ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Clopidogrel Qualimed 75 mg film-coated tablets
2.
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.
3.
Film-coated tablet.
Pink, round and slightly convex film-coated tablets.
4.
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in:
•
Patients suffering from myocardial infarction (from a few days until less than 35 days),
ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial
disease.
For further information please refer to section 5.1.
•
Adults and elderly
Clopidogrel should be given as a single daily dose of 75 mg with or without food.
•
Pharmacogenetics
CYP2C19 poor metaboliser status is associated with diminished response to clopidogrel. The
optimal dose regimen for poor metabolisers has yet to be determined (see section 5.2).
•
Paediatric patients
The safety and efficacy of clopidogrel in children and adolescents have not yet been established.
•
Renal impairment
Therapeutic experience is limited in patients with renal impairment (see section 4.4).
•
Hepatic impairment
Therapeutic experience is limited in patients with moderate hepatic disease who may have
bleeding diatheses (see section 4.4).
•
Hypersensitivity to the active substance or to any of the excipients.
•
Severe liver impairment.
•
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
2
Bleeding and haematological disorders
Due to the risk of bleeding and haematological adverse reactions, blood cell count determination
and/or other appropriate testing should be promptly considered whenever clinical symptoms
suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet
agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding
from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA,
heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including
Cox-2 inhibitors. Patients should be followed carefully for any signs of bleeding including occult
bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or
surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended
since it may increase the intensity of bleedings (see section 4.5).
If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable,
clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and
dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal
product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who
have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).
Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel
(alone or in combination with ASA), and that they should report any unusual bleeding (site or
duration) to their physician.
Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of
clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and
microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction
or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.
Recent ischaemic stroke
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute
ischaemic stroke.
Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19 function have
lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses,
and generally exhibit higher cardiovascular event rates following myocardial infarction than do
patients with normal CYP2C19 function (see section 5.2).
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products
that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active
metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution
concomitant use of medicinal products that inhibit CYP2C19 should be discouraged (see section 4.5
for a list of CYP2C19 inhibitors, see also section 5.2).
Renal impairment
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore
clopidogrel should be used with caution in these patients (see section 4.2).
Hepatic impairment
Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.
Clopidogrel should therefore be used with caution in this population (see section 4.2).
Excipients
3
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).
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). 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 precaution concomitant use of medicinal products that inhibit CYP2C19
should be discouraged (see sections 4.4 and 5.2).
Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine,
fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine,
carbamazepine, oxcarbazepine and chloramphenicol.
Proton Pump Inhibitors (PPI):
In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with
omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the
active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when clopidogrel
and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with
5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole
were administered together. In another study it was shown that administering clopidogrel and
omeprazole 12 hours apart did not prevent their interaction that is likely to be driven by the inhibitory
4
effect of omeprazole on CYP2C19. Esomeprazole is expected to give a similar interaction with
clopidogrel.
Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD)
interaction in terms of major cardiovascular events have been reported from both observational and
clinical studies. As a precaution, concomitant use of omeprazole or esomeprozole should be
discouraged (see section 4.4). No conclusive data on the pharmacodynamic interaction of clopidogrel
and other PPIs are available.
There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers
(except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of
clopidogrel.
Other medicinal products: A number of other clinical studies have been conducted with clopidogrel
and other concomitant medicinal products to investigate the potential for pharmacodynamic and
pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed
when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine.
Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the
coadministration of phenobarbital, or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of
clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of
clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to
increased plasma levels of medicinal products such as phenytoin and tolbutamide and the NSAIDs,
which are metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that
phenytoin and tolbutamide can be safely co-administered with clopidogrel.
Apart from the specific medicinal product interaction information described above, interaction studies
with clopidogrel and some medicinal products commonly administered in patients with
atherothrombotic disease have not been performed. However, patients entered into clinical trials with
clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers,
ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents
(including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically
significant adverse interactions.
As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to
use clopidogrel during pregnancy as a precautionary measure. Animal studies do not indicate direct or
indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or
postnatal development (see section 5.3).
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown
excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be
continued during treatment with Clopidogrel Qualimed.
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
5
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 1.4% for clopidogrel and 1.6% for ASA.
In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA (<100 mg:
2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo+ASA
(<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%). The risk of bleeding (life-threatening, major,
minor, other) decreased during the course of the trial: 0-1 months (clopidogrel: 9.6%; placebo: 6.6%),
1-3 months (clopidogrel: 4.5%; placebo: 2.3%), 3-6 months (clopidogrel: 3.8%; placebo: 1.6%),
6-9 months (clopidogrel: 3.2%; placebo: 1.5%), 9-12 months (clopidogrel: 1.9%; placebo: 1.0%).
There was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft
surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel+ASA
vs. 5.3% placebo+ASA). In patients who remained on therapy within five days of bypass graft
surgery, the event rate was 9.6% for clopidogrel+ASA, and 6.3% for placebo+ASA.
In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs.
the placebo + ASA group (12.9%). The incidence of major bleeding was similar between groups
(1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). This was
consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or
heparin therapy.
In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar
in both groups (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups,
respectively).
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are
presented in the table below. Their frequency is defined using the following conventions: common
(≥1/100 to <1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000 to <1/1,000); very rare
(<1/10,000).
Within each system organ class, adverse drug reactions are presented in order of decreasing
seriousness.
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
6
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
Renal and urinary
disorders
Haematuria
Glomerulonephritis,
blood creatinine
increased
7
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.
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 other drugs, not all patients will have adequate platelet inhibition.
Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation
from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At
steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and
60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within
5 days after treatment was discontinued.
The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving over
80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY
and COMMIT studies comparing clopidogrel to placebo, both medicinal products given in
combination with ASA and other standard therapy.
Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease
The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent
myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or
established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or
ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of
the patients received ASA for the first few days following the acute myocardial infarction.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of
myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention
8
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.
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
its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple
cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite.
Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the
active metabolite, a thiol derivative of clopidogrel.
In vitro
, this metabolic pathway is mediated by
CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated
in vitro
, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
Elimination
Following an oral dose of 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
Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of
both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active
metabolite pharmacokinetics and antiplatelet effects, as measured by
ex vivo
platelet aggregation
assays, differ according to CYP2C19 genotype. The CYP2C19*1 allele corresponds to fully functional
metabolism while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The
CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced function alleles in whites and 99%
in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8,
but these are less frequent in the general population. Published frequencies for the common CYP2C19
phenotypes and genotypes are listed in the table below.
9
CYP2C19 Phenotype and Genotype Frequency
Frequency (%)
White (n=1356) Black (n=966) Chinese (n=573)
Extensive metabolism: CYP2C19*1/*1
74
66
38
Intermediate metabolism: CYP2C19*1/*2 or *1/*3
26
29
50
Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3
2
4
14
To date, the impact of CYP2C19 genotype on the pharmacokinetics of the active metabolite of
clopidogrel has been evaluated in 227 subjects from 7 reported studies. Reduced CYP2C19
metabolism in intermediate and poor metabolisers decreased the C
max
and AUC of the active
metabolite by 30-50% following 300- or 600-mg loading doses and 75-mg maintenance doses. Lower
active metabolite exposure results in less platelet inhibition or higher residual platelet reactivity. To
date, diminished antiplatelet responses to clopidogrel have been described for intermediate and poor
metabolisers in 21 reported studies involving 4,520 subjects. The relative difference in antiplatelet
response between genotype groups varies across studies depending on the method used to evaluate
response, but is typically greater than 30%.
The association between CYP2C19 genotype and clopidogrel treatment outcome was evaluated in 2
post hoc clinical trial analyses (substudies of CLARITY [n=465] and TRITON-TIMI 38 [n=1,477])
and 5 cohort studies (total n=6,489). In CLARITY and one of the cohort studies (n=765; Trenk),
cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and 3 of the
cohort studies (n= 3,516; Collet, Sibbing, Giusti), patients with an impaired metaboliser status
(intermediate and poor combined) had a higher rate of cardiovascular events (death, myocardial
infarction, and stroke) or stent thrombosis compared to extensive metabolisers. In the fifth cohort study
(n=2,208; Simon), the increased event rate was observed only in poor metabolisers.
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form the active
metabolite of clopidogrel.
Special populations
The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.
Renal impairment
After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine
clearance from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation was lower (25%) than
that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen
in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in
all patients.
Hepatic impairment
After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic
impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy
subjects. The mean bleeding time prolongation was also similar in the two groups. The
pharmacokinetics and pharmacodynamics of clopidogrel were assessed in a single and multiple dose
study in both healthy subjects and those with cirrhosis (Child-Pugh class A or B). Daily dosing for
10 days with clopidogrel 75 mg/day was safe and well tolerated. Clopidogrel C
max
for both single dose
and steady state for cirrhotics was many fold higher than in normal subjects. However, plasma levels
10
of the main circulating metabolite together with the effect of clopidogrel on ADP-induced platelet
aggregation and bleeding time were comparable between these 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. 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.
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
11
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.
Perforated unit dose blister of OPA/Al/PVC-Al containing 30x1 film-coated tablets in the box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Qualimed, 117 allée des Parcs, 69 800 Saint Priest, France
8.
EU/1/09/557/001-010
9.
Date of first authorisation: 23 September 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
12
ANNEX II
A. THE MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
13
A. THE MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer 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, as described in version 1.3 ( 21 April
2008) presented in Module 1.8.1. of the Marketing Authorisation Application, 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 Qualimed film coated tablets should follow PSURs
submission schedule for the reference medicinal product.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Clopidogrel Qualimed 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.
4.
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
30x 1 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
17
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
11.
Qualimed, 117 allée des Parcs, 69 800 Saint Priest, France
12.
7 film-coated tablets: EU/1/09/557/001
14 film-coated tablets: EU/1/09/557/002
28 film-coated tablets: EU/1/09/557/003
30 film-coated tablets: EU/1/09/557/004
50 film-coated tablets: EU/1/09/557/005
56 film-coated tablets: EU/1/09/557/006
84 film-coated tablets: EU/1/09/557/007
90 film-coated tablets: EU/1/09/557/008
100 film-coated tablets: EU/1/09/557/009
30x1 film-coated tablets EU/1/09/557/010
13.
BATCH NUMBER
Batch:
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Clopidogrel Qualimed 75 mg
18
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Clopidogrel Qualimed 75 mg film-coated tablets
Clopidogrel
2.
Qualimed
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
Batch:
5.
OTHER
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
Clopidogrel Qualimed 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 Qualimed is and what it is used for
2. Before you take Clopidogrel Qualimed
3. How to take Clopidogrel Qualimed
4. Possible side effects
5.
How to store Clopidogrel Qualimed
6. Further information
1.
WHAT CLOPIDOGREL QUALIMED IS AND WHAT IT IS USED FOR
Clopidogrel Qualimed belongs to a group of medicines called antiplatelet medicinal products. Platelets
are very small structures in the blood, smaller than red or white blood cells, 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 Qualimed 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 Qualimed 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 QUALIMED
Do not take Clopidogrel Qualimed
•
if you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel
Qualimed;
•
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 Qualimed.
Take special care with Clopidogrel Qualimed
If any of the situations mentioned below apply to you, you should tell your doctor before taking
Clopidogrel Qualimed:
21
•
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 Qualimed:
•
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 Qualimed 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 Qualimed 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 medicine used to reduce blood clotting,
•
or if you take a proton pump inhibitor (e.g, omeprazole) for upset stomach,
•
fluconazole, voriconazole, ciprofloxacin, or chloramphenicol, medicines to treat bacterial and
fungal infections,
•
cimetidine, medicine to treat upset stomach,
•
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 Qualimed with food and drink
Clopidogrel Qualimed may be taken with or without food.
Pregnancy and breast-feeding
It is preferable not to use this product during pregnancy and breast-feeding.
22
If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist
before taking Clopidogrel Qualimed. If you become pregnant while taking Clopidogrel Qualimed,
consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant.
While taking Clopidogrel Qualimed, consult your doctor about the breast-feeding of a baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Clopidogrel Qualimed is unlikely to affect your ability to drive or to use machines.
Important information about some of the ingredients of Clopidogrel Qualimed
Clopidogrel Qualimed contains hydrogenated castor oil which may cause stomach upset and diarrhoea.
3.
HOW TO TAKE CLOPIDOGREL QUALIMED
Always take Clopidogrel Qualimed 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 Qualimed per day to be taken orally with or without
food, and at the same time each day.
You should take Clopidogrel Qualimed for as long as your doctor continues to prescribe it.
If you take more Clopidogrel Qualimed 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 Qualimed:
If you forget to take a dose of Clopidogrel Qualimed, 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 Qualimed:
Do not stop the treatment. 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 Qualimed can cause side effects, although not everybody gets them.
Contact your doctor immediately if you experience
:
-
fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood
cells.
-
signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not
associated with bleeding which appears under the skin as red pinpoint dots and/or confusion
(see section 2 ‘Take special care with Clopidogrel Qualimed’).
-
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
(affects 1 to 10 patients in 100) reported
is bleeding
.
23
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 Qualimed
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
Qualimed’).
Other side effects reported are
Common side effects (affects 1 to 10 patients in 100): Diarrhoea, abdominal pain, indigestion or
heartburn.
Uncommon side effects (affects 1 to 10 patients in 1,000): Headache, stomach ulcer, vomiting,
nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of
tingling and numbness.
Rare side effect (affects 1 to 10 patients in 10,000): Vertigo.
Very rare side effects (affects less than 1 patient in 10,000): 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 QUALIMED
Keep out of the reach and sight of children.
Do not use Clopidogrel Qualimed 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 Qualimed contains
-
The active substance is clopidogrel. Each film-coated tablet
contains 75 mg of clopidogrel (as
hydrochloride).
-
The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone
(type A), macrogol 6000, hydrogenated castor oil in the tablet core and hydroxypropylcellulose
(E463), titanium dioxide (E171), red iron oxide (E172), talc and propylene glycol in the film-
coating.
24
What Clopidogrel Qualimed 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.
Boxes of 30x1 film-coated tablets in perforated unit dose blisters are available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Qualimed, 117 allée des Parcs, 69 800 Saint Priest, France
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
Qualimed
Tel: +33 4 37 25 75 00
România
Mylan SAS
Tel: +33 4 37 25 75 00 (France)
Ireland
Mc Dermott Laboratories Ltd
Slovenija
Mylan SAS
25
Tel: + 1800 272 272
Allphar +353 1 4041600
Tel: +33 4 37 25 75 00 (France)
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/
26
Source: European Medicines Agency
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