Clopidogrel / Acetylsalicylic Acid Viatris (Previously Clopidogrel / Acetylsalicylic Acid Mylan)

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 30,000 patients treated with clopidogrel plus ASA, and over 9,000 patients treated for 1 year or more.

The clinically relevant adverse reactions 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.

Overall clopidogrel 75 mg/day was similar 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 the post-marketing experience where it was mostly reported during the first month of treatment.

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.

3% for placebo plus ASA. In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the group taking ASA alone. 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. 0001). Tabulated list of adverse reactions Adverse reactions that occurred with clopidogrel alone, with ASA alone or with clopidogrel in combination with ASA 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.

4) 14 System organ class Common Uncommon Rare Very rare, not known Psychiatric disorders Hallucinations, confusion Nervous system disorders Intracranial bleeding (some cases were reported with fatal outcome, especially in 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, non- cardiogenic pulmonary edema with chronic use and in the context of a hypersensitivity reaction due to acetylsalicylic acid*, eosinophilic pneumonia.

15 System organ class Common Uncommon Rare Very rare, not known 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.

4); these ASA related GI reactions may or may not be associated with haemorrhage, and may occur at any dose of acetylsalicylic acid and in patients with or without warning symptoms or a previous history of serious GI events*. Colitis (including ulcerative or lymphocytic colitis), stomatitis, acute pancreatitis in the context of a hypersensitivity reaction due to acetylsalicylic acid* Hepatobiliary disorders Acute liver failure, […]

8). 5). 8). 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. 5). Patients should inform physicians and dentists that they are taking Clopidogrel/Acetylsalicylic acid Viatris 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, Clopidogrel/Acetylsalicylic acid Viatris should be discontinued 7 days prior to surgery.

5 Clopidogrel/Acetylsalicylic acid Viatris 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 also be told that it might take longer than usual to stop bleeding when they take Clopidogrel/Acetylsalicylic acid Viatris, 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. 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. Recent transient ischaemic attack or stroke 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.

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. 2). 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.

5). 5). 8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous 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. 6 Caution required due to ASA • In patients with a history of asthma or allergic disorders since they are at increased risk of hypersensitivity reactions.

• In patients with gout since low doses of ASA increase urate concentrations. • In children under 18 years of age, there is a possible association between ASA and Reye’s syndrome. Reye’s syndrome is a very rare disease which can be fatal.

• This medicinal product must be administered under close medical supervision in patients with […]

1. • Severe hepatic impairment. • Active pathological bleeding such as peptic ulcer or intracranial haemorrhage. In addition, due to the presence of ASA, its use is also contraindicated in: • Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and syndrome of asthma, rhinitis, and nasal polyps.

Patients with pre-existing mastocytosis, in whom the use of acetylsalicylic acid may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting). • Severe renal impairment (creatinine clearance <30 ml/min).

6).