Product Characteristics
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT
Clopidogrel Teva 75 mg film-coated tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 75 mg clopidogrel (as hydrogen sulfate).
Excipients: each tablet contains 62.16 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
Film-coated tablet.
Light pink to pink, capsule-shaped film-coated tablets debossed with “93” on one side and “7314” on
the other side.
4.1 Therapeutic indications
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in:
•
Patients suffering from myocardial infarction (from a few days until less than 35 days),
ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial
disease.
Patients suffering from acute coronary syndrome:
−
Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave
myocardial infarction), including patients undergoing a stent placement following
percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).
−
ST segment elevation acute myocardial infarction, in combination with ASA in medically
treated patients eligible for thrombolytic therapy.
For further information please refer to section 5.1.
4.2
Posology and method of administration
Adults and elderly
Clopidogrel should be given as a single daily dose of 75 mg with or without food.
In patients suffering from acute coronary syndrome:
−
Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave
myocardial infarction): clopidogrel treatment should be initiated with a single 300 mg
loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA)
75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding
risk it is recommended that the dose of ASA should not be higher than 100 mg. The
optimal duration of treatment has not been formally established. Clinical trial data support
use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1).
−
ST segment elevation acute myocardial infarction: clopidogrel should be given as a single
daily dose of 75 mg initiated with a 300 mg loading dose in combination with ASA and
with or without thrombolytics. For patients over 75 years of age clopidogrel should be
initiated without a loading dose. Combined therapy should be started as early as possible
after symptoms start and continued for at least four weeks. The benefit of the combination
of clopidogrel with ASA beyond four weeks has not been studied in this setting (see
section 5.1).
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.
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
4.4 Special warnings and precautions for use
Bleeding and haematological disorders
Due to the risk of bleeding and haematological adverse reactions, blood cell count determination
and/or other appropriate testing should be promptly considered whenever clinical symptoms
suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet
agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding
from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA,
heparin, glycoprotein IIb/IIIa inhibitors or 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 Teva contains lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Oral anticoagulants
: the concomitant administration of clopidogrel with oral anticoagulants is not
recommended since it may increase the intensity of bleedings (see section 4.4).
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.
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 co-
administration 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.
4.6 Pregnancy and lactation
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 Teva.
4.7 Effects on ability to drive and use machines
Clopidogrel has no or negligible influence on the ability to drive and use machines.
Clopidogrel has been evaluated for safety in more than 42,000 patients who have participated in
clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant
adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed
below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of
age, gender and race. 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.
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
Serum sickness,
anaphylactoid
reactions
Hallucinations,
confusion
Intracranial
bleeding (some
cases were reported
with fatal outcome),
headache,
paraesthesia,
dizziness
Eye bleeding
(conjunctival,
ocular, retinal)
Ear and labyrinth
disorders
Serious
haemorrhage,
haemorrhage of
operative wound,
vasculitis,
hypotension
Respiratory,
thoracic and
mediastinal
disorders
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
Acute liver failure,
hepatitis, abnormal
liver function test
Skin and
subcutaneous
tissue disorders
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
Glomerulonephritis,
blood creatinine
increased
General disorders
and
administration
site conditions
Bleeding at
puncture site
Bleeding time
prolonged,
neutrophil count
decreased, platelet
count decreased
Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent
bleeding complications. Appropriate therapy should be considered if bleedings are observed.
No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of
prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC Code: B01AC-04.
Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel
must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet
aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine
diphosphate (ADP) to its platelet 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
to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA
(relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every
1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from
experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show
any significant difference between clopidogrel (5.8%) and ASA (6.0%).
In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the
benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due
to PAD (especially those who also had a history of myocardial infarction) (RRR=23.7%; CI: 8.9 to
36.2) and weaker (not significantly different from ASA) in stroke patients (RRR=7.3%; CI: -5.7 to
18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial
infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR=-4.0%;
CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of
clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear
whether the differences in relative risk reduction across qualifying conditions are real, or a result of
chance.
Acute coronary syndrome
The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome
(unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the
most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to
have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or
T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading
dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA
(75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In
CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins
were administered in more than 90% of the patients and the relative rate of bleeding between
clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.
The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial
infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the
placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the
clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29%
when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent
and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events
(primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI:
12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3,
3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit
observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage
persisted (see section 4.4).
The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy
(RRR=43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR=18.2%; CI: 6.5%, 28.3%).
The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory
ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebo-
treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel-
treated group. This benefit was mostly driven by the statistically significant reduction in the incidence
of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group].
There was no observed effect on the rate of rehospitalisation for unstable angina.
The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave
MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with
the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the
total CURE population) who underwent stent placement (Stent-CURE), the data showed that
clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for
the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second
co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of
clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this
subset are in line with the overall trial results.
The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular
therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta
blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of
ASA (75-325 mg once daily).
In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been
evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.
The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation
MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose,
followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to
325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate,
heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the
composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent
MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint
was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population
included 19.7% women and 29.2% patients ≥65 years. A total of 99.7% of patients received
fibrinolytics (fibrin specific: 68.7%, non- fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers,
54.7% ACE inhibitors and 63% statins.
Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached
the primary endpoint, representing an absolute reduction of 6.7% and a 36% odds reduction in favor of
clopidogrel (95% CI: 24, 47%; p<0.001), mainly related to a reduction in occluded infarct-related
arteries. This benefit was consistent across all prespecified subgroups including patients’ age and
gender, infarct location, and type of fibrinolytic or heparin used.
The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the
onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST
depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or
placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge.
The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke
or death. The population included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years) and
54.5% patients who received fibrinolytics.
Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the
relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an
absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and
with or without fibrinolytics, and was observed as early as 24 hours.
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
14
C-labelled clopidogrel in man, approximately 50% was excreted in the
urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral
dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the
main circulating (inactive) metabolite was 8 hours after single and repeated administration.
Pharmacogenetics
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.
CYP2C19 Phenotype and Genotype Frequency
Extensive metabolism: CYP2C19*1/*1
Intermediate metabolism: CYP2C19*1/*2 or *1/*3
Poor metabolism: CYP2C19*2/*2, *2/*3 or *3/*3
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.
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.
PHARMACEUTICAL PARTICULARS
Tablet core
Lactose monohydrate
Cellulose, microcrystalline
Hydroxypropylcellulose (E463)
Crospovidone (type A)
Hydrogenated vegetable oil
Sodium laurilsulfate
Film-coating
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 4000
Iron oxide red (E172)
Iron oxide yellow (E172)
Indigo carmine aluminium lake (E132)
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Aluminium-aluminium peelable perforated unit-dose blisters, aluminium-aluminium perforated unit
dose blisters and HDPE bottles with polypropylene closures or child resistant polypropylene closures
and silica gel desiccant.
Peelable perforated blisters contain 14x1, 28x1, 30x1, 50x1, 84x1, 90x1 or 100x1 film-coated tablets.
Perforated blisters contain 14x1, 28x1, 30x1, 50x1, 84x1, 90x1 or 100x1 film-coated tablets.
Bottles contain 30 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
MARKETING AUTHORISATION HOLDER
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
MARKETING AUTHORISATION NUMBER(S)
Cartons of 14x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
Cartons of 28x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
Cartons of 30x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
Cartons of 50x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
Cartons of 84x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
Cartons of 90x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
Cartons of 100x1 film-coated tablets in peelable perforated unit-dose
aluminium-aluminium blisters
HDPE bottles of 30 film-coated tablets
HDPE bottles of 100 film-coated tablets
Cartons of 14x1 film-coated tablets in perforated aluminium-aluminium
blisters
Cartons of 28x1 film-coated tablets in perforated aluminium-aluminium
blisters
Cartons of 30x1 film-coated tablets in perforated aluminium-aluminium
blisters
Cartons of 50x1 film-coated tablets in perforated aluminium-aluminium
blisters
Cartons of 84x1 film-coated tablets in perforated aluminium-aluminium
blisters
Cartons of 90x1 film-coated tablets in perforated aluminium-aluminium
blisters
Cartons of 100x1 film-coated tablets in perforated aluminium-aluminium
blisters
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 28 July 2009
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
CONDITIONS OF THE MARKETING AUTHORISATION
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13
4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
2100 Gödöllő
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne
East Sussex
BN22 9AG
United Kingdom
TEVA Santé SA
Rue Bellocier
89107 Sens
France
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
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5 of 29 May
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
Not applicable.
The application is based on a reference medicinal product for which no safety concerns requiring
additional risk minimisation activities have been identified.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
ANNEX III
LABELLING AND PACKAGE LEAFLET
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
NAME OF THE MEDICINAL PRODUCT
Clopidogrel Teva 75 mg film-coated tablets
clopidogrel
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 75 mg clopidogrel (as hydrogen sulfate)
It also contains lactose. See leaflet for further information
PHARMACEUTICAL FORM AND CONTENTS
14x1 film-coated tablets
28x1 film-coated tablets
30x1 film-coated tablets
50x1 film-coated tablets
84x1 film-coated tablets
90x1 film-coated tablets
100x1 film-coated tablets
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
1.
Separate one indivudal blister cell from the rest of the strip by gently tearing along the
perforations around it.
2.
Carefully peel off the backing
3.
Push the tablet out
4.
Put the tablet in your mouth and swallow with water or another liquid.
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.
OTHER SPECIAL WARNING(S), IF NECESSARY
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
12. MARKETING AUTHORISATION NUMBER(S)
100x1 film-coated tablets
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
16. INFORMATION IN BRAILLE
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
NAME OF THE MEDICINAL PRODUCT
Clopidogrel Teva 75 mg film-coated tablets
clopidogrel
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 75 mg clopidogrel (as hydrogen sulfate)
It also contains lactose. See leaflet for further information
PHARMACEUTICAL FORM AND CONTENTS
14x1 film-coated tablets
28x1 film-coated tablets
30x1 film-coated tablets
50x1 film-coated tablets
84x1 film-coated tablets
90x1 film-coated tablets
100x1 film-coated tablets
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
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.
OTHER SPECIAL WARNING(S), IF NECESSARY
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
NAME OF THE MEDICINAL PRODUCT
Clopidogrel Teva 75 mg film-coated tablets
clopidogrel
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 75 mg clopidogrel (as hydrogen sulfate)
It also contains lactose. See leaflet for further information
PHARMACEUTICAL FORM AND CONTENTS
30 film-coated tablets
100 film-coated tablets
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
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
OTHER SPECIAL WARNING(S), IF NECESSARY
SPECIAL STORAGE CONDITIONS
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING
BOTTLE LABEL (30 or 100 film-coated tablets)
NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
Clopidogrel Teva 75 mg film-coated tablets
clopidogrel
oral use
Read the package leaflet before use.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 film-coated tablets
100 film-coated tablets
PACKAGE LEAFLET: INFORMATION FOR THE USER
Clopidogrel Teva 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 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 Teva is and what it is used for
2. Before you take Clopidogrel Teva
3. How to take Clopidogrel Teva
4. Possible side effects
5.
How to store Clopidogrel Teva
6.
WHAT CLOPIDOGREL TEVA IS AND WHAT IT IS USED FOR
Clopidogrel belongs to a group of medicines called “platelet aggregation inhibitors.” It works by
stopping certain particles in your blood (“platelets”) from sticking together to form blood clots which
can block blood flow to important parts of your body including your heart and your brain.
If you suffer from hardening of the arteries (“atherosclerosis”) there is an increased risk of a blood clot
forming in your blood vessels. Clopidogrel Teva reduces the risk of blood clots forming which in turn
reduces the risk of serious conditions such as heart attack and stroke from occurring.
You have been prescribed Clopidogrel Teva because:
•
You have hardening of the arteries and have recently suffered from a heart attack, a stroke or
have a condition known as “peripheral arterial disease” (diseases of the blood vessels except
those in the brain and heart).
•
You have hardening of the arteries and have experienced severe chest pains known as “unstable
angina”, have symptoms that indicate that a heart attack is developing or are suffering from a
heart attack. Your doctor should also give you another medicine called “acetyl salicylic acid” to
use together with Clopidogrel Teva.
If you have unstable angina or symptoms of a developing heart attack your doctor may also have
inserted a device called a “stent” into the blocked or narrowed blood vessel to hold it open and to
restore blood flow.
Keep this leaflet. You may need to read it again.
2. BEFORE YOU TAKE CLOPIDOGREL TEVA
Do not take Clopidogrel Teva
•
If you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Clopidogrel
Teva
•
If you have severe liver disease
•
If you are suffering from another condition which is currently causing bleeding such as a stomach
ulcer.
If you think any of these apply to you, or if you are in any doubt at all, consult your doctor before
taking Clopidogrel Teva.
Take special care with Clopidogrel Teva
Tell your doctor before you start to take this medicine if:
•
You are at increased risk of bleeding. For example:
o
If you have recently suffered from a serious injury
o
If you have recently undergone surgery or are due to have surgery (including dental surgery)
o
If you have any blood disorder which makes internal bleeding (bleeding inside your body)
more likely
o
If you suffer from any other illness which makes internal bleeding more likely (e.g. stomach
ulcers or wounds inside the eye)
•
You have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last
seven days
•
You have liver or kidney disease.
While you are taking Clopidogrel Teva:
•
You should tell your doctor if 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 altered behaviour, headaches,
coma, visual disturbances, seizures (fitting), kidney failure, fever, extreme tiredness, weakness or
bleeding into the stomach, bowels or skin (including small red spots or large bruised areas) (see
section 4 ‘POSSIBLE SIDE EFFECTS’ section)
•
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’ section)
•
Your doctor may order blood tests
Clopidogrel Teva is not recommended for use in children or adolescents under 18 years of age.
Using other medicines
Talk to your doctor if you are using or have recently used any of the following medicines:
•
Oral anticoagulants (medicines used to stop blood clotting) such as warfarin.
•
Glycoprotein IIb/IIIa inhibitors (medicines used to stop blood clotting). E.g. abciximab,
eptifibatide or tirofiban.
•
Acetylsalicylic acid (active substance present in many medicines used to relieve pain and reduce
fever as well as to prevent blood clotting). Your doctor may have told you to take acetylsalicylic
acid together with Clopidogrel Teva. If not, occasional use (e.g. to relieve pain) of doses not
exceeding 1000 mg in any 24 hour period should not be associated with any significant
complications. Prolonged use however should be discussed with your doctor first.
•
Heparin (medicine used to prevent blood clotting).
•
Medicines used to break down blood clots (e.g. alteplase and streptokinase).
•
Non-steroidal anti-inflammatory medicines (used to treat painful inflammatory conditions of the
joints or muscles). E.g. ibuprofen, diclofenac and meloxicam.
•
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.
Taking these medicines in combination with Clopidogrel Teva could result in an increased risk of
bleeding.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Taking Clopidogrel Teva with food and drink
You can take Clopidogrel Teva with or without food.
Pregnancy and breast-feeding
It is preferable not to use this medicine during pregnancy and breast-feeding.
If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist
before taking Clopidogrel Teva. If you become pregnant while taking Clopidogrel Teva, consult your
doctor immediately as it is recommended not to take clopidogrel while you are pregnant.
While taking Clopidogrel Teva, consult your doctor about the breastfeeding of a baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Clopidogrel Teva is unlikely to affect your ability to drive or operate machinery.
Important information about some of the ingredients of Clopidogrel Teva
Your medicine contains lactose. If you have been told by your doctor that you have an intolerance to
some sugars (e.g. lactose), contact your doctor before taking this medicinal product.
3. HOW TO TAKE CLOPIDOGREL TEVA
Always take Clopidogrel Teva 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 per day which should be swallowed with water or another liquid.
You should take your medicine regularly at the same time each day. You can take it with or without
food.
In addition, if you have experienced severe chest pain (unstable angina or heart attack), your doctor
may give you 300 mg of Clopidogrel Teva (4 tablets of 75 mg) once at the start of treatment.
You should continue taking Clopidogrel Teva for as long as your doctor has told you to take it.
If you take more Clopidogrel Teva than you should
If you (or someone else) swallow a lot of the tablets all together, or if you think a child has swallowed
any of the tablets, contact your nearest hospital casualty department or your doctor immediately. An
overdose is likely to cause an increased risk of bleeding. Please take this leaflet, any remaining tablets
and the container with you to the hospital or doctor so that they know which tablets were consumed.
If you forget to take Clopidogrel Teva
If you forget to take a dose of Clopidogrel Teva, but remember within 12 hours of the missed dose,
take your tablet straight away and then take your next tablet at the usual time.
If you forget to take a dose of Clopidogrel Teva, but don’t remember within 12 hours of the missed
dose, skip the missed dose and 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 Teva
Do not stop taking Clopidogrel Teva without discussing it with your doctor first.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Like all medicines, Clopidogrel Teva can cause side effects, although not everybody gets them.
Some of the side effects may be serious. If you suffer from any of the following symptoms you should
contact your doctor immediately:
•
Fever, signs of infection (e.g. sore throat), pale skin or extreme tiredness. These may be due to a
decrease of some blood cells
•
Altered behaviour, headaches, coma, visual disturbances, seizures (fitting), kidney failure, fever,
extreme tiredness, weakness or bleeding into the stomach, bowels or skin (including small red
spots or large bruised areas). This could indicate that you are suffering from a serious condition
called thrombotic thrombocytic purpura (rare disorder of the blood clotting system which causes
multiple blood clots to form around the body)
•
Signs of liver problems such as yellowing of the skin and whites of the eyes (jaundice), whether or
not associated with bleeding which appears under the skin as red pinpoint dots and/or confusion
•
Swelling in the mouth or skin disorders such as rashes, itching and blistering of the skin. These
may be the signs of an allergic reaction.
The most common side effect (affects 1 to 10 users in 100) reported for medicines containing
clopidogrel is bleeding. Bleeding may occur as bleeding in the stomach or bowels, bruising,
haematoma (unusual bleeding or bruising under the skin), nose bleeds or blood in the urine. In a small
number of cases, bleeding in the eye, inside the head, the abdomen, the lung and the joints have also
been reported.
If you cut or injure yourself, it may take slightly longer than usual for bleeding to stop. This is linked
to the way that your medicine works. For minor cuts and injuries (e.g. shaving cuts) you should not
worry. However, if you are in any doubt, bleeding becomes serious or you experience unexpected
bleeding from unusual parts of your body you should contact your doctor straight away.
The following side effects have been reported. They are listed according to frequency as follows:
Very common: affects more than 1 user in 10
Common:
affects 1 to 10 users in 100
affects 1 to 10 users in 1,000
affects 1 to 10 users in 10,000
affects less than 1 user in 10,000
Frequency cannot be estimated from the available data
Common side effects:
•
Bruising, haematoma (unusual bleeding under the skin), nose bleeds, bleeding in the stomach or
bowels, increased bleeding at the site of a puncture wound
•
Diarrhoea, abdominal pain, indigestion or heartburn
Uncommon side effects:
•
Headache and dizziness
•
Prolonged bleeding, bleeding inside the head, bleeding in the eye, blood in the urine and/or
purpura (red spots on the skin caused by bleeding underneath the skin)
•
Rashes, itching, sensation of tingling and numbness
•
Ulcers in the stomach and small intestine, nausea, vomiting, constipation, flatulence (wind) and
inflammation of the stomach leading to sickness, loss of appetite and discomfort after eating
•
Reduction in blood platelets which makes bleeding or bruising more likely
•
Blood disorders including a reduction in the number of white blood cells which makes infections
more likely.
Rare side effects:
•
Reduced levels of certain white blood cells which increases the risk of infection (neutropenia)
•
Vertigo (dizziness accompanied by a whirling sensation)
•
Bleeding inside the abdomen
Very rare side effects:
•
A serious condition called thrombotic thrombocytic purpura (rare disorder of the blood clotting
system which causes multiple blood clots to form around the body). Symptoms may include
altered behaviour, headaches, coma, visual disturbances, seizures (fitting), kidney failure, fever,
extreme tiredness, weakness, or bleeding into the stomach, bowels or skin (including small red
spots or large bruised areas)
•
Severe reduction in certain blood cells leading to increased risk of bleeding or bruising, increased
risk of infections, pale skin and extreme tiredness
•
Generalised allergic reactions, breathing difficulties, swelling or inflammation of the mouth, skin
allergy, blisters on the skin
•
Confusion or hallucinations
•
Changes in the way things taste
•
Inflammation of the blood vessels, decrease in blood pressure
•
Yellowing of the skin and whites of the eyes (jaundice)
•
Bleeding in the lungs, throat, stomach or bowels, abdomen or joints
•
Bleeding of post-operative wounds or other serious bleeds
•
Severe abdominal pain with or without back pain, pain in the joints and muscular pain
•
Diarrhoea
•
Fever
•
Changes in levels of certain substances in your blood or urine. This may be detectable via blood
or urine tests.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5. HOW TO STORE CLOPIDOGREL TEVA
Keep out of the reach and sight of children.
Do not use Clopidogrel Teva after the expiry date that is stated on the
outer carton, bottle or blister
after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
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.
What Clopidogrel Teva contains
•
The active substance is clopidogrel. Each film-coated tablet contains 75 mg of clopidogrel (as
hydrogen sulfate).
•
The other ingredients in the tablet core are lactose monohydrate, microcrystalline cellulose,
hydroxypropylcellulose (E463), crospovidone (type A), hydrogenated vegetable oil and sodium
laurilsulfate, and in the film-coating are lactose monohydrate, hypromellose (E464), titanium
dioxide (E171), macrogol 4000, iron oxide red (E172), iron oxide yellow (E172), indigo carmine
aluminium lake (E132).
What Clopidogrel Teva looks like and contents of the pack
•
The film-coated tablets are light pink to pink, film coated, capsule shaped tablets. One side of the
tablet is debossed with the number “93”. The other side of the tablet is debossed with the number
“7314”.
•
Clopidogrel Teva is supplied in peelable perforated blisters of aluminium/aluminium containing
14x1, 28x1, 30x1, 50x1, 84x1, 90x1 or 100x1 tablets; perforated blisters of aluminium/aluminium
containing 14x1, 28x1, 30x1, 50x1, 84x1, 90x1 or 100x1 tablets or HDPE bottles with
polypropylene closures or child resistant polypropylene closures and silica gel desiccant
containing 30 or 100 tablets. Not all pack sizes may be marketed.
•
Please note that instructions on how to remove the tablet from the blister strip are given on the
outer carton of the peelable blisters.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.,
Computerweg 10,
3542 DR Utrecht,
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13,
4042 Debrecen,
Hungary
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82,
2100 Gödöllő,
Hungary
TEVA UK Ltd
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG,
United Kingdom
TEVA Santé SA,
Rue Bellocier,
89107 Sens,
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information is available on the European Medicines Agency website:
http://www.ema.europa.eu.
Source: European Medicines Agency
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