PRAXBIND 2.5g / 50ml solution for injection / infusion medication leaflet

Praxbind 2.5 g/50 mL solution for injection/infusion

Each mL of solution for injection/infusion contains 50 mg idarucizumab.

Each vial contains 2.5 g idarucizumab in 50 mL.

Idarucizumab is produced by recombinant DNA technology in Chinese hamster ovary cells.

Each vial contains 2 g sorbitol and 25 mg sodium in 50 mL (see section 4.4).

For the full list of excipients, see section 6.1.

Solution for injection/infusion

Clear to slightly opalescent, colourless to slightly yellow solution.

Praxbind is a specific reversal agent for dabigatran and is indicated in adult patients treated withdabigatran etexilate when rapid reversal of its anticoagulant effects is required:

- For emergency surgery/urgent procedures;

- In life-threatening or uncontrolled bleeding.

Restricted to hospital use only.

The recommended dose is 5 g idarucizumab (2 vials of 2.5 g/50 mL).

In a subset of patients, recurrence of plasma concentrations of unbound dabigatran and concomitantprolongation of clotting tests have occurred up to 24 hours after administration of idarucizumab (seesection 5.1).

Administration of a second 5 g dose of idarucizumab may be considered in the following situations:

- recurrence of clinically relevant bleeding together with prolonged clotting times, or

- if potential re-bleeding would be life-threatening and prolonged clotting times are observed, or

- patients require a second emergency surgery/urgent procedure and have prolonged clottingtimes.

Relevant coagulation parameters are activated partial thromboplastin time (aPTT), diluted thrombintime (dTT) or ecarin clotting time (ECT) (see section 5.1).

A maximum daily dose has not been investigated.

Dabigatran etexilate treatment can be re-initiated 24 hours after administration of idarucizumab, if thepatient is clinically stable and adequate haemostasis has been achieved.

After administration of idarucizumab, other antithrombotic therapy (e.g. low-molecular weightheparin) can be started at any time, if the patient is clinically stable and adequate haemostasis has beenachieved.

Absence of antithrombotic therapy exposes patients to the thrombotic risk of their underlying diseaseor condition.

No dose adjustment is required in elderly patients aged 65 years and above (see section 5.2).

No dose adjustment is required in renally impaired patients. Renal impairment did not impact thereversal effect of idarucizumab (see section 5.2).

No dose adjustment is required in patients with hepatic injury (see section 5.2).

The safety and efficacy of Praxbind in children below the age of 18 years have not been established.

Currently available data are described in section 5.1.

Praxbind (2 vials of 2.5 g/50 mL) is administered intravenously as two consecutive infusions over5 to 10 minutes each or as a bolus injection.

For additional instructions for use and handling see section 6.6.

None.

Idarucizumab binds specifically to dabigatran and reverses its anticoagulant effect. It will not reversethe effects of other anticoagulants (see section 5.1).

Praxbind treatment can be used in conjunction with standard supportive measures, which should beconsidered as medically appropriate.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

The risk of using Praxbind in patients with known hypersensitivity (e.g. anaphylactoid reaction) toidarucizumab or to any of the excipients needs to be weighed cautiously against the potential benefitof such an emergency treatment. If an anaphylactic reaction or other serious allergic reaction occurs,administration of Praxbind should be discontinued immediately and appropriate therapy initiated.

Hereditary fructose intolerance

The recommended dose of Praxbind contains 4 g sorbitol as an excipient. In patients with hereditaryfructose intolerance, parenteral administration of sorbitol has been associated with reports ofhypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure withbreakdown of excretory and synthetic function, and death. Therefore, in patients with hereditaryfructose intolerance the risk of treatment with Praxbind must be weighed against the potential benefitof such an emergency treatment. If Praxbind is administered in these patients, intensified medical careduring Praxbind exposure and within 24 hours of exposure is required.

Patients being treated with dabigatran have underlying disease states that predispose them tothromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of theirunderlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered assoon as medically appropriate (see section 4.2).

Urinary protein testing

Praxbind causes transient proteinuria as a physiologic reaction to renal protein overflow afterbolus/short term application of 5 g idarucizumab intravenously (see section 5.2). The transientproteinuria is not indicative of renal damage, which should be taken into account for urine testing.

This medicinal product contains 50 mg sodium per dose, equivalent to 2.5% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No formal interaction studies with Praxbind and other medicinal products have been performed. Basedon the pharmacokinetic properties and the high specificity in binding to dabigatran, clinically relevantinteractions with other medicinal products are considered unlikely.

Preclinical investigations with idarucizumab have shown no interactions with

- volume expanders.

- coagulation factor concentrates, such as prothrombin complex concentrates (PCCs, e.g. 3 factorand 4 factor), activated PCCs (aPCCs) and recombinant factor VIIa.

- other anticoagulants (e.g. thrombin inhibitors other than dabigatran, factor Xa inhibitorsincluding low-molecular weight heparin, vitamin K-antagonists, heparin). Thus idarucizumabwill not reverse the effects of other anticoagulants.

There are no data for the use of idarucizumab in pregnant women. Reproductive and developmentaltoxicity studies have not been performed, given the nature and the intended clinical use of themedicinal product. Praxbind may be used during pregnancy, if the expected clinical benefit outweighsthe potential risks.

It is unknown whether idarucizumab/metabolites are excreted in human milk.

There are no data on the effect of idarucizumab on fertility (see section 5.3).

Not relevant.

In a phase III study the safety of Praxbind has been evaluated in 503 patients, who had uncontrolledbleeding or required emergency surgery or procedures and were under treatment with Pradaxa(dabigatran etexilate), as well as in 224 volunteers in phase I studies. Furthermore, 359 patients wereenrolled in a global idarucizumab administration surveillance program to collect data on usage patternsin a real-world-setting. One paediatric patient was treated in the context of a paediatric safety trial.

No adverse reactions have been identified.

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.

There is no clinical experience with overdoses of idarucizumab.

The highest single dose of idarucizumab studied in healthy subjects was 8 g. No safety signals havebeen identified in this group.

Pharmacotherapeutic group: all other therapeutic products, antidotes, ATC code: V03AB37

Idarucizumab is a specific reversal agent for dabigatran. It is a humanised monoclonal antibodyfragment (Fab) that binds to dabigatran with very high affinity, approximately 300-fold more potentthan the binding affinity of dabigatran for thrombin. The idarucizumab-dabigatran complex ischaracterised by a rapid on-rate and extremely slow off-rate resulting in a very stable complex.

Idarucizumab potently and specifically binds to dabigatran and its metabolites and neutralises theiranticoagulant effect.

The pharmacodynamics of idarucizumab after administration of dabigatran etexilate were investigatedin 141 subjects in phase I studies, of which data for a representative subgroup of 6 healthy subjectsaged 45 to 64 years receiving a dose of 5 g as intravenous infusion are presented. The median peakdabigatran exposure in the investigated healthy subjects was in the range of a twice dailyadministration of 150 mg dabigatran etexilate in patients.

Effect of idarucizumab on the exposure and anticoagulant activity of dabigatran

Immediately after the administration of idarucizumab, the plasma concentrations of unbounddabigatran were reduced by more than 99%, resulting in levels with no anticoagulant activity.

The majority of the patients showed sustained reversal of dabigatran plasma concentrations up to12 hours (≥ 90%). In a subset of patients, recurrence of plasma levels of unbound dabigatran andconcomitant elevation of clotting times was observed, possibly due to re-distribution of dabigatranfrom the periphery. This occurred 1-24 hours after administration of idarucizumab mainly attimepoints ≥ 12 hours.

Figure 1. Plasma-levels of unbound dabigatran in the representative group of healthy subjects(administration of idarucizumab or placebo at 0 h)

Dabigatran prolongs the clotting time of coagulation markers such as dTT, TT, aPTT and ECT, whichprovide an approximate indication of the anticoagulation intensity. A value in the normal range afteradministration of idarucizumab indicates that a patient is no longer anticoagulated. A value above thenormal range may reflect residual active dabigatran or other clinical conditions e.g., presence of otheractive substances or transfusion coagulopathy. These tests were used to assess the anticoagulant effectof dabigatran. A complete and sustained reversal of dabigatran-induced clotting time prolongation wasobserved immediately after the idarucizumab infusion, lasting over the entire observation period of atleast 24 h.

Figure 2. Reversal of dabigatran-induced clotting time prolongation determined by dTT in therepresentative group of healthy subjects (administration of idarucizumab or placebo at 0 h)

Figure 3. Reversal of dabigatran-induced clotting time prolongation determined by ECT in therepresentative group of healthy subjects (administration of idarucizumab or placebo at 0 h)

Thrombin generation parameters

Dabigatran exerts pronounced effects on parameters of the endogenous thrombin potential (ETP).

Idarucizumab treatment normalised both thrombin lag time ratio and time to peak ratio to baselinelevels as determined 0.5 to 12 hours after the end of the idarucizumab infusion. Idarucizumab alonehas shown no procoagulant effect measured as ETP. This suggests that idarucizumab has noprothrombotic effect.

Re-administration of dabigatran etexilate24 hours after the idarucizumab infusion, re-administration of dabigatran etexilate resulted in expectedanticoagulant activity.

Preclinical pharmacodynamics

A trauma model in pigs was performed using a blunt liver injury after dosing with dabigatran toachieve supratherapeutic concentrations of about 10-fold of human plasma levels. Idarucizumabeffectively and rapidly reversed the life-threatening bleeding within 15 min after the injection. All pigssurvived at idarucizumab doses of approximately 2.5 and 5 g. Without idarucizumab, the mortality inthe anticoagulated group was 100%.

Three randomised, double-blind, placebo-controlled phase I studies in 283 subjects (224 treated withidarucizumab) were conducted to assess the safety, efficacy, tolerability, pharmacokinetics andpharmacodynamics of idarucizumab, given alone or after administration of dabigatran etexilate. Theinvestigated population consisted of healthy subjects and subjects exhibiting specific populationcharacteristics covering age, body weight, race, sex and renal impairment. In these studies the doses ofidarucizumab ranged from 20 mg to 8 g and the infusion times ranged from 5 minutes to 1 hour.

Representative values for pharmacokinetic and pharmacodynamic parameters were established on thebasis of healthy subjects aged 45-64 years receiving 5 g idarucizumab (see sections 5.1 and 5.2).

One prospective, open-label, non-randomised, uncontrolled study (RE-VERSE AD) was conducted toinvestigate the treatment of adult patients who presented with dabigatran-related life-threatening oruncontrolled bleeding (group A) or who required emergency surgery or urgent procedures (group B).

The primary endpoint was the maximum percentage reversal of the anticoagulant effect of dabigatranwithin 4 hours after the administration of idarucizumab, based on central laboratory determination ofdTT or ECT. A key secondary endpoint was the restoration of haemostasis.

RE-VERSE AD included data for 503 patients: 301 patients with serious bleeding (group A) and202 patients requiring an urgent procedure/surgery (group B). Approximately half of the patients ineach group were male. The median age was 78 years and the median creatinine clearance (CrCl) was52.6 mL/min. 61.5% of patients in group A and 62.4% of patients in group B had been treated withdabigatran 110 mg twice daily.

Reversal was only evaluable for those patients showing prolonged coagulation times prior toidarucizumab treatment. Most patients in both groups A and B, achieved complete reversal of theanticoagulant effect of dabigatran (dTT: 98.7%; ECT: 82.2%; aPTT: 92.5% of evaluable patients,respectively) in the first 4 hours after administration of 5 g idarucizumab. Reversal effects wereevident immediately after administration.

Figure 4. Reversal of dabigatran-induced clotting time prolongation determined by dTT in patientsfrom the RE-VERSE AD study (N = 487)

Figure 5. Reversal of dabigatran-induced clotting time prolongation determined by ECT in patientsfrom the RE-VERSE AD study (N = 487)

Figure 6. Reversal of dabigatran-induced clotting time prolongation determined by aPTT in patientsfrom the RE-VERSE AD study (N = 486)

Restoration of haemostasis was achieved in 80.3% of evaluable patients who had serious bleeding andnormal haemostasis was observed in 93.4% of patients who required an urgent procedure.

Of the total 503 patients, 101 patients died; each of these deaths could be attributed either as acomplication of the index event or associated with co-morbidities. Thrombotic events were reported in34 patients (23 out of the 34 patients were not on antithrombotic therapy at the time of the event) andin each of these cases, the thrombotic event could be attributed to the underlying medical condition ofthe patient. Mild symptoms of potential hypersensitivity (pyrexia, bronchospasm, hyperventilation,rash or pruritus) were reported. A causal relationship to idarucizumab could not be established.

One paediatric patient was included in a single dose, open label, safety trial of intravenousadministration of idarucizumab. The trial enrolled paediatric patients from clinical trials withdabigatran etexilate for the treatment and secondary prevention of venous thromboembolism (VTE).

For inclusion, patients required rapid reversal of the anticoagulant effect of dabigatran. The patient(between 16-< 18 years old) was treated with dabigatran etexilate for secondary prevention of VTEdue to the presence of a clinical risk factor. A bleeding event required a surgical intervention andadequate haemostasis. Treatment with 5 g idarucizumab resulted in a rapid and complete reversal ofthe anticoagulant effect of dabigatran. The pharmacokinetics of idarucizumab and its effects onpharmacodynamics were consistent with data obtained in adults.

Serum samples from 283 subjects in phase I studies (224 volunteers treated with idarucizumab) and501 patients were tested for antibodies to idarucizumab before and after treatment. Pre-existingantibodies with cross-reactivity to idarucizumab were detected in approximately 12% (33/283) of thephase I subjects and 3.8% (19/501) of the patients. No impact on the pharmacokinetics or the reversaleffect of idarucizumab or hypersensitivity reactions were observed.

Treatment-emergent possibly persistent anti-idarucizumab antibodies with low titers were observed in4% (10/224) of the phase I subjects and 1.6% (8/501) of the patients suggesting a low immunogenicpotential of idarucizumab. In a subgroup of 6 phase I subjects, idarucizumab was administered asecond time, two months after the first administration. No anti-idarucizumab antibodies were detectedin these subjects prior to the second administration. In one subject, treatment-emergent anti-idarucizumab antibodies were detected after the second administration. Nine patients were re-dosedwith idarucizumab. All 9 patients were re-dosed within 6 days after the first idarucizumab dose. Noneof the patients re-dosed with idarucizumab tested positive for anti-idarucizumab antibodies.

The pharmacokinetics of idarucizumab were investigated in 224 subjects in phase I studies, of whichdata for a representative subgroup of 6 healthy subjects aged 45 to 64 years receiving a dose of 5 g asintravenous infusion are presented.

Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution.

Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steadystate (Vdss) was 8.9 L (geometric coefficient of variation (gCV) 24.8%).

Several pathways have been described that may contribute to the metabolism of antibodies. All ofthese pathways involve biodegradation of the antibody to smaller molecules, i.e. small peptides oramino acids, which are then reabsorbed and incorporated in the general protein synthesis.

Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initialhalf-life (t1/2) of 47 minutes (gCV 11.4%) and a terminal t1/2 of 10.3 h (gCV 18.9%). After intravenousadministration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within acollection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the doseis assumed to be eliminated via protein catabolism, mainly in the kidney.

After treatment with idarucizumab proteinuria has been observed. The transient proteinuria is aphysiologic reaction to renal protein overflow after bolus/short term application of 5 g idarucizumabintravenously. The transient proteinuria usually peaked about 4 h after idarucizumab administrationand normalised within 12-24 hours. In single cases the transient proteinuria persisted for more than24 hours.

In phase I studies Praxbind has been investigated in subjects with a creatinine clearance ranging from44 to 213 mL/min. Subjects with a creatinine clearance below 44 mL/min have not been studied inphase I. Depending on the degree of renal impairment the total clearance was reduced compared tohealthy subjects, leading to an increased exposure of idarucizumab.

Based on pharmacokinetic data from 347 patients with different degrees of renal function (median

CrCl 21-99 mL/min) it is estimated that mean idarucizumab exposure (area under the concentration-time curve (AUC0-24h)) increases by 38% in patients with mild (CrCl 50-< 80 mL/min), by 90% inmoderate (30-< 50 mL/min) and by 146% in severe (0-< 30 mL/min) renal impairment. Sincedabigatran is also excreted primarily via the kidneys, increases in the exposure to dabigatran are alsoseen with worsening renal function.

Based on these data and the extent of reversal of the anticoagulant effect of dabigatran in patients,renal impairment does not impact the reversal effect of idarucizumab.

An impact of hepatic impairment, assessed by hepatic injury as determined by elevated liver functiontests, on the pharmacokinetics of idarucizumab has not been observed.

Idarucizumab has been studied in 58 patients with varying degrees of hepatic impairment. Comparedto 272 patients without hepatic impairment, the median AUC of idarucizumab was changed by -6%,37% and 10% in patients with AST/ALT elevations of 1 to < 2 times the upper limit of normal (ULN)(N = 34), 2 to < 3 times the ULN (N = 3) and > 3 times the ULN (N = 21), respectively. Based onpharmacokinetic data from 12 patients with liver disease, the AUC of idarucizumab was increased by10% as compared to patients without liver disease.

Elderly/Gender/Race

Based on population pharmacokinetic analyses, age, gender and race do not have a clinicallymeaningful effect on the pharmacokinetics of idarucizumab.

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies of up to4 weeks in rats and 2 weeks in monkeys. Safety pharmacology studies have demonstrated no effectson the respiratory, central nervous or cardiovascular system.

Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not beenperformed. Based on its mechanism of action and the characteristics of proteins no carcinogenic orgenotoxic effects are anticipated.

Studies to assess the potential reproductive effects of idarucizumab have not been performed. Notreatment-related effects have been identified in reproductive tissues of either sex during repeat doseintravenous toxicity studies of up to 4 weeks in the rat and 2 weeks in monkeys. Additionally, noidarucizumab binding to human reproductive tissues was observed in a tissue cross-reactivity study.

Therefore, preclinical results do not suggest a risk to fertility or embryo-fetal development.

No local irritation of the blood vessel was observed after i.v. or paravenous administration ofidarucizumab. The idarucizumab formulation did not produce haemolysis of human whole bloodin vitro.

sodium acetate trihydrate (E262)acetic acid (E260, for pH adjustment)sorbitol (E420)polysorbate 20 (E432)water for injections

This medicinal product must not be mixed with other medicinal products.

4 years.

After opening the vial, chemical and physical in-use stability of idarucizumab has been demonstratedfor 6 hours at room temperature (up to 30 °C).

From a microbiological point of view, unless the method of opening precludes the risk of microbialcontamination, the medicinal product shall be used immediately after opening. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

Store in the original package in order to protect from light.

Prior to use, the unopened vial may be kept at room temperature (up to 30 °C) for up to 48 hours, ifstored in the original package in order to protect from light. The solution should not be exposed tolight for more than 6 hours (in unopened vial and/or in-use).

For storage conditions after opening of the medicinal product, see section 6.3.

50 mL solution in a glass vial (type I glass), with a butyl rubber stopper, an aluminium cap and a labelwith integrated hanger.

Pack size of 2 vials.

Parenteral medicinal products such as Praxbind should be inspected visually for particulate matter anddiscoloration prior to administration.

Praxbind must not be mixed with other medicinal products. A pre-existing intravenous line may beused for administration of Praxbind. The line must be flushed with sodium chloride 9 mg/ml (0.9%)solution for injection prior to and at the end of infusion. No other infusion should be administered inparallel via the same intravenous access.

Praxbind is for single-use only and does not contain preservatives (see section 6.3).

No incompatibilities between Praxbind and polyvinyl chloride, polyethylene or polyurethane infusionsets or polypropylene syringes have been observed.

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

Boehringer Ingelheim International GmbH

Binger Str. 17355216 Ingelheim am Rhein

Germany

EU/1/15/1056/001

Date of first authorisation: 20 November 2015

Date of latest renewal: 27 July 2020

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

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