Cangrelor

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.

No effect on female fertility parameters were observed in animal studies of cangrelor. A reversible effect on fertility was observed in male rats treated with cangrelor.

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.

Treatment with cangrelor 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%).

There are no or limited amount of data from the use of cangrelor in pregnant women. Studies in animals have shown reproductive toxicity.

Cangrelor should not be used during pregnancy.

It is not known whether cangrelor is excreted in human milk. A risk to the suckling child cannot be excluded.

Fertility

No effect on female fertility parameters were observed in animal studies of cangrelor. A reversible effect on fertility was observed in male rats treated with cangrelor.

Cangrelor has no 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.

List of adverse reactions

The llist below 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).

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 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 1.

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 1. 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.