Clopidogrel Mylan 75 mg film-coated tablets

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Secondary Pprevention of atherothrombotic events

4.8 Undesirable effects

System Organ Class	Common	Uncommon	Rare	Very rare, not known*
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, acquired haemophilia A, granulocytopenia, anaemia
Cardiac disorders				Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel*

10. DATE OF REVISION OF THE TEXT

0713 December April 20157

Section 4.4:

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, or selective serotonin reuptake inhibitors (SSRIs)

 

, or other medicinal products

 

associated with bleeding risk such as pentoxifylline (see section 4.5)

 

 

.

 

CYP2C8 substrates

Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate

medicinal products (see section 4.5).

Section 4.5:

Medicinal products associated with bleeding risk

 

 

: There is an increased risk of bleeding due to the

 

potential additive effect. The concomitant administration of medicinal products associated with

bleeding risk should be undertaken with caution (see section 4.4).

Medicinal products that

 

are strong or moderate inhibit CYP2C19 inhibitors include, for example,

 

omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole,

ticlopidine,

 

ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol efavirenz.

 

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.

CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure

in healthy volunteers.

 

 

In vitro studies have shown the increase in repaglinide exposure is due to

 

inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased

plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by

CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4).

Section 5.2:

 

Biotransformation

 

 

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.

 

The active metabolite is formed mostly by

 

CYP2C19 with contributions from several other CYP enzymes, including

 

 

In vitro, this metabolic

 

pathway is mediated by CYP3A4, CYP2C19,

 

 

CYP1A2, and CYP2B6 and CYP3A4. The active thiol

 

metabolite which has been isolated

 

in vitro, binds rapidly and irreversibly to platelet receptors, thus

 

inhibiting platelet aggregation.

Section 4.8:
Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme, acute generalised exanthematous pustulosis (AGEP)), angioedema, drug induced hypersensitivity syndrome, drug rash with eosinophilia and
systemic symptoms (DRESS), rash erythematous or exfoliative, urticaria, eczema, lichen planus


Reproductive system and breast disorders
Gynaecomastia

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie.

IMB Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

Section 2:
Excipient with known effect:
Each film-coated tablet contains 13 mg hydrogenated castor oil.

Section 4.4:
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, or selective serotonin reuptake inhibitors (SSRIs). 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).

Section 4.5:
SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant
administration of SSRIs with clopidogrel should be undertaken with caution.

Section 4.8:
Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme), angioedema, drug
induced
hypersensitivity
syndrome, drug
rash with
eosinophilia and
systemic symptoms
(DRESS), rash erythematous or
exfoliative, urticaria, eczema, lichen planus

Section 2:
Excipients Excipient with known effect:

Section 3:
Pink, round and slightly convex biconvex film-coated tablets.

Section 4.1:
Clopidogrel is indicated in:
• Adults Adult 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.
• Adult 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.


Prevention of atherothrombotic and thromboembolic events in atrial fibrillation
• In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

Section 4.2:
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).
In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75 - 100 mg daily) should be initiated and continued in combination with clopidogrel (see section 5.1).

Section 4.3:
• Hypersensitivity to the active substance or to any of the excipients listed in section 2 or 6.1.

Section 4.4:
Allergic cross-reactivityCross-reactions among thienopyridines
Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, another thienopyridine (such as
ticlopidine, prasugrel) since allergic cross-reactivity among thienopyridines has been reported (see
section 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who have had developed a previous hypersensitivity to other thienopyridines should be
carefully monitored allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.to clopidogrel during treatment.

Section 4.5:
Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration co-administration of phenobarbital, or oestrogen.

Section 4.6:
BreastfeedingBreast-feeding

Section 4.8:
Clopidogrel has been evaluated for safety in more than 4244,000 patients, who have participated in clinical studies, including over 912,000 patients treated for 1 year or more. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via

IMB Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

Section 5.1:

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excl. heparin, ATC code: B01AC-04B01AC04.

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition.


Clinical efficacy and safety

The safety and efficacy of clopidogrel have been evaluated in 4 5 double-blind studies involving over 8088,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, and COMMIT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy.

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.

Atrial fibrillation
The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment.

The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was more effective than with clopidogrel and ASA.

The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE program were those presenting with documented AF, i.e., either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the following risk factors: age ≥75 years or age 55 to 74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior stroke, transient ischaemic attack (TIA), or non-CNS systemic embolus; left ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral vascular disease. The mean CHADS2 score was 2.0 (range 0-6).

The major exclusion criteria for patients were documented peptic ulcer disease within the previous 6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 109/l); requirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds.

Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with INR (international normalised ratio) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician’s decision was based on the patient’s unwillingness to take VKA.

The patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins.

The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of 2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001).

Section 5.2:
In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.

Section 9:
Date of latest renewal: 20 March 2014

Section 2:
Excipients with known effect:
Each film-coated tablet contains 13 mg hydrogenated castor oil.

For thea full list of excipients, see section 6.1.


Section 4.2:
Posology

• Adults and elderlyolder people

Section 4.3:
Hypersensitivity to the active substance or to any of the excipients listed in section 2 or 6.1.

Section 4.4:
Acquired haemophilia
Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.


Allergic cross-reactivity
Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as
ticlopidine, prasugrel) since allergic cross-reactivity among thienopyridines has been reported (see
section 4.8). Patients who have had previous hypersensitivity to other thienopyridines should be
carefully monitored for signs of hypersensitivity to clopidogrel during treatment.

Section 4.8:

Summary of the safety profile

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.


Tabulated list of adverse reactions

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), not known (cannot be estimated from the available data). Within each system organ class,
adverse reactions are presented in order of decreasing seriousness.

 

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


Serum sickness,
anaphylactoid
reactions,
cross-reactive drug
hypersensitivity
among
thienopyridines
(such as ticlopidine,
prasugrel) (see
section 4.4)*

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


Bullous dermatitis
(toxic epidermal
necrolysis, Stevens
Johnson Syndrome,
erythema
multiforme),
angioedema, drug
induced
hypersensitivity
syndrome, drug
rash with
eosinophilia and
systemic symptoms
(DRESS), rash
erythematous,
urticaria, eczema,
lichen planus


* Information related to clopidogrel with frequency “not known”.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via
the national reporting system listed in Appendix V.

Section 5.1:


Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC code: B01AC-04.

Mechanism of action

Pharmacodynamic effects

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.

Clinical efficacy and safety

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.

Section 5.2:
BiotransformationMetabolism
Clopidogrel is extensively metabolised by the liver.

In section 6.3, the shelf-life has been changed from 2 to 3 years.

Section 6.1:

Tablet core:
Cellulose, microcrystalline
Colloidal anhydrous silica
Crospovidone (type A)
Macrogol 6000
Hydrogenated castor oil

Film coating:
Hydroxypropylcellulose (E463)
Titanium dioxide (E171)
Polyvinyl alcohol
Titanium dioxide (E171)
Red iron oxide (E172)
Yellow iron oxide (E172)
Talc
Macrogol 3000 (Polyethyleneglycol)
Propylene glycol

Section 4.2:

Paediatric population

Clopidogrel should not be used in children because of efficacy concerns (see section

5.1).

Section 5.1:

Paediatric population

In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis

(PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and

infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition

of 49.3% (5 μM ADP-induced platelet aggregation) which was comparable to that of adults taking

Plavix 75 mg/day.

In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates

and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial

shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with

concomitant background therapy up to the time of second stage surgery. The mean time between shunt

palliation and first administration of study medicinal product was 20 days. Approximately 88% of

patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference

between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related

intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%]

for the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the

most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was

no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this

study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months

of age. No new safety concerns were noted during this long-term follow-up.

 

The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In

a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent

and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the

authorised tablet.

Section 4.1:

Prevention of atherothrombotic events

 

Clopidogrel is indicated in:

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

 

For further information please refer to section 5.1.

Section 4.2:

Posology

 Posology

• Adults and elderly
Clopidogrel should be given as a single daily dose of 75.

If a dose is missed:
- Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.
- For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.

• Paediatric population
The safety and efficacy of clopidogrel in children and adolescents have not yet been established.

• Renal impairment
Therapeutic experience is limited in patients with renal impairment (see section 4.4).

• Hepatic impairment
Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4).

Method of administration
For oral use
It may be given with or without food.

Section 4.3:
• Hypersensitivity to the active substance or to any of the excipients.
• Severe hepatic impairment.
• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

Section 4.4:

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).
Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Recent ischaemic stroke
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

Renal impairment

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section 4.2).

 

Hepatic impairment

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2).

 

Excipients

This medicinal product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

Section 4.4:

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S‑warfarin or International Normalised Ratio (INR) in patients receiving long‑term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.

 

 

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

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 strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2).

 

Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol.

 

Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel.

 

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD)  interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprozole should be discouraged (see section 4.4).

 

Less pronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole.

The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole.

 

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers (except cimetidine which is a CYP2C19 inhibitor) or antacids interfere with antiplatelet activity of clopidogrel.

 

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital or oestrogen.

 

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

 

Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel.

Section 4.6:

Pregnancy

As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure.

 

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

 

Breastfeeding

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with Clopidogrel Mylan.

 

Fertility

Clopidogrel was not shown to alter fertility in animal studies.

Section 4.8:

Clopidogrel has been evaluated for safety in more than 42,000 patients, who have participated in clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT studies are discussed below.  In addition to clinical studies experience, adverse reactions have been spontaneously reported.

 

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment.

 

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.

 

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery . In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA.

 

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group. The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

 

In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups.

 

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (³1/100 to <1/10); uncommon (³1/1,000 to < 1/100); rare (³1/10,000 to <1/1,000); very rare (<1/10,000). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

Section 5.1:

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y₁₂ receptor and the subsequent ADP‑mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

 

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by medicinal products, not all patients will have adequate platelet inhibition.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Clopidogrel Mylan in one or more subsets of the paediatric population for the prevention of thromboembolic events (see section 4.2 for information on paediatric use).

Section 5.2:

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.

 

The C_max of the active metabolite is twice as high following a single 300‑mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. C_max occurs approximately 30 to 60 minutes after dosing.

 

Elimination

 

 

 

 

 

Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120‑hour interval after dosing. After a single oral dose of 75 mg, clopidogrel has a half‑life of approximately 6 hours. The elimination halflife of the main circulating metabolite was 8 hours after single and repeated administration.

 

Pharmacogenetics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

 

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as defined above. Published frequencies for the poor CYP2C19 metaboliser  genotypes are  approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype.

 

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63‑71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

 

Consistent with the above results, in a meta‑analysis including 6 studies of 335 clopidogrel‑treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.

 

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been a number of retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY‑TIMI 28 (n=227), TRITON‑TIMI 38 (n=1477), and ACTIVE‑A (n=601), as well as a number of published cohort studies.

 

In TRITON‑TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.

 

In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.

 

In CURE, CLARITY and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.

 

None of these analyses were adequately sized to detect differences in outcome in poor metabolisers.

 

Special populations

 

The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.

 

 

Renal impairment

After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min) inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

 

Hepatic impairment

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP‑induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.

 

Race

The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

Section 6.1:

Hypromellose (E463)

Section 6.5:

Calendar Blister of OPA/Al/PVC-Al containing 7, 14, 28, 56, 84 film-coated tablets in the box.

Perforated unit dose blister of OPA/Al/PVC-Al containing 30x1 and 50x1 film-coated tablets in the box.

Section 10:

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA)  http://www.ema.europa.eu/

None provided