Table 3 Definition of adverse events

Definition of serious adverse reaction

Any thrombotic event e.g. stroke, TIA

Major Bleeding- Defined as clinically overt bleeding that is associated with:

• A fall in haemoglobin of 2 g/dl or more, or

• A transfusion of 2 or more units of packed red blood cells or whole blood, or

• A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or

• A fatal outcome

Definition of a non serious adverse reaction

Defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a clinician, (temporary) cessation of warfarin treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life.

Examples of non-major clinically relevant bleeding are:

• Epistaxis if it lasts for more than 5 minutes, if it is repetitive (i.e., 2 or more episodes of true bleeding, i.e., not spots on a handkerchief, within 24 hours), or leads to an intervention (packing, electrocautery, etc.) and no admission to hospital.

• Gingival bleeding if it occurs spontaneously (i.e., unrelated to tooth brushing or eating), or if it lasts for more than 5 minutes

• Haematuria if it is macroscopic, and either spontaneous or lasts for more than 24 hours after instrumentation (e.g., catheter placement or surgery) of the urogenital tract

• Macroscopic gastrointestinal haemorrhage: at least 1 episode of melena or hematemesis, if clinically apparent

• Rectal blood loss, if more than a few spots

• Haemoptysis, if more than a few speckles in the sputum, or

• Intramuscular hematoma

• Subcutaneous hematoma if the size is larger than 25 cm² or larger than 100 cm² if provoked

Definition of serious adverse event

A serious adverse event is defined as an untoward medical occurrence in a participant of a study that does not necessarily have a causal relationship with the treatment that results in:

• Death,

• Is life threatening

• Requires hospitalisation or prolongation of existing hospitalisation

• Results in persistent or significant disability or incapacity

• Consists of a congenital abnormality or birth defect

Other known rare adverse reaction listed in the SmPC are:

Skin reactions: Purpura and ecchymosis

Pruritic lesions

Skin necrosis

Alopecia

Diarrhoea

An unexplained fall in haematocrit

Jaundice and hepatic dysfunction

Fever, nausea, vomiting and pancreatitis

Hypersensitivity reactions are extremely rare and if any of these reactions occur they will be reported and it will be recommended to the clinician responsible for the participants warfarin management that warfarin is replaced by an alternative anticoagulant drug

A thrombotic event can also be defined as a serious adverse event related to warfarin.