ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Clopidogrel Apotex 75 mg film-coated tablets
Each film-coated tablet contains 75 mg of clopidogrel (as besilate).
Excipients: Each film-coated tablet contains 2.6 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
Film-coated tablet.
Pink, round, biconvex, film-coated tablets.
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
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
Clopidogrel Apotex contains lactose. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicinal product
(see section 4.2).
3
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 effect of omeprazole on CYP2C19. Esomeprazole is expected to
give a similar interaction with clopidogrel.
4
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 Apotex.
4.7
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
5
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 (<100mg:
2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo+ASA
(<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 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
Nervous system
disorders
Intracranial
bleeding (some
cases were
reported with fatal
outcome),
Taste disturbances
6
System Organ
Class
Common
Uncommon
Rare
Very rare
headache,
paraesthesia,
dizziness
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
7
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: B01AC04.
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.
8
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.
5.2 Pharmacokinetic properties
Absorption
After repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels
of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) occurred
approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of
clopidogrel metabolites.
Distribution
Clopidogrel and the main circulating (inactive) metabolite bind reversibly
in
vitro
to human plasma
proteins (98% and 94% respectively). The binding is non-saturable
in vitro
over a wide concentration
range.
Metabolism
Clopidogrel is extensively metabolised by the liver.
In vitro
and
in vivo
, clopidogrel is metabolised
according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into
its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple
cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite.
Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the
active metabolite, a thiol derivative of clopidogrel.
In vitro
, this metabolic pathway is mediated by
CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated
in vitro
, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
Elimination
Following an oral dose of
14
C-labelled clopidogrel in man, approximately 50% was excreted in
theurine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral
dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the
main circulating (inactive) metabolite was 8 hours after single and repeated administration.
Pharmacogenetics
Several polymorphic CYP450 enzymes activate clopidogrel. CYP2C19 is involved in the formation of
both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active
metabolite pharmacokinetics and antiplatelet effects, as measured by
ex vivo
platelet aggregation
9
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.
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) compared 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
10
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.
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
Hydroxypropylcellulose (E463)
Mannitol (E421)
Crospovidone (type A)
Citric acid, monohydrate
Macrogol 6000
Stearic acid
Talc
Film-coating:
Hypromellose (E464)
Iron oxide red (E172)
Lactose monohydrate
Triacetin (E1518)
Titanium dioxide (E171)
6.2 Incompatibilities
11
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blisters of white PVC/PE/PVDC-aluminium foil or PA/ALL/PVC-aluminium foil.
Packs of 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Apotex Europe BV
Darwinweg 20
2333 CR, Leiden
The Netherlands
8. MARKETING AUTHORISATION NUMBERS
EU/1/09/568/001-018
16.10.2009
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.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Pharmathen S.A.
6, Dervenakion
15351 Pallini Attiki
Greece
Pharmathen International S.A
Industrial Park Sapes
Rodopi Prefecture, Block No 5
Rodopi 69300
Greece
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 1.5 dated
8 May 2009 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
Not applicable
The application is based on a reference medicinal product for which no safety concerns requiring
specific risk minimization activities have been identified.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON for blisters of 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets
Clopidogrel Apotex 75 mg film-coated tablets
clopidogrel
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 75 mg of clopidogrel (as besilate).
3. LIST OF EXCIPIENTS
It also contains lactose. 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
Oral use.Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
17
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Apotex Europe BV
Darwinweg 20
2333 CR, Leiden
The Netherlands
EU/1/09/568/001-018
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Clopidogrel Apotex 75 mg
18
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS containing 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets
1.
Clopidogrel Apotex 75 mg film-coated tablets
clopidogrel
2.
Apotex Europe BV
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
Clopidogrel Apotex 75 mg film-coated tablets
clopidogrel
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or your 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 Apotex is and what it is used for
2. Before you use Clopidogrel Apotex
3. How to use Clopidogrel Apotex
4. Possible side effects
5. How to store Clopidogrel Apotex
6. Further information
1. WHAT CLOPIDOGREL APOTEX IS AND WHAT IT IS USED FOR
Clopidogrel Apotex contains the active substance clopidogrel, a platelet aggregation blocker. Platelets
are very small structures which clump together (aggregate) during blood clotting. By preventing
formation of blood clots (thrombi) in hardened blood vessels, clopidogrel reduces the risk of stroke or
heart attack.
Clopidogrel Apotex is used if you have hardening of the arteries (atherosclerosis), and you have either:
-
you have a condition which causes disturbed blood flow in arms or legs due to blockade of the
blood vessels (peripheral arterial disease)
2. BEFORE YOU TAKE CLOPIDOGREL APOTEX
Do not take Clopidogrel Apotex
-
if you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel
Apotex (listed in section 6 ‘What Clopidogrel Apotex contains’)
-
if you have a medical condition that is currently causing bleeding such as a stomach ulcer or
bleeding within the brain
-
if you have severe liver disease
Take special care with Clopidogrel Apotex
Tell your doctor before you start taking this medicine:
•
if you are at increased risk of bleeding (haemorrhage), such as:
- any condition (e.g. stomach ulcer) or blood disorder that makes you prone to internal
bleeding (inside tissues, organs or joints of your body)
- recent serious injury
- surgery (including dental), recent or due in the next 7 days
•
if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the
last seven days
21
-
Keep this leaflet. You may need to read it again.
-
had a recent heart attack (myocardial infarction) or previous stroke, or
•
if you have kidney or liver disease
While you are taking Clopidogrel Apotex:
•
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 is not intended for use in children or adolescents.
Using other medicines
Tell your doctor or pharmacist if you are using or have recently used any other medicines, including
medicines obtained without a prescription.
Some other medicines may influence the use of Clopidogrel Apotex or vice versa.
This applies specially to medicines containing any of the following active substances:
-
oral anticoagulants, medicines used to reduce blood clotting
-
non-steroidal anti-inflammatory medicines, used to treat fever, pain and inflammation of
muscles or joints
-
heparin or any other medicine used to reduce blood clotting
-
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
-
carbamazepine, or oxcarbazepine, medicines to treat some forms of epilepsy
-
ticlopidine, other antiplatelet agent.
Acetylsalicylic acid (an NSAID) may be used if prescribed, or occasionally up to 1000 mg in 24 h.
However, discuss with your doctor its prolonged use in other circumstances.
Taking Clopidogr
el
Apotex with food and drink
You can take Clopidogrel Apotex with food or without food.
Pregnancy and breast-feeding
It is not recommended to use this medicine during pregnancy.
If you are pregnant or think you might be pregnant, tell your doctor before treatment start. If you
become pregnant while taking Clopidogrel Apotex, tell your doctor immediately.
You should stop breast-feeding while taking Clopidogrel Apotex, as it is not known if clopidogrel
passes into breast milk.
Driving and using machines
Clopidogrel Apotex is unlikely to affect your ability to drive or use machines.
Important information about some of the ingredients of Clopidogrel Apotex
Clopidogrel Apotex contains lactose. If you have been told by your doctor that you have an
intolerance to some sugars, contact you doctor before taking this medicine.
22
-
fluoxetine, fluvoxamine, or moclobemide, medicines to treat depression
3. HOW TO TAKE CLOPIDOGREL APOTEX
Always take Clopidogrel Apotex 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 daily, every day at the same time.
Take the tablet(s) with some liquid, with or without food.
If you take more Clopidogrel Apotex than you should
Contact your doctor or the nearest hospital emergency department immediately because of the
increased risk of bleeding.
If you forget to take Clopidogrel Apotex
If you forget to take Clopidogrel Apotex, but remember within 12 hours of your usual time, take your
tablet straightaway. Then take your next tablet at the usual time.
If you forget for more than 12 hours, skip the missed dose. Then take the next tablet at the usual time.
Do not take a double dose to make up for a forgotten tablet.
If you stop taking Clopidogrel Apotex
You should take Clopidogrel Apotex as long as your doctor prescribes it.
Do not stop the treatment without discussing it with your doctor first.
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 Apotex can cause side effects, although not everybody gets them.
Side effects may occur with certain frequencies, which are defined as follows:
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 date
Contact your doctor immediately if you experience
:
-
liver problems: 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 Apotex’).
-
allergic reactions: swelling in the mouth, skin rash, itching and blistering.
The most common side effect is bleeding
, which may appear as:
-
bruising and haematoma
-
bleeding in the stomach or bowels or less frequently in the eye, head, lung or joints
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 ‘Take special care with Clopidogrel
Apotex’).
Other side effects:
23
-
decrease of some blood cells: fever, signs of infection or extreme tiredness.
-
nose bleed, blood in the urine
Common side effects
-
abdominal pain, indigestion or heartburn
-
diarrhoea
Uncommon side effects
-
headache, dizziness
-
vomiting, nausea
-
constipation, excessive gas in stomach or intestines
-
rashes, itching
-
sensation of tingling and numbness
Rare side effects
-
vertigo
Very rare side effects
-
fever
-
severe abdominal pain with or without back pain, pain in joints or muscles
-
generalised allergic reactions
-
blisters of the skin and skin allergy
-
swelling in the mouth
-
inflammation of the mouth (stomatitis)
-
breathing difficulties, sometimes with cough
-
decrease in blood pressure
-
confusion, hallucinations
-
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 APOTEX
Keep out of the reach and sight of children.
Do not use Clopidogrel Apotex after the expiry date which is stated on the carton and on the blister
after EXP.
This medicinal product does not require any special storage conditions.
Do not use Clopidogrel Apotex if you notice any visible sign of deterioration.
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 Apotex contains
-
The active substance is clopidogrel. Each film-coated tablet contains 75 mg of clopidogrel (as
besilate).
-
The other ingredients are:
24
-
stomach ulcer
-
jaundice
Core:
Microcrystalline cellulose,
hydroxypropylcellulose (E463)
,
mannitol (E421)
,
crospovidone (type A)
,
citric acid monohydrate
,
macrogol 6000
,
stearic acid
,
talc
Coating:
Hypromellose (E464)
,
iron oxide red (E172)
,
lactose monohydrate
,
triacetin (E1518)
,
titanium dioxide (E171)
What Clopidogrel Apotex looks like and contents of the pack
Clopidogrel Apotex film-coated tablets are pink, round and biconvex.
They are supplied in PVC/PE/PVDC/Alu blisters or in PA/ALL/PVC-Alu blisters packed in cartons
containing 7, 14, 28, 30, 50, 56, 84, 90 or 100 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Apotex Europe BV
Darwinweg 20
2333 CR, Leiden
The Netherlands
Manufacturer
Pharmathen S.A.,
6 Dervenakion
15351 Pallini Attiki
Greece
Or
Pharmathen International S.A
Industrial Park Sapes
Rodopi Prefecture, Block No 5
Rodopi 69300
Greece
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
NV Apotex SA
Tél/Tel:+32 475.35.40.
Luxembourg/Luxemburg
NV Apotex SA
Tel: +32 475.35.40
България
Apotex Europe B.V.
Tel: +31 71. 565.77. 77
Magyarország
Apotex Europe B.V.
Tel: +31 71. 565.77. 77
Česká republika
Apotex (ČR) s.r.o.
Tel:+ 420 234.705.700
Malta
Apotex UK Limited
Tel:+44 15.25. 24.35.50
Danmark
Apotex Europe B.V.
Tlf:+31 71. 565.77. 77
Nederland
Apotex Nederland B.V.
Tel:+31 71. 52.43.100
Deutschland
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
Norge
Apotex Europe B.V.
Tlf:+31 71. 565.77. 77
Eesti
Österreich
25
Apotex Europe B.V.
Tel: +31 71. 565.77. 77
Apotex Europe B.V.
Tel: +31 71. 565.77. 77
Ελλάδα
NEXUS MEDICALS S.A.
Τηλ:+30 210 28 52 266
Polska
Apotex Inc. Korporacja Przedstawicielstwo w
Polsce
Tel:+48 22.311.20.00
España
APOTEX ESPAÑA S.L.
Tel:+34 91.486.15.65
Portugal
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
France
NV APOTEX SA
Tel:+32 475.35.40
România
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
Ireland
Apotex UK Limited
Tel:+44 15.25. 24.35.50
Slovenija
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
Ísland
Apotex Europe B.V.
Sími:+31 71. 565.77. 77
Slovenská republika
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
Italia
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
Suomi/Finland
Apotex Europe B.V.
Puh/Tel:+31 71. 565.77. 77
Κύπρος
Apotex Europe B.V.
Τηλ:+31 71. 565.77. 77
Sverige
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
Latvija
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
United Kingdom
Apotex UK Limited
Tel:+44 15.25. 24.35.50
Lietuva
Apotex Europe B.V.
Tel:+31 71. 565.77. 77
This leaflet was last approved in:
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu/
26
Source: European Medicines Agency
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