Kengrexal · 4.3 Contraindications · 1

HOS-216735 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most common adverse reactions with cangrelor include mild and moderate bleeding and dyspnoea. Serious adverse reactions associated with cangrelor in patients with coronary artery disease include severe/life threatening bleeding and hypersensitivity. Tabulated list of adverse reactions Table 1 depicts adverse reactions that have been identified based upon a pooling of combined data from all CHAMPION studies. Adverse reactions are classified according to frequency and system organ class. Frequency categories are defined according to the following conventions: Very common (≥1/10), 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). Table 1: Adverse reactions for cangrelor in CHAMPION pooled studies within 48 hours System organ class Common Uncommon Rare Very rare Infections and Haematoma infestations infection Neoplasms benign, Skin malignant and neoplasm unspecified (includes bleeding cysts and polyps) Blood and lymphatic Anaemia, thrombo- system disorders cytopenia Immune system Anaphylactic disorders reaction (anaphylactic shock), hypersensitivity Nervous system Haemorrhage disorders intracranial d * Eye disorders Eye haemorrhage 6  System organ class Common Uncommon Rare Very rare Ear and labyrinth Ear disorders haemorrhage Cardiac disorders Cardiac

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HOS-216731 · has-contraindication-information · PDF-Seite 3

• Active bleeding or increased risk of bleeding, because of impaired haemostasis and/or irreversible coagulation disorders or due to recent major surgery/trauma or uncontrolled severe hypertension. • Any history of stroke or transient ischaemic attack (TIA). • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-216730 · has-indication-information · PDF-Seite 2

Kengrexal, co-administered with acetylsalicylic acid (ASA), is indicated for the reduction of thrombotic cardiovascular events in adult patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.

HOS-216733 · has-interaction-information · PDF-Seite 4

Interaction studies have only been performed in adults. 4 Oral P2Y12 agents (clopidogrel, prasugrel, ticagrelor) When clopidogrel is administered during infusion of cangrelor, the expected inhibitory effect of clopidogrel on platelets is not achieved. Administration of 600 mg clopidogrel immediately after the cessation of the cangrelor infusion results in the anticipated full pharmacodynamic effect. No clinically relevant interruption of P2Y12 inhibition was observed in phase III studies when 600 mg clopidogrel was administered immediately after discontinuation of the cangrelor infusion. A pharmacodynamic interaction study has been conducted with cangrelor and prasugrel, which demonstrated that cangrelor and prasugrel can be administered concomitantly. Patients can be transitioned from cangrelor to prasugrel when prasugrel is administered immediately following discontinuation of the cangrelor infusion or up to 30 minutes before the end of the cangrelor infusion to limit recovery of platelet reactivity. A pharmacodynamic interaction study has also been conducted with cangrelor and ticagrelor. No interaction on cangrelor was observed. Patients can be transitioned from cangrelor to ticagrelor without interruption of antiplatelet effect, see section 4.2. Pharmacodynamic effects Cangrelor exhibits inhibition of activation and aggregation of platelets as shown by aggregometry (light transmission and impedance), point-of care assays, such as the VerifyNow P2Y12 test, VASP-P and flow cytometry. Following the administration of a 30 micrograms/kg bolus followed by a 4 micrograms/kg/min infusion (the PCI dose), platelet inhibition is observed within two minutes. The pharmacokinetic/pharmacodynamic (PK/PD) effect of cangrelor is maintained consistently for the duration of the infusion. Irrespective of dose, following cessation of the infusion, cangrelor blood levels decrease rapidly and platelet function returns to normal within one hour. Acetylsalicylic acid, heparin, nitrogycerin No pharmacokinetic or pharmacodynamic interaction with cangrelor was observed in an interaction study with aspirin, heparin, or nitroglycerin. Bivalirudin, low molecular weight heparin, fondaparinux, and GP IIb/IIIa inhibitors In clinical studies, cangrelor has been co-administered with bivalirudin, low molecular weight heparin, fondaparinux, and GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) with no apparent e

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HOS-216734 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no or limited amount of data from the use of Kengrexal in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Kengrexal is not recommended during pregnancy. Breast-feeding It is unknown whether Kengrexal is excreted in human milk. A risk to the newborns/infants cannot be excluded. Fertility No effect on female fertility parameters were observed in animal studies of Kengrexal. A reversible effect on fertility was observed in male rats treated with Kengrexal (see section 5.3).

HOS-216732 · has-warning-information · PDF-Seite 3

Risk of bleeding Treatment with Kengrexal may increase the risk of bleeding. In pivotal studies conducted in patients undergoing PCI, GUSTO (Global Use of Strategies to Open Occluded Arteries), moderate and mild bleeding events were more common in patients treated with cangrelor than in patients treated with clopidogrel, see section 4.8. Although most bleeding associated with the use of cangrelor occurs at the site of arterial puncture, haemorrhage can occur at any site. Any unexplained fall in blood pressure or haematocrit should lead to the serious consideration of a haemorrhagic event and the cessation of cangrelor administration. Cangrelor should be used with caution in patients with disease states associated with an increased bleeding risk. Cangrelor should be used with caution in patients taking medicines that may increase the risk of bleeding. 3 Cangrelor has a half-life of three to six minutes. Platelet function is restored within 60 minutes of stopping infusion. Intracranial haemorrhage Treatment with Kengrexal may increase the risk of intracranial haemorrhage. In pivotal studies conducted in patients undergoing PCI, there were more intracranial bleeds at 30 days with cangrelor (0.07%) than with clopidogrel (0.02%), of which 4 bleeds with cangrelor and 1 bleed with clopidogrel were fatal. Cangrelor is contraindicated in patients with any history of stroke/TIA, (see sections 4.3 and 4.8). Cardiac tamponade Treatment with Kengrexal may increase the risk of cardiac tamponade. In pivotal studies conducted in patients undergoing PCI, there were more cardiac tamponades at 30 days with cangrelor (0.12%) than with clopidogrel (0.02%), (see section 4.8). Effects on renal function In pivotal studies conducted in patients undergoing PCI, events of acute renal failure (0.1%), renal failure (0.1%) and increased serum creatinine (0.2%) were reported to occur after administration of cangrelor in clinical trials (see section 4.8). In patients with severe renal impairment (creatinine clearance 15-30 mL/min) a higher rate of worsening in renal function (3.2%) was reported in the cangrelor group compared to clopidogrel (1.4%). In addition, a higher rate of GUSTO moderate bleeding was reported in the cangrelor group (6.7%) compared to clopidogrel (1.4%). Cangrelor should be used with caution in these patients. Hypersensitivity Hypersensitivity reactions may occur after treatment with Kengrexal. A high

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