doctor before taking this medicine. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Clopidogrel Acino Pharma is unlikely to affect your ability to drive or to use machines. 
 
Important information about some of the ingredients of Clopidogrel Acino Pharma: 
Clopidogrel Acino Pharma contains hydrogenated castor oil which  
may cause stomach upset or diarrhoea. 
 
 
3. HOW TO TAKE CLOPIDOGREL ACINO PHARMA 
 
Always take Clopidogrel Acino Pharma exactly as your doctor has told you. You should check with 
your doctor or pharmacist if you are not sure.  
  
The usual dose is one 75 mg tablet of Clopidogrel Acino Pharma per day to be taken orally with or 
without food, and at the same time each day. 
 
You should take Clopidogrel Acino Pharma for as long as your doctor continues to prescribe it. 
 
If you take more Clopidogrel Acino Pharma than you should 
Contact your doctor or the nearest hospital emergency department because of the increased risk of 
bleeding. 
 
If you forget to take Clopidogrel Acino Pharma 
If you forget to take a dose of Clopidogrel Acino Pharma, but remember within 12 hours of your usual 
time, take your tablet straight away 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 the forgotten individual doses.  
 
If you stop taking Clopidogrel Acino Pharma 
Do not stop the treatment unless your doctor tells you so.. Contact your doctor or pharmacist 
before stopping.  
 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Clopidogrel Acino Pharma can cause side effects, although not everybody gets 
them.  
 
The frequency of possible side effects listed below is defined using the following convention: 
 very common (affects more than 1 user  in 10) 
 common (affects 1 to 10 users in 100) 
 uncommon (affects 1 to 10 users in 1,000) 

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 rare (affects 1 to 10 users in 10,000) 
 very rare (affects less than 1 user in 10,000) 
 not known (frequency cannot be estimated from the available data) 
 
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 ‘Take special care with Clopidogrel Acino Pharma’).  

- 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 reported with clopidogrel 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, the lung or 
the joints has also been reported. 
 
If you experience prolonged bleeding when taking Clopidogrel Acino Pharma.  
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 2 ‘Take special care with 
Clopidogrel Acino Pharma’). 
 
Other side effects reported with Clopidogrel Acino Pharma are:  
-Common side effects:  
Diarrhoea, abdominal pain, indigestion or heartburn.  
 
-Uncommon side effects:  
Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, 
rashes, itching, dizziness, sensation of tingling and numbness. 
 
-Rare side effect:  
Vertigo.  
 
-Very rare side effects:  
Jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes 
associated with cough; generalised allergic reactions; swelling in the mouth; blisters of the skin; skin 
allergy; inflammation of the mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; 
joint pain; muscular pain; changes in the way things taste. 
 
In addition, your doctor may identify changes in your blood or urine test results. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist.  
 
 
5. HOW TO STORE CLOPIDOGREL ACINO PHARMA 
 
Store in the original blister in order to protect from moisture. 
 
Keep out of the reach and sight of children.  
 
Do not use Clopidogrel Acino Pharma 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. 
 

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26 

Do not use Clopidogrel Acino Pharma if you notice any visible sign of damage of blister or 
film-coated tablets. 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment.  
 
 
6. FURTHER INFORMATION 
 
What Clopidogrel Acino Pharma contains 
The active substance is clopidogrel. Each tablet contains 75 mg of clopidogrel (as besilate). 
 
The other ingredients are: 
 
Tablet core: 
Macrogol 6000 
Cellulose, microcrystalline (E460) 
Crospovidone type A 
Castor oil, hydrogenated 
 
Film-coating: 
Macrogol 6000 
Ethylcellulose (E462) 
Titanium dioxide (E 171) 
 
What Clopidogrel Acino Pharma looks like and contents of the pack  
 
Clopidogrel Acino Pharma 75 mg film-coated tablets are white to off-white, marbled, round and 
biconvex. They are supplied in cardboard cartons containing 14, 28, 30, 50, 84, 90 and 100 tablets in 
aluminium blisters. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
 
Acino Pharma GmbH 
Am Windfeld 35 
83714 Miesbach 
Germany 
 
Manufacturer 
 
Acino AG 
Am Windfeld 35 
83714 Miesbach 
Germany 
 
For any information about this medicine, please contact the Marketing Authorisation Holder. 
 
This leaflet was last approved in. 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/ 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET