ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Clopidogrel dura 75 mg film-coated tablets
Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride).
Excipient:
Each film-coated tablet contains 13 mg hydrogenated castor oil.
For a full list of excipients, see section 6.1.
Film-coated tablet.
Pink, round and slightly convex film-coated tablets.
Prevention of atherothrombotic events
Clopidogrel is indicated in:
·
Adults 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.
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
The safety and efficacy of clopidogrel in children and adolescents have not yet been established.
·
Renal impairment
Therapeutic experience is limited in patients with renal impairment (see section 4.4).
·
Hepatic impairment
2
Therapeutic experience is limited in patients with moderate hepatic disease who may have
bleeding diatheses (see section 4.4).
Method of administration
For oral use
It may be given with or without food.
·
Hypersensitivity to the active substance or to any of the excipients.
·
Severe hepatic impairment.
·
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
Bleeding and haematological disorders
Due to the risk of bleeding and haematologicaladverse reactions, blood cell count determination and/or
other appropriate testing should be promptly considered whenever clinical symptoms suggestive of
bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents,
clopidogrel should be used with caution in patients who may be at risk of increased bleeding from
trauma, surgery or other pathological conditions and in patients receiving treatment with ASA,
heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including
Cox-2 inhibitors. Patients should be followed carefully for any signs of bleeding including occult
bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or
surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended
since it may increase the intensity of bleedings (see section 4.5).
If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable,
clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and
dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal
product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who
have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).
Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel
(alone or in combination with ASA), and that they should report any unusual bleeding (site or
duration) to their physician.
Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of
clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and
microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction
or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.
Recent ischaemic stroke
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute
ischaemic stroke.
Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: 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
3
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).
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
This medicinal product contains hydrogenated castor oil which may cause stomach upset and
diarrhoea.
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 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). However, clopidogrel and ASA have been administered together for up to one year (see
section 5.1).
Heparin
: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification
of the heparin dose or alter the effect of heparin on coagulation. 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
4
precaution concomitant use of strong or moderateCYP2C19 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.
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 esomeprozole 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 product interaction information described above, interaction studies
with clopidogrel and some medicinal products commonly administered in patients with
atherothrombotic disease have not been performed. However, patients entered into clinical trials with
clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers,
ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents
(including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically
significant adverse interactions.
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.
5
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).
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 dura.
Fertility
Clopidogrel was not shown to alter fertility in animal studies.
Clopidogrel has no or negligible influence on the ability to drive and use machines.
Clopidogrel has been evaluated for safety in more than 42,000 patients, who have participated in
clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant
adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed
below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of
age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE,
CLARITY, COMMIT studies are discussed below. 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 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
placebo plus ASA group. The incidence of major bleeding was similar between groups. This was
consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or
heparin therapy.
In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar
in both groups
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are
presented in the table below. Their frequency is defined using the following conventions: common
(³1/100 to <1/10); uncommon (³1/1,000 to < 1/100); rare (³1/10,000 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
6
System Organ
Class
Common
Uncommon
Rare
Very rare
section 4.4),
aplastic anaemia,
pancytopenia,
agranulocytosis,
severe
thrombocytopenia,
granulocytopenia,
anaemia
Immune system
disorders
Serum sickness,
anaphylactoid
reactions
Psychiatric
disorders
Hallucinations,
confusion
Nervous system
disorders
Intracranial
bleeding (some
cases were
reported with fatal
outcome),
headache,
paraesthesia,
dizziness
Taste disturbances
Eye disorders
Eye bleeding
(conjunctival,
ocular, retinal)
Ear and labyrinth
disorders
Vertigo
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
7
System Organ
Class
Common
Uncommon
Rare
Very rare
Johnson Syndrome,
erythema
multiforme),
angioedema, rash
erythematous,
urticaria, eczema,
lichen planus
Musculoskeletal,
connective tissue
and bone
disorders
Musculo-skeletal
bleeding
(haemarthrosis),
arthritis, arthralgia,
myalgia
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
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.
5.1 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 P2Y
12
receptor and the subsequent ADP-mediated activation of the
glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible
binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days)
and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet
aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of
platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or
subject to inhibition by 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
8
steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and
60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within
5 days after treatment was discontinued.
The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving over
80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY
and COMMIT studies comparing clopidogrel to placebo, both medicinal products given in
combination with ASA and other standard therapy.
Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease
The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent
myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or
established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or
ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of
the patients received ASA for the first few days following the acute myocardial infarction.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of
myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention
to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA
(relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p = 0.045), which corresponds, for every
1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from
experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show
any significant difference between clopidogrel (5.8%) and ASA (6.0%).
In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the
benefit appeared to be strongest (achieving statistical significance at p = 0.003) in patients enrolled
due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9
to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to
18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial
infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR =
-4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit
of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear
whether the differences in relative risk reduction across qualifying conditions are real, or a result of
chance.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Clopidogrel Dura in one or more subsets of the paediatric population for the prevention of
thromboembolic events (see section 4.2 for information on paediatric use).
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.
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
9
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 C
max
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. C
max
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 halflife 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.
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
10
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 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.
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.
11
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.
6.1 List of excipients
Tablet core:
Cellulose, microcrystalline
Colloidal anhydrous silica
Crospovidone (type A)
Macrogol 6000
Hydrogenated castor oil
Film coating:
Hydroxypropylcellulose (E463)
Titanium dioxide (E171)
Red iron oxide (E172)
Talc
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture and light.
6.5 Nature and contents of container
Blister of OPA/Al/PVC-Al containing 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in the
box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Mylan dura GmbH, Wittichstraße 6, D-64295 Darmstadt, Germany
12
EU/1/09/560/001-009
Date of first authorisation: 21 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
/.
13
ANNEX II
A. THE MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
14
A. THE MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer(s) responsible for batch release
KRKA, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia
TAD Pharma GmbH
Heinz-Lohmann-Straße 5
27472 Cuxhaven
Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
·
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
Risk Management Plan was not submitted. The application is based on a reference medicinal product
for which no safety concerns requiring additional risk minimization activities have been identified.
PSURs
The PSUR submission schedule for Clopidogrel dura film coated tablets should follow PSURs
submission schedule for the reference medicinal product.
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
Clopidogrel dura 75 mg film-coated tablets
Clopidogrel
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet
contains 75 mg of clopidogrel (as hydrochloride).
3. LIST OF EXCIPIENTS
It also contains hydrogenated castor oil.
See leaflet for further information.
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
50 film-coated tablets
56 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
18
EXP:
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture and light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Mylan dura GmbH, Wittichstraße 6, D-64295 Darmstadt, Germany
EU/1/09/560/001-009
13. BATCH NUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Clopidogrel dura 75 mg
19
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
Clopidogrel dura 75 mg film-coated tablets
Clopidogrel
Mylan dura GmbH
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
Batch:
5. OTHER
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
Clopidogrel dura 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 dura is and what it is used for
2. Before you take Clopidogrel dura
3. How to take Clopidogrel dura
4. Possible side effects
5. How to store Clopidogrel dura
6. Further information
1.
WHAT CLOPIDOGREL DURA IS AND WHAT IT IS USED FOR
Clopidogrel dura 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, antiplatelet medicinal products reduce the chances of blood clots forming (a process called
thrombosis).
Clopidogrel dura 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 dura 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.
2.
BEFORE YOU TAKE CLOPIDOGREL DURA
Do not take Clopidogrel dura
·
if you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel
dura;
·
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 dura.
Take special care with Clopidogrel dura
If any of the situations mentioned below apply to you, you should tell your doctor before taking
Clopidogrel dura:
·
if you have a risk of bleeding such as
22
-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 dura:
·
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.
Clopidogrel dura 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 dura 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 for 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.
An occasional use of acetylsalicylic acid (no more than 1000 mg in any 24 hour period), a substance
present in many medicines used to relieve pain and lower fever, should generally not cause a problem,
but prolonged use in other circumstances should be discussed with your doctor.
Taking Clopidogrel dura with food and drink
Clopidogrel dura may be taken with or without food.
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 dura. If you become pregnant while taking Clopidogrel dura, consult your
doctor immediately as it is recommended not to take clopidogrel while you are pregnant.
23
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 dura is unlikely to affect your ability to drive or to use machines.
Important information about some of the ingredients of Clopidogrel dura
Clopidogrel dura contains hydrogenated castor oil which may cause stomach upset and diarrhoea.
3.
HOW TO TAKE CLOPIDOGREL DURA
Always take Clopidogrel dura 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 dura per day to be taken orally with or without food,
and at the same time each day.
You should take Clopidogrel dura for as long as your doctor continues to prescribe it.
If you take more Clopidogrel dura 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 dura:
If you forget to take a dose of Clopidogrel dura, 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 dose.
If you stop taking Clopidogrel dura:
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 dura 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)
·
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 dura’).
24
-
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
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 dura
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 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 dura’).
Other side effects reported 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 DURA
Keep out of the reach and sight of children.
Do not use Clopidogrel dura after the expiry date which is stated on the carton and blister after EXP.
The expiry date refers to the last day of that month.
Store in the original package in order to protect from moisture and light.
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 dura contains
The active substance is clopidogrel. Each film-coated tablet
contains 75 mg of clopidogrel (as
hydrochloride).
The other ingredients are:
-
Tablet core: microcrystalline cellulose, colloidal anhydrous silica, crospovidone (type A),
macrogol 6000, hydrogenated castor oil
-
-Tablet coating: hydroxypropylcellulose (E463), titanium dioxide (E171), red iron oxide (E172),
talc and propylene glycol.
25
What Clopidogrel dura looks like and contents of the pack
The film-coated tablets are pink, round and slightly convex.
Boxes of 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in blisters are available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Mylan dura GmbH, Wittichstraße 6, D-64295 Darmstadt, Germany
Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Mylan bvba/sprl
Tél/Tel: + 0032 2 658 61 00
Luxembourg/Luxemburg
Mylan bvba/sprl
Tél/Tel: + 0032 2 658 61 00 (Belgium)
Bulgaria
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
Hungary
Mylan Kft
Tel: 36 1 8026993
Ceská republika
MylanPharmaceuticals s.r.o.
Tel: +420 274 770 201
Malta
George Borg Barthet Ltd
Tel: +356 21244205
Danmark
Mylan ApS
Tlf: + 45 3694 4568
Nederland
Mylan B.V
Tel: + 31 (0)33 2997080
Deutschland
Mylan dura GmbH
Tel: + 49-(0) 6151 9512 0
Norge
Mylan AB
Tlf: + 46 8-555 227 50 (Sverige)
Eesti
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
Österreich
Arcana Arzneimittel GmbH
Tel: +43 1 416 24 18
Greece
Generics Pharma Hellas ΕΠΕ
Τηλ: +30 210 9936410
Polska
Mylan Sp.z.o.o
Tel: +48 22 5466400
España
Mylan Pharmaceuticals, S.L
tel: + 34 93 3786400
Portugal
Mylan, Lda.
Phone: + 00351 21 412 7200
France
Mylan SAS
Tel: +33 4 37 25 75 00
România
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
Ireland
Mc Dermott Laboratories Ltd
Tel: + 1800 272 272
Allphar +353 1 4041600
Slovenija
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
26
Ísland
Actavis Group PTC ehf
Sími: + 354 5503300
Slovenská republika
Mylan sr.o
Tel:
+421 2 32 604 901
Italia
Mylan S.p.A
Tel: + +39/02-61246921
Suomi/Finland
Mylan OY
Puh/Tel: + 358 9-46 60 03
Cyprus
Pharmaceutical Trading Co Ltd
Τηλ: +35 7 24656165
Sverige
Mylan AB
Tel: + 46 8-555 227 50
Latvija
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
United Kingdom
Generics [UK] Ltd
Tel: +44 1707 853000
Lietuva
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
This leaflet was last approved in
MM/YYYY.
Detailed information is available on the European Medicines Agency website:
http://www.ema.europa.eu.
27
Source: European Medicines Agency
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