KENGREXAL Powder for concentrate solution Ref.[6492] Active ingredients: Cangrelor

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.

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 higher rate of serious cases of hypersensitivity were recorded with cangrelor (0.05%) than with control (0.007%). These included cases of anaphylactic reactions/shock and angioedema (see section 4.8).

Risk of dyspnoea

Treatment with Kengrexal may increase the risk of dyspnoea. In pivotal studies conducted in patients undergoing PCI dyspnoea (including exertional dyspnoea) occurred more commonly in patients treated with cangrelor (1.3%) than clopidogrel (0.4%). Most dyspnoea events were mild or moderate in severity and the median duration of dyspnoea was two hours in patients receiving cangrelor (see section 4.8).

Fructose intolerance

This medicinal product contains 52.2 mg sorbitol in each vial. Patients with hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

Interaction studies have only been performed in adults.

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 one hour before, optimally at 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.

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 effect upon the pharmacokinetics or pharmacodynamics of cangrelor.

Cytochrome P450 (CYP)

Metabolism of cangrelor is not dependent on CYPs and CYP isoenzymes are not inhibited by therapeutic concentrations of cangrelor or its major metabolites.

Breast cancer resistance protein (BCRP)

In vitro inhibition of BCRP by the metabolite ARC-69712XX at clinically relevant concentrations has been observed. Possible implications for the in vivo situation have not been investigated, but caution is advised when cangrelor is to be combined with a BCRP substrate.

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).

Kengrexal has no or negligible influence on the ability to drive and use machines.

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:

Infections and infestations

Very rare: Haematoma infection

Neoplasms benign, malignant and unspecified (includes cysts and polyps)

Very rare: Skin neoplasm bleeding

Blood and lymphatic system disorders

Rare: Anaemia, thrombocytopenia

Immune system disorders

Rare: Anaphylactic reaction (anaphylactic shock), hypersensitivity

Nervous system disorders

Rare: Haemorrhage intracranial^d*

Eye disorders

Rare: Eye haemorrhage

Ear and labyrinth disorders

Very rare: Ear haemorrhage

Cardiac disorders

Uncommon: Cardiac tamponade (pericardial haemorrhage)

Vascular disorders

Common: Haematoma <5 cm, haemorrhage

Uncommon: Haemodynamic instability

Rare: Wound haemorrhage, vascular pseudoaneurysm

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea (dyspnoea exertional)

Uncommon: Epistaxis, haemoptysis

Rare: Pulmonary haemorrhage

Gastrointestinal disorders

Uncommon: Retroperitoneal haemorrhage,* peritoneal haematoma, gastrointestinal haemorrhage^a

Skin and subcutaneous tissue disorders

Common: Ecchymosis (petechiae, purpura)

Uncommon: Rash, pruritus, urticaria^f

Rare: Angioedema

Renal and urinary disorders

Uncommon: Haemorrhage urinary tract^e, acute renal failure (renal failure)

Reproductive system and breast disorders

Rare: Pelvic haemorrhage

Very rare: Menorrhagia, penile haemorrhage

General disorders and administration site conditions

Common: Vessel puncture site discharge

Uncommon: Vessel puncture site haematoma^b

Investigations

Common: Haematocrit decreased, haemoglobin decreased**

Uncommon: Blood creatinine increased

Rare: Platelet count decreased, red blood cell count decreased, international normalised ratio increased^c

Injury, poisoning and procedural complications

Common: Haematoma >5 cm

Rare: Contusion

Very rare: Periorbital haematoma, subcutaneous haematoma

Multiple related adverse reaction terms have been grouped together in the table and include medical terms as described below:

^a Upper gastrointestinal haemorrhage, mouth haemorrhage, gingival bleeding, oesophageal haemorrhage, duodenal ulcer haemorrhage, haematemesis, lower gastrointestinal haemorrhage, rectal haemorrhage, haemorrhoidal haemorrhage, haematochezia.
^b Application site bleeding, catheter site haemorrhage or haematoma, infusion site haemorrhage or haematoma.
^c Coagulation time abnormal, prothrombin time prolonged.
^d Cerebral haemorrhage, cerebrovascular accident.
^e Haematuria, blood urine present, urethral haemorrhage.
^f Erythema, rash erythematous, rash pruritic.
* Including events with fatal outcome.
** Transfusion was uncommon 101/12,565 (0.8%).

Description of selected adverse reactions

The GUSTO bleeding scale was measured in the CHAMPION (PHOENIX, PLATFORM, and PCI) clinical trials. An analysis of non-coronary artery bypass grafting (CABG)-related bleeding is presented in Table 2.

When administered in the PCI setting, cangrelor was associated with a greater incidence of GUSTO mild bleeding compared with clopidogrel. Further analysis of GUSTO mild bleeding revealed that a large proportion of mild bleeding events were ecchymosis, oozing and <5 cm haematoma. Transfusion and GUSTO severe/life-threatening bleeding rates were similar. In the pooled safety population from the CHAMPION trials, the incidence of fatal bleeding within 30 days of dosing was low and similar in patients who received cangrelor compared to clopidogrel (8 [0.1%] vs. 9 [0.1%]).

No baseline demographic factor altered the relative risk of bleeding with cangrelor.

Table 2. Non-CABG-related bleeding:

CABG: Coronary Artery Bypass Graft Surgery; GUSTO: Global Use of Strategies to Open Coronary Arteries; w/o: without
^a In the CHAMPION pooled analysis, GUSTO Mild was defined as other bleed not requiring blood transfusion or causing haemodynamic compromise.
^b In CHAMPION PHOENIX, GUSTO Mild was defined as other bleeding requiring intervention but not requiring blood transfusion or causing haemodynamic compromise.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.