Source: Marketing Authorisation Holder Revision Year: 2022 Publisher: SANOFI WINTHROP INDUSTRIE, 1, rue de la Vierge, Ambarès et Lagrave, 33565 Carbon Blanc cedex, France
Due to the presence of both components of the product, CoPlavix is contraindicated in case of:
In addition, due to the presence of ASA, its use is also contraindicated:
Due to the risk of bleeding and haematological undesirable effects, 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 “Undesirable effects”). As a dual antiplatelet agent, CoPlavix 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 other NSAIDs including Cox-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), CYP2C19 strong inducers, or thrombolytics. 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 CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see section “Interaction with other medicinal products and other forms of interaction”).
Patients should inform physicians and dentists that they are taking CoPlavix before any surgery is scheduled and before any new medicinal product is taken. Where elective surgery is being considered, the need for dual antiplatelet therapy should be reviewed and consideration given to the use of a single antiplatelet agent. If patients must temporarily stop antiplatelet therapy, CoPlavix should be discontinued 7 days prior to surgery. CoPlavix 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 antiplatelet agents such as clopidogrel, ASA or both combined, and that they should report any unusual bleeding (site or duration) to their physician.
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 hemolytic anemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.
Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed insolated 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.
In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of ASA and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.
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 drugs 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 “Interaction with other medicinal products and other forms of interaction” for a list of CYP2C19 inhibitors, see also section “Pharmacokinetic properties”).
Use of medicinal products that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see section “Interaction with other medicinal products and other forms of interaction”).
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 “Undesirable effects”). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopenia and neutropenia. Patients who have had previous hypersensitivity to other thienopyridines should be carefully monitored for signs of hypersensitivity to clopidogrel during treatment.
CoPlavix should be used with caution in patients with a history of peptic ulcer or gastroduodenal haemorrhage or minor upper GI symptoms as this may be due to gastric ulceration which may lead to gastric bleeding. GI undesirable effects including stomach pain, heartburn, nausea, vomiting, and GI bleeding may occur. Minor GI symptoms, such as dyspepsia, are common and can occur anytime during therapy. Physicians should remain alert for signs of GI ulceration and bleeding, even in the absence of previous GI symptoms. Patients should be told about the signs and symptoms of GI undesirable effects and what steps to take if they occur (see section “Undesirable effects”).
In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see section “Interactions”).
CoPlavix contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product also contains hydrogenated castor oil which may cause stomach upset and diarrhea (see section “List of excipients”).
Drugs associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of drug associated with bleeding risk should be undertaken with caution.
Nicorandil: In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see Section “Special warnings and precautions for use”).
Oral anticoagulants: the concomitant administration of CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see section “Special warnings and precautions for use”). 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, co-administration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.
Glycoprotein IIb/IIIa inhibitors: CoPlavix should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions that receive concomitant glycoprotein IIb/IIIa inhibitors. (see section “Special warnings and precautions for use”).
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. Coadministration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between CoPlavix and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section “Special warnings and precautions for use”).
Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or nonfibrin 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 “Undesirable effects”) The safety of the concomitant administration of CoPlavix with other thrombolytic agents has not been formally established and should be undertaken with caution (see section “Special warnings and precautions for use”).
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 CoPlavix should be co-administered with caution (see section “Special warnings and precautions for use”).
Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section “Pharmacodynamic properties”).
Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.
Other concomitant therapy with clopidogrel: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs 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 “Special warnings and precautions for use” and “Pharmacokinetic properties”).
Drugs 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 administration 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 esomeprazole should be discourage (see section “Special warnings and precautions for use”).
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 in 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 medications 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, cimetidine, or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolized by CYP2C9 can be safely co-administered with clopidogrel.
CYP2C8 substrate drugs: 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 increase plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g. repaglinide, paclitaxel) should be undertaken with caution.
Other concomitant therapy with ASA:
Inducers of CYP2C19
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel.
Rifampicin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see section “Special warnings and precautions for use”).
Inhibitors of CYP2C19
Interactions with the following medicinal products have been reported with ASA:
Uricosurics (benzbromarone, probenecid, sulfinpyrazone): Caution is required because ASA may inhibit the effect of uricosuric agents through competitive elimination of uric acid.
Methotrexate: Due to the presence of ASA, methotrexate should be used with caution with CoPlavix as it can inhibit renal clearance of methotrexate, which may lead to bone marrow toxicity.
Metamizole: Metamizole may reduce the effect of ASA on platelet aggregation when taken concomitantly. Therefore, this combination should be used with caution in patients taking low-dose ASA for cardioprotection.
Acetazolamide: Caution is recommended when co-administering salicylates with acetazolamide as there is an increased risk of metabolic acidosis.
Varicella vaccine: It is recommended that patients not be given salicylates for an interval of six weeks after receiving the varicella vaccine. Cases of Reye’s syndrome have occurred following the use of salicylates during varicella infections (see section “Special warnings and precautions for use”).
Levothyroxine: Salicylates, specifically at doses greater than 2.0 g/day, may inhibit binding of thyroid hormones to carrier proteins and thereby lead to an initial transient increase in free thyroid hormones, followed by an overall decrease in total thyroid hormone levels. Thyroid hormone levels should be monitored (see section “Special warnings and precautions for use”).
Valproic acid: The concomitant administration of salicylates and valproic acid may result in decreased valproic acid protein binding and inhibition of valproic acid metabolism resulting in increased serum levels of total and free valproic acid.
Tenofovir: Concomitant administration of tenofovir disoproxil fumarate and NSAIDs may increase the risk of renal failure.
Other interactions with ASA: Interactions with the following medicinal products with higher (anti-inflammatory) doses of ASA have also been reported: angiotensin converting enzyme (ACE) inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), beta blockers, diuretics, and oral hypoglycemic agents.
Alcohol: Alcohol may increase the risk of gastrointestinal injury when taken with ASA. Therefore, alcohol should be used with caution in patients taking ASA (see section “Special warnings and precautions for use”).
Other interactions with clopidogrel and ASA: More than 30,000 patients entered into clinical trials with clopidogrel plus ASA at maintenance doses lower than or equal to 325 mg received a variety of concomitant medications including diuretics, beta blockers, ACE Inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. Apart from the specific drug interaction information described above, interaction studies with CoPlavix and some drugs commonly administered in patients with atherothrombotic disease have not been performed.
As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.
No clinical data on exposed pregnancies with CoPlavix are available, and no adequate data are available for clopidogrel alone. Animal studies have demonstrated a teratogenic effect arising from ASA. It is preferable not to use CoPlavix during the first two trimesters of pregnancy unless the clinical condition of the woman requires treatment with clopidogrel/ASA. Due to the presence of ASA, CoPlavix is contraindicated during the third trimester of pregnancy. (see section “Preclinical safety data”).
Since ASA is known to be excreted in human breast milk and studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk, nursing is not recommended if treatment with CoPlavix is required.
CoPlavix 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, including over 30,000 patients treated with clopidogrel plus ASA, and over 9,000 patients treated for 1 year or more. The clinically relevant adverse effects observed in four major studies, the CAPRIE study (a study comparing clopidogrel alone to ASA) and the CURE, CLARITY and COMMIT studies (studies comparing clopidogrel plus ASA to ASA alone) are discussed below. Clopidogrel 75 mg/day was well tolerated compared to ASA 325 mg/day in CAPRIE. The overall tolerability of clopidogrel in this study was similar to ASA, regardless of age, gender and race.
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 patients that received clopidogrel, gastrointestinal bleeding occurred at a rate of 2.0%, and required hospitalisation in 0.7%. In patients who received ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The incidence of other bleedings was higher in patients who received clopidogrel compared to ASA (7.3% vs. 6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs. 0.4%). The most frequently reported events in both treatment groups were: purpura/bruising and epistaxis. Other less frequently reported events were haematoma, haematuria, and eye bleeding (mainly conjunctival).
The incidence of intracranial bleeding was 0.4% in patients who received clopidogrel and 0.5% for patients who received ASA.
In CURE, the administration of clopidogrel plus ASA as compared to ASA alone was not associated with a statistically significant increase in life-threatening bleeds (event rates 2.2% vs. 1.8%) or fatal bleeds (0.2% vs. 0.2%), but the risk of major, minor and other bleedings was significantly higher with clopidogrel plus ASA: non-life-threatening major bleeds (1.6% clopidogrel plus ASA vs. 1.0% ASA alone), primarily gastrointestinal and at puncture sites, and minor bleeds (5.1% clopidogrel plus ASA vs. 2.4% ASA alone). The incidence of intracranial bleeding was 0.1% in both groups.
The major bleeding event rate for clopidogrel plus ASA was dose-dependent on ASA (<100mg: 2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for ASA alone (<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding (life-threatening, major, minor, other) decreased during the course of the trial: 0-1 months [clopidogrel plus ASA: 599/6259 (9.6%); ASA alone: 413/6303 (6.6%)], 1-3 months [clopidogrel plus ASA: 276/6123 (4.5%); ASA alone: 144/6168 (2.3%)], 3-6 months [clopidogrel plus ASA: 228/6037 (3.8%); ASA alone: 99/6048 (1.6%)], 6-9 months [clopidogrel plus ASA: 162/5005 (3.2%); ASA alone: 74/4972 (1.5%)], 9-12 months [clopidogrel plus ASA: 73/3841 (1.9%); ASA alone: 40/3844 (1.0%)].
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel plus ASA vs. 5.3% ASA alone). 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 (17.4%) vs. the group taking ASA alone (12.9%). The incidence of major bleeding was similar between groups (1.3% versus 1.1% for the clopidogrel plus ASA group and the group taking ASA alone, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel plus ASA group and the group taking ASA alone, respectively) and intracranial haemorrhage (0.5% versus 0.7% in the clopidogrel plus ASA group and the group taking ASA alone, respectively) was low and similar in both groups.
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 plus ASA group and the group taking ASA alone, respectively).
In CAPRIE, severe neutropenia (<0.45 × 10 9 /l) was observed in 4 patients (0.04%) who received clopidogrel and 2 patients (0.02%) who received ASA. Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received ASA had neutrophil counts of zero. One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopenia (<80 × 10 9 /l) was 0.2% on clopidogrel and 0.1% on ASA.
In CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups.
Other clinically relevant adverse drug reactions pooled from clinical studies or that were spontaneously reported are presented in the table below according to the World Health Organisation classification. Their frequency is defined using the following conventions: common (>1/100, <1/10); uncommon (>1/1,000, < 1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each organ class, adverse reactions are presented in order of decreasing seriousness.
| 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 “Special warnings and precautions for use”), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, acquired haemophilia A, granulocytopenia, anaemia, haemolytic anaemia in patients with glucose – 6 – phosphate dehydrogenase (G6PD) deficiency (see section “Special warnings and precautions for use”), bicytopenia, bone marrow failure | |
| Cardiac disorders | Kounis syndrome (in the context of a hypersensitivity reaction due to ASA) | |||
| Immune system disorders | Anaphylactic shock*, serum sickness, anaphylactoid reactions, cross – reactive drug hypersensitivity among thienopyridines** (such as ticlopidine, prasugrel) (see section “Special warnings and precautions for use”), insulin autoimmune syndrome, which can lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype** (more frequent in the Japanese population), aggravation of allergic symptoms of food allergy* | |||
| Metabolism and nutrition disorders | Hypoglycaemia*, gout* (see section “Special warnings and precautions for use”) | |||
| Psychiatric disorders | Hallucinations, confusion | |||
| Nervous system disorders | Intracranial bleeding (some cases were reported with fatal outcome, especially in the elderly), headache, paraesthesia, dizziness | Taste disturbances, ageusia | ||
| Eye disorders | Eye bleeding (conjunctival, ocular, retinal) | |||
| Ear and labyrinth disorders | Vertigo | Hearing loss* or tinnitus* | ||
| Vascular disorders> | Haematoma | Serious haemorrhage, haemorrhage of operative wound, vasculitis including Henoch-Schönlein purpura, hypotension | ||
| Respiratory, thoracic and mediastinal disorders | Epistaxis | Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis, noncardiogenic pulmonary edema with chronic use and in the context of a hypersensitivity reaction due to ASA*, eosinophilic pneumonia | ||
| 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. Upper gastrointestinal disorders* (oesophagitis, oesophageal ulceration, perforation, erosive gastritis, erosive duodenitis; gastro-duodenal ulcer/perforations) ; lower gastrointestinal disorders* (small [jejunum and ileum] and large [colon and rectum] intestinal ulcers, colitis and intestinal perforation); upper gastrointestinal symptoms* such as gastralgia (see section “Special warnings and precautions for use”); these ASA-related GI reactions may or may not be associated with haemorrhage, and may occur at any dose of ASA and in patients with or without warning symptoms or a previous history of serious GI events*. Colitis (including ulcerative or lymphocytic colitis), stomatitis |
| Hepatobiliary disorders | Acute liver failure, liver injury, mainly hepatocellular*, hepatitis, elevation of hepatic enzymes*, abnormal liver function test | |||
| Skin and subcutaneous tissue disorders | Bruising | Rash, pruritus, skin bleeding (purpura) | Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnsons Syndrome, erythema multiforme), angioedema, druginduced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rash erythematous or exfoliative, urticarial, eczema, lichen planus, fixed eruption, acute generalised exanthematous pustulosis (AGEP) | |
| Musculoskeleta l and connective tissue disorders | Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia | |||
| Renal and urinary disorders | Haematuria | Acute renal impairment* (especially in patients with existing renal impairment, heart decompensation, nephritic syndrome, or concomitant treatment with diuretics), glomerulonephritis, blood creatinine increased, renal failure | ||
| Reproductive systems and breast disorders | Gynaecomastia | |||
| General disorders and administration site conditions | Bleeding at the puncture site | Fever, edema | ||
| Investigations | Bleeding time prolonged, neutrophil count decreased, platelet count decreased |
* Information reported in published information for ASA with frequency “not known”.
** Information related to clopidogrel with frequency “not known”.
Not applicable.
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