Leaflet KENGREXAL 50mg concentrate powder for injection / infusion solution

Kengrexal 50 mg powder for concentrate for solution for injection/infusion

Each vial contains cangrelor tetrasodium corresponding to 50 mg cangrelor. After reconstitution 1 mLof concentrate contains 10 mg cangrelor. After dilution 1 mL of solution contains 200 microgramscangrelor.

Each vial contains 52.2 mg sorbitol.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for injection/infusion.

White to off-white lyophilised powder.

Kengrexal, co-administered with acetylsalicylic acid (ASA), is indicated for the reduction ofthrombotic cardiovascular events in adult patients with coronary artery disease undergoingpercutaneous 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.

Kengrexal should be administered by a physician experienced in either acute coronary care or incoronary intervention procedures and is intended for specialised use in an acute and hospital setting.

The recommended dose of Kengrexal for patients undergoing PCI is a 30 micrograms/kg intravenousbolus followed immediately by 4 micrograms/kg/min intravenous infusion. The bolus and infusionshould be initiated prior to the procedure and continued for at least two hours or for the duration of theprocedure, whichever is longer. At the discretion of the physician, the infusion may be continued for atotal duration of four hours, see section 5.1.

Patients should be transitioned to oral P2Y12 therapy for chronic treatment. For transition, a loadingdose of oral P2Y12 therapy (clopidogrel, ticagrelor or prasugrel) should be administered immediatelyfollowing discontinuation of cangrelor infusion. Alternatively, a loading dose of ticagrelor orprasugrel, but not clopidogrel, may be administered up to 30 minutes before the end of the infusion,see section 4.5.

Use with other anticoagulant agents

In patients undergoing PCI, standard procedural adjunctive therapy should be implemented (seesection 5.1).

No dose adjustment is needed in elderly (≥75 years) patients.

No dose adjustment is needed in patients with mild, moderate or severe renal insufficiency (seesections 4.4 and 5.2).

No dose adjustment is needed (see section 5.2).

The safety and efficacy of cangrelor in children aged less than 18 years has not yet been established.

Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology canbe made.

Kengrexal is intended for intravenous use, only after reconstitution and dilution.

Kengrexal should be administered via an intravenous line. The bolus volume should be administeredrapidly (<1 minute), from the diluted bag via manual intravenous push or pump. Ensure the bolus iscompletely administered before the start of PCI. Start the infusion immediately after administration ofthe bolus.

For instructions on reconstitution and dilution of the medicinal product before administration seesection 6.6.

* Active bleeding or increased risk of bleeding, because of impaired haemostasis and/orirreversible coagulation disorders or due to recent major surgery/trauma or uncontrolled severehypertension.

* 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.

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 withcangrelor 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 leadto 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 increasedbleeding risk. Cangrelor should be used with caution in patients taking medicines that may increasethe risk of bleeding.

Cangrelor has a half-life of three to six minutes. Platelet function is restored within 60 minutes ofstopping infusion.

Intracranial haemorrhage

Treatment with Kengrexal may increase the risk of intracranial haemorrhage. In pivotal studiesconducted 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 clopidogrelwere fatal. Cangrelor is contraindicated in patients with any history of stroke/TIA, (see sections 4.3and 4.8).

Cardiac tamponade

Treatment with Kengrexal may increase the risk of cardiac tamponade. In pivotal studies conducted inpatients undergoing PCI, there were more cardiac tamponades at 30 days with cangrelor (0.12%) thanwith 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%), renalfailure (0.1%) and increased serum creatinine (0.2%) were reported to occur after administration ofcangrelor in clinical trials (see section 4.8). In patients with severe renal impairment (creatinineclearance 15-30 mL/min) a higher rate of worsening in renal function (3.2%) was reported in thecangrelor group compared to clopidogrel (1.4%). In addition, a higher rate of GUSTO moderatebleeding was reported in the cangrelor group (6.7%) compared to clopidogrel (1.4%). Cangrelorshould be used with caution in these patients.

Hypersensitivity reactions may occur after treatment with Kengrexal. A higher rate of serious cases ofhypersensitivity were recorded with cangrelor (0.05%) than with control (0.007%). These includedcases 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 patientsundergoing PCI dyspnoea (including exertional dyspnoea) occurred more commonly in patientstreated with cangrelor (1.3%) than clopidogrel (0.4%). Most dyspnoea events were mild or moderatein severity and the median duration of dyspnoea was two hours in patients receiving cangrelor (seesection 4.8).

Fructose intolerance

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

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 ofclopidogrel on platelets is not achieved. Administration of 600 mg clopidogrel immediately after thecessation of the cangrelor infusion results in the anticipated full pharmacodynamic effect. Noclinically relevant interruption of P2Y12 inhibition was observed in phase III studies when 600 mgclopidogrel was administered immediately after discontinuation of the cangrelor infusion.

A pharmacodynamic interaction study has been conducted with cangrelor and prasugrel, whichdemonstrated that cangrelor and prasugrel can be administered concomitantly. Patients can betransitioned from cangrelor to prasugrel when prasugrel is administered immediately followingdiscontinuation of the cangrelor infusion or up to one hour before, optimally at 30 minutes before theend of the cangrelor infusion to limit recovery of platelet reactivity.

A pharmacodynamic interaction study has also been conducted with cangrelor and ticagrelor. Nointeraction on cangrelor was observed. Patients can be transitioned from cangrelor to ticagrelorwithout interruption of antiplatelet effect.

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-Pand flow cytometry.

Following the administration of a 30 micrograms/kg bolus followed by a 4 micrograms/kg/mininfusion (the PCI dose), platelet inhibition is observed within two minutes. Thepharmacokinetic/pharmacodynamic (PK/PD) effect of cangrelor is maintained consistently for theduration of the infusion.

Irrespective of dose, following cessation of the infusion, cangrelor blood levels decrease rapidly andplatelet function returns to normal within one hour.

Acetylsalicylic acid, heparin, nitrogycerin

No pharmacokinetic or pharmacodynamic interaction with cangrelor was observed in an interactionstudy 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 effectupon the pharmacokinetics or pharmacodynamics of cangrelor.

Cytochrome P450 (CYP)

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

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

There are no or limited amount of data from the use of Kengrexal in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3).

Kengrexal is not recommended during pregnancy.

It is unknown whether Kengrexal is excreted in human milk. A risk to the newborns/infants cannot beexcluded.

No effect on female fertility parameters were observed in animal studies of Kengrexal. A reversibleeffect 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.

The most common adverse reactions with cangrelor include mild and moderate bleeding anddyspnoea. Serious adverse reactions associated with cangrelor in patients with coronary artery diseaseinclude severe/life threatening bleeding and hypersensitivity.

Table 1 depicts adverse reactions that have been identified based upon a pooling of combined datafrom all CHAMPION studies. Adverse reactions are classified according to frequency and systemorgan 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 Haematomainfestations infection

Neoplasms benign, Skinmalignant and neoplasmunspecified (includes bleedingcysts and polyps)

Blood and lymphatic Anaemia, thrombo-system disorders cytopenia

Immune system Anaphylacticdisorders reaction (anaphylacticshock),hypersensitivity

Nervous system Haemorrhagedisorders intracranial d *

Eye disorders Eye haemorrhage

Ear and labyrinth Eardisorders haemorrhage

Cardiac disorders Cardiactamponade(pericardialhaemorrhage)

System organ class Common Uncommon Rare Very rare

Vascular disorders Haematoma Haemodynamic Wound haemorrhage,<5 cm, instability vascularhaemorrhage pseudoaneurysm

Respiratory, thoracic Dyspnoea Epistaxis, Pulmonaryand mediastinal (dyspnoea haemoptysis haemorrhagedisorders exertional)

Gastrointestinal Retroperitonealdisorders haemorrhage,*peritonealhaematoma,gastrointestinalhaemorrhage a

Skin and Ecchymosis Rash, pruritus, Angioedemasubcutaneous tissue (petechiae, urticaria fdisorders purpura)

Renal and urinary Haemorrhagedisorders urinary tract, eacute renal failure(renal failure)

Reproductive system Pelvic haemorrhage Menorrhagia,and breast disorders penilehaemorrhage

General disorders Vessel Vessel punctureand administration puncture site site haematoma bsite conditions discharge

Investigations Haematocrit Blood creatinine Platelet countdecreased, increased decreased, red bloodhaemoglobin cell count decreased,decreased** internationalnormalised ratioincreased c

Injury, poisoning and Haematoma Contusion Periorbitalprocedural ≥5 cm haematoma,complications subcutaneoushaematoma

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

a. Upper gastrointestinal haemorrhage, mouth haemorrhage, gingival bleeding, oesophagealhaemorrhage, duodenal ulcer haemorrhage, haematemesis, lower gastrointestinal haemorrhage,rectal haemorrhage, haemorrhoidal haemorrhage, haematochezia.

b. Application site bleeding, catheter site haemorrhage or haematoma, infusion site haemorrhageor 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%).

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 ispresented in Table 2.

When administered in the PCI setting, cangrelor was associated with a greater incidence of GUSTOmild bleeding compared with clopidogrel. Further analysis of GUSTO mild bleeding revealed that alarge proportion of mild bleeding events were ecchymosis, oozing and <5 cm haematoma. Transfusionand GUSTO severe/life-threatening bleeding rates were similar. In the pooled safety population fromthe CHAMPION trials, the incidence of fatal bleeding within 30 days of dosing was low and similar inpatients 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

GUSTO bleeding, n (%)

CHAMPION pooled Cangrelor Clopidogrel(N=12,565) (N=12,542)

Any GUSTO bleeding 2,196 (17.5) 1,696 (13.5)

Severe/life-threatening 28 (0.2) 23 (0.2)

Moderate 76 (0.6) 56 (0.4)

Mild a 2,109 (16.8) 1,627 (13.0)

Mild w/o ecchymosis, oozing and haematoma <5 cm 707 (5.6) 515 (4.1)

Patients with any transfusion 90 (0.7) 70 (0.6)

CHAMPION PHOENIX Cangrelor Clopidogrel(N=5,529) (N=5,527)

Any GUSTO bleeding 178 (3.2) 107 (1.9)

Severe/life-threatening 9 (0.2) 6 (0.1)

Moderate 22 (0.4) 13 (0.2)

Mild b 150 (2.7) 88 (1.6)

Mild w/o ecchymosis, oozing and haematoma <5 cm 98 (1.8) 51 (0.9)

Patients with any transfusion 25 (0.5) 16 (0.3)

CABG: Coronary Artery Bypass Graft Surgery; GUSTO: Global Use of Strategies to Open Coronary

Arteries; w/o: withouta In the CHAMPION pooled analysis, GUSTO Mild was defined as other bleed not requiring bloodtransfusion or causing haemodynamic compromise.b In CHAMPION PHOENIX, GUSTO Mild was defined as other bleeding requiring intervention butnot requiring blood transfusion or causing haemodynamic compromise.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, healthy volunteers received up to two times the proposed daily dose. In clinicaltrials, the maximum accidental overdose was 10 times (bolus) or 3.5 times the infusion dose normallyadministered and bleeding was the most frequently observed adverse event.

Bleeding is the most likely pharmacological effect of overdose. If bleeding occurs appropriatesupportive measures should be taken, which may include stopping the medicinal product so plateletfunction can return.

There is no antidote to Kengrexal, however, the pharmacokinetic half-life of Kengrexal is three tosix minutes. Platelet function is restored within 60 minutes of stopping the infusion.

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC25.

Kengrexal contains cangrelor, a direct P2Y12 platelet receptor antagonist that blocks adenosinediphosphate (ADP)-induced platelet activation and aggregation in vitro and ex vivo. Cangrelor bindsselectively and reversibly to the P2Y12 receptor to prevent further signalling and platelet activation.

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 P2Y12test, VASP-Pand flow cytometry. Onset of P2Y12 inhibition occurs rapidly upon cangrelor administration.

Following the administration of a 30 microgram/kg bolus followed by a 4 microgram/kg/min infusion,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, blood levels decrease rapidly and plateletfunction returns to normal within one hour.

The primary clinical evidence for the efficacy of cangrelor is derived from CHAMPION PHOENIX, arandomised, double-blind study comparing cangrelor (n=5,472) to clopidogrel (n=5,470), both givenin combination with aspirin and other standard therapy, including unfractionated heparin (78%),bivalirudin (23%), LMWH (14%) or fondaparinux (2.7%). The median duration of cangrelor infusionwas 129 minutes. GP IIb/IIIa inhibitors were permitted for bailout use only and were used in 2.9% ofpatients. Patients with coronary atherosclerosis were included who required PCI for stable angina(58%), non-ST-segment elevation acute coronary syndrome (NSTE-ACS) (26%), or ST-elevationmyocardial infraction (STEMI) (16%).

Data from the CHAMPION pooled population of over 25,000 PCI patients provide additional clinicalsupport for safety.

In CHAMPION PHOENIX, cangrelor significantly reduced (relative risk reduction 22%; absolute riskreduction 1.2%) the primary composite endpoint of all-cause mortality, MI, IDR, and ST compared toclopidogrel at 48 hours (Table 3).

Table 3: Thrombotic events at 48 hours in CHAMPION PHOENIX (mITT population)

Cangrelor vs. Clopidogrel

Cangrelor Clopidogreln (%) N=5,470 N=5,469 OR (95% CI) p-value

Primary Endpoint

Death/MI/IDR/ST a 257 (4.7) 322 (5.9) 0.78 (0.66,0.93) 0.005

Key Secondary Endpoint

Stent thrombosis 46 (0.8) 74 (1.4) 0.62 (0.43, 0.90) 0.010

Death 18 (0.3) 18 (0.3) 1.00 (0.52, 1.92) >0.999

MI 207 (3.8) 255 (4.7) 0.80 (0.67, 0.97) 0.022

IDR 28 (0.5) 38 (0.7) 0.74 (0.45, 1.20) 0.217a Primary endpoint from logistic regression adjusted for loading dose and patient status. p-values forsecondary endpoints based on Chi-squared test.

OR = odds ratio; CI = confidence interval; IDR = ischaemia-driven revascularisation; MI =myocardial infarction; mITT = modified intent-to-treat; ST = stent thrombosis.

Significant reductions in death/MI/IDR/ST and ST observed in the cangrelor group at 48 hours weremaintained at 30 days (Table 4).

Table 4: Thrombotic events at 30 days in CHAMPION PHOENIX (mITT population)

Cangrelor vs. Clopidogrel

Cangrelor Clopidogreln (%) N=5,462 N=5,457 OR (95% CI) p-value a

Primary Endpoint

Death/MI/IDR/ST 326 (6.0) 380 (7.0) 0.85 (0.73, 0.99) 0.035

Key Secondary Endpoint

Stent thrombosis 71 (1.3) 104 (1.9) 0.68 (0.50, 0.92) 0.012

Death 60 (1.1) 55 (1.0) 1.09 (0.76, 1.58) 0.643

MI 225 (4.1) 272 (5.0) 0.82 (0.68, 0.98) 0.030

IDR 56 (1.0) 66 (1.2) 0.85 (0.59, 1.21) 0.360a p-values based on Chi-squared test.

OR = odds ratio; CI = confidence interval; IDR = ischaemia-driven revascularisation; MI =myocardial infarction; mITT = modified intent-to-treat; ST = stent thrombosis.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Kengrexal in one or more subsets of the paediatric population in the prevention of non-site specificembolism and thrombosis, for the treatment of thrombosis in paediatric patients undergoing diagnosticand/or therapeutic percutaneous vascular procedures. See section 4.2 for information on paediatricuse.

In a prospective, open-label, single-arm, multi-center, Phase I study, cangrelor was evaluated at 2 doselevels of 0.5 and 0.25 micrograms/kg/min in 15 neonates ≤28 days of life with congenital heart diseaserequiring palliation with a systemic-to-pulmonary artery shunt, a right ventricle-to-pulmonary arteryshunt, or a ductus arteriosus stent (see section 4.2). Platelet aggregation inhibition was assessed bylight transmission aggregometry (LTA) in response to stimulation with 20 and 5 µM ADP. The %inhibition of maximal aggregation 45 minutes into cangrelor infusion and the number of subjects whoachieved >90% of maximal platelet aggregation inhibition are summarized in the table below.

Cangrelor 0.5 mcg/kg/min Cangrelor 0.25 mcg/kg/min

N=8 N=7using ADP using ADP using ADP using ADP

LTA method20 µM 5 µM 20 µM 5 µM

N 6 5 7 5% inhibition of maximalaggregation 45 minutesinto the infusion,mean (SD) 89.0 (11.42) 93.7 (6.45) 76.3 (16.89) 88.2 (13.49)median (min; max) 91.2 (69.0; 92.9 (84.8; 69.6 (53.2; 96.0 (68.1;100.0) 100.0) 98.3) 100.0)

Subjects who achieved>90% of maximal plateletaggregation inhibition,n (%) 3 (50) 4 (80) 2 (28.6) 3 (60)

The bioavailability of cangrelor is complete and immediate. Cangrelor is rapidly distributed reaching

Cmax within two minutes after administration of an intravenous bolus followed by infusion. The meansteady state concentration of cangrelor during a constant intravenous infusion of 4 micrograms/kg/minis 488 ng/mL.

Cangrelor has a volume of distribution of 3.9 L. Cangrelor is 97-98% plasma-protein bound.

Cangrelor is deactivated rapidly in the plasma by dephosphorylation to form its primary metabolite, anucleoside. The metabolism of cangrelor is independent of organ function and does not interfere withother drugs metabolised by hepatic enzymes.

The half-life of Kengrexal is three to six minutes, independent of dose. Following the intravenousadministration of a 2 micrograms/kg/min infusion of [3H] cangrelor to healthy male volunteers, 93%of total radioactivity was recovered. Of the recovered material, 58% was found in urine and theremaining 35% was found in faeces, presumably following biliary excretion. Initial excretion wasrapid, such that approximately 50% of the administered radioactivity was recovered in the first24 hours, and 75% was recovered by 48 hours. Mean clearance was approximately 43.2 L/kg.

The pharmacokinetic properties of cangrelor have been evaluated and found to be linear in patientsand healthy volunteers.

The pharmacokinetics of cangrelor are not affected by gender, age, or renal or hepatic status. No doseadjustment is needed for these populations.

Cangrelor infusion has been evaluated in neonatal patients (age from birth to 28 days) at a dose levelof 0.25 and 0.5 micrograms/kg/min. The maximum concentrations were 19 ng/mL and 60 ng/mL,respectively, and were observed approximately 45 minutes following start of infusion. In neonates,cangrelor is rapidly metabolised into its primary metabolite AR-C69712XX. Very low or non-detectable levels of cangrelor were found 5-10 minutes post-infusion and relatively high levels of theprimary metabolite were detected.

Non-clinical data reveal no special safety risk for humans based on studies of safety pharmacology,mutagenicity and clastogenic potential.

Carcinogenicity studies have not been performed.

The primary adverse effects of cangrelor in rats and dogs occurred in the upper urinary tract andconsisted of injury to renal tubules, renal pelvis, and ureter. Anatomical changes correlated withincreased plasma creatinine and urea, and increased albumin and blood cells in urine. Injury to theurinary tract was reversible following cessation of dosing in an investigative study in rats.

Cangrelor produced dose-related foetal growth retardation characterised by increased incidences ofincomplete ossification and unossified hind limb metatarsals in rats. In rabbits, cangrelor wasassociated with increased incidences of abortion and intrauterine losses, as well as foetal growthretardation at higher doses which may have been secondary to maternal toxicity. Cangrelor did notproduce malformations in either the rat or rabbit reproductive studies.

Effects on fertility, ability to produce a pregnancy with female partner(s), sperm morphology andsperm motility were observed in the male rat fertility study when cangrelor was administered at humanequivalent doses equal to 1.8 fold the recommended PCI dose. These effects were not apparent atlower doses and were reversible following cessation of dosing. In this study, semen analysis wasconducted after 8 weeks of continuous treatment.

Female fertility was not affected at any dose.

Mannitol

Sorbitol

Sodium hydroxide (for pH-adjustment)

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

3 years.

The powder should be reconstituted immediately prior to dilution and use. Do not refrigerate.

From a microbiological point of view, unless the method of reconstitution/dilution precludes the riskof microbiological contamination, the product should be used immediately. If not used immediately,in-use storage times and conditions prior to use are the responsibility of the user.

This medicinal product does not require any special storage conditions. For storage conditions afterreconstitution and dilution of the medicinal product see section 6.3.

Powder in 10 mL glass vials (Type 1) closed with a Flurotec coated butyl rubber stopper and sealedwith crimped aluminium seal.

Kengrexal is available in packs of 10 vials.

Instructions for preparation

Aseptic procedures should be used for the preparation of Kengrexal.

The vial should be reconsituted immediately prior to dilution and use. Reconstitute each 50 mg/vial byadding 5 mL of sterile water for injection. Swirl gently until all material is dissolved. Avoid vigorousmixing. Allow any foam to settle. Ensure that the contents of the vial are fully dissolved and thereconstituted material is a clear, colourless to pale yellow solution.

Do not use without dilution. Before administration, 5 mL reconstituted solution has to be withdrawnfrom each vial and must be diluted further with 250 mL sodium chloride 9 mg/mL (0.9%) solution forinjection or glucose (5%) solution for injection. Mix the bag thoroughly.

The medicinal product should be inspected visually for particulate matter after reconstitution.

Kengrexal is administered as a weight-based regimen consisting of an initial intravenous bolusfollowed by an intravenous infusion. The bolus and infusion should be administered from the infusionsolution.

This dilution will generate a concentration of 200 micrograms/mL and should be sufficient for at leasttwo hours of dosing as required. Patients 100 kg and over will require a minimum of two bags.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Chiesi Farmaceutici S.p.A.

Via Palermo, 26/A43122 Parma

Italy

EU/1/15/994/001

Date of first authorisation: 23 March 2015

Date of latest renewal: 16 December 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.