Leaflet COAGADEX 250UI / ml powder+solvent for injection

Coagadex 250 IU powder and solvent for solution for injection

Coagadex 500 IU powder and solvent for solution for injection

Coagadex 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU human coagulation factor X.

Coagadex contains approximately 100 IU/mL human coagulation factor X after reconstitution with 2.5 mLsterilised water for injections.

Coagadex 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU human coagulation factor X.

Coagadex contains approximately 100 IU/mL human coagulation factor X after reconstitution with 5 mLsterilised water for injections.

Produced from the plasma of human donors.

Coagadex contains up to 0.4 mmol/mL (9.2 mg/mL) of sodium.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder vial containing white or off-white powder.

Solvent vial containing clear colourless liquid.

Coagadex is indicated for the treatment and prophylaxis of bleeding episodes and for perioperativemanagement in patients with hereditary factor X deficiency.

Coagadex is indicated in all age groups

Treatment should be initiated under the supervision of a physician experienced in the treatment of rarebleeding disorders.

The dose and duration of the treatment depend on the severity of the factor X deficiency (i.e. the patient’sbaseline factor X level), on the location and extent of the bleeding and on the patient’s clinical condition.

Careful control of replacement therapy is especially important in cases of major surgery or life-threateningbleeding episodes.

Not more than 60 IU/kg daily should be administered in any age group.

In adults and adolescents at least 12 years of age, the expected in vivo peak increase in factor X level expressedas IU/dL (or % of normal) can be estimated using the following formulae:

Dose (IU) = body weight (kg) x desired factor X rise (IU/dL or % of normal) x 0.5

OR

Increase in factor X level (IU/dL or % of normal) = [total dose (IU)/body weight (kg)] x 2

The following examples assume the patient’s baseline factor X level is <1 IU/dL:

1. A dose of 2000 IU Coagadex administered to a 70 kg patient should be expected to result in a peak post-infusion factor X increase of 2000 x {[2 IU/dL]/[IU/kg]}/[70 kg] = 57 IU/dL (i.e. 57% of normal)2. A peak factor X level of 90% of normal is required in a 70 kg patient. In this situation, the appropriatedose would be:

70 kg x 90 IU/dL/{[2 IU/dL]/[IU/kg]} = 3150 IU.

The dose and frequency should be based on the individual clinical response. Patients may vary in theirpharmacokinetic (e.g. half-life, in vivo recovery) and clinical responses to Coagadex. Although the dose canbe estimated using the calculations above, whenever possible appropriate laboratory tests, such as serial factor

X assays, should be performed to guide dose adjustments.

Control of bleeding episodes

Adults and adolescents aged 12 years or more for treatment of bleeding episodes: 25 IU/kg Coagadex shouldbe injected when the first sign of bleeding occurs or just before the expected onset of menstrual bleeding.

Repeat at intervals of 24 hours until the bleed stops. Each individual bleed should be judged on its own severity.

For secondary prophylaxis against re-bleeding or short-term prophylaxis prior to anticipated physical activityor dental appointments: 25 IU/kg Coagadex should be injected and repeated as required.

Routine prophylaxis of bleeding episodes

Due to inter-and intra-patient variability, it is recommended that trough blood levels of Factor X should bemonitored at intervals, especially in the first weeks of therapy or after dose changes. Dose regimen should beadjusted to clinical response and trough levels of Factor X of at least 5 IU/dL.

There are limited data on the use of Coagadex for long periods of prophylaxis in adults. There are no dataavailable on routine prophylaxis in paediatric patients aged >12 to <18 years. 25 IU/kg twice weekly is theproposed starting dose for prophylaxis in patients >12 years of age with dose levels and dosing intervals tobe adjusted as clinically indicated. Depending on individual clinical response, longer intervals, e.g. onceweekly, might be adequate (see section 5.1).

Perioperative Management (Adults and adolescents aged at least 12 years of age)

Pre-surgery: calculate dose of Coagadex to raise plasma factor X levels to 70-90 IU/dL. The careful controlof dose and duration of treatment is especially important in cases of major surgery.

Required dose (IU) = body weight (kg) x desired factor X rise (IU/dL) x 0.5

The desired factor X rise is the difference between the patient’s plasma factor X level and the desired level,and based on the observed recovery of 2 IU/dL per IU/kg.

Example: to raise plasma factor X level from 15 IU/dL to 90 IU/dL in a 70 kg patient, the appropriate dose is:

70 x (90-15) x 0.5 = 2,625 IU.

Post-surgery: dose as necessary to maintain plasma factor X levels at a minimum of 50 IU/dL until thesubject is no longer at risk of bleeding due to surgery.

It is recommended that post-infusion plasma factor X levels are measured for each patient before and aftersurgery, to ensure that haemostatic levels are obtained and maintained.

No dose adjustment is necessary.

No dose adjustment is necessary.

No dose adjustment is necessary.

For on-demand control of bleeding in children aged less than 12 years: 30 IU/kg Coagadex should beinjected when the first sign of bleeding occurs. Repeat at intervals of 24 hours until the bleed stops. Eachindividual bleed should be judged on its own severity.

For secondary prophylaxis against re-bleeding or short-term prophylaxis prior to anticipated physical activityor dental appointments: 30 IU/kg Coagadex should be injected and repeated as required.

For routine prophylaxis of bleeding episodes in children aged less than 12 years: 40 IU/kg twice weekly.

Due to inter-and intra-patient variability, it is recommended that trough blood levels of Factor X should bemonitored at intervals, especially in the first weeks of therapy or after dose changes. Dose regimen should beadjusted to clinical response and trough levels of Factor X of at least 5 IU/dL. Some patients may achievedesired FX trough levels on once weekly prophylactic therapy (see section 5.1).

For perioperative management in children aged less than 12 years: Pre-surgery: calculate dose of

Coagadex to raise plasma factor X levels to 70-90 IU/dL. The careful control of dose and duration oftreatment is especially important in cases of major surgery.

The expected in vivo peak increase in factor X level expressed as IU/dL (or % of normal) can be estimatedusing the following formulae:

Dose (IU) = body weight (kg) x desired factor X rise (IU/dL or % of normal) x 0.6

OR

Increase in factor X level (IU/dL or % of normal) = [total dose (IU)/body weight (kg)] x 1.7

Post-surgery: dose as necessary to maintain plasma factor X levels at a minimum of 50 IU/dL until thesubject is no longer at risk of bleeding due to surgery.

It is recommended that post-infusion plasma factor X levels are measured for each patient before and aftersurgery, to ensure that haemostatic levels are obtained and maintained.

After reconstitution, the product should be administered intravenously at a suggested rate of 10 mL/min, butno more than 20 mL/min.

For home therapy, the patient should be given appropriate training and reviewed at intervals.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Allergic type hypersensitivity reactions, including anaphylaxis, are possible. Coagadex contains traces ofhuman proteins other than factor X. Patients should be informed of the early signs of hypersensitivityreactions including angioedema, infusion site inflammation (e.g. burning, stinging, erythema), chills, cough,dizziness, fever, flushing, generalised urticaria, headache, hives, hypotension, lethargy, musculoskeletalpains, nausea, pruritus, rash, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing. Ifany of these symptoms occur, they should be advised to discontinue use of the product immediately andcontact their physician. In case of shock, the current medical standards for shock treatment should beobserved.

The formation of neutralising antibodies (inhibitors) to factor X is a possible complication in the managementof individuals with factor X deficiency.

In general, all patients treated with human coagulation factor X should be carefully monitored for thedevelopment of inhibitors by appropriate clinical observations and laboratory tests. If expected factor Xactivity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay thatmeasures factor X inhibitor concentration.

Factor Xa inhibitors

Coagadex is likely to be counteracted by factor Xa inhibitors, direct or indirect. These antithrombotic agentsshould not be used in patients with factor X deficiency. Coagadex should not be used as an antidote to theeffects of direct oral anti-coagulants (DOACs) in patients who do not have factor X deficiency.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from humanblood or plasma include selection of donors, screening of individual donations and plasma pools for specificmarkers of infection and the inclusion of effective manufacturing steps for the inactivation/removal ofviruses. Despite this, when medicinal products prepared from human blood or plasma are administered, thepossibility of transmitting infective agents cannot be totally excluded. This also applies to unknown oremerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for thenon-enveloped viruses HAV and parvovirus B19.

Vaccination against hepatitis A and B in patients who regularly or repeatedly receive human plasma-derived

Factor X products may be warranted.

Coagadex contains up to 9.2 mg sodium per mL of reconstituted solution, equivalent to 0.0046% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Coagadex is likely to be counteracted by factor Xa inhibitors, direct or indirect (see section 4.4).

Due to the rarity of hereditary factor X deficiency, experience regarding the use of Coagadex during pregnancyand breast-feeding is not available. Therefore, Coagadex should be used during pregnancy only if clearlyindicated.

Due to the rarity of hereditary factor X deficiency, experience regarding the use of Coagadex during pregnancyand breast-feeding is not available. Therefore, Coagadex should be used during breast-feeding only if clearlyindicated.

Animal reproduction studies have not been conducted with Coagadex.

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

The adverse reactions (ADRs) that occurred in the highest frequency were infusion site erythema, infusion sitepain, fatigue, and back pain.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusionsite, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness,tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely with treatment ofother haemophilias and may in some cases have progressed to severe anaphylaxis (including shock).

Hypersensitivity reactions, allergic reactions, and anaphylaxis have not been reported in Coagadex clinicaltrials.

The following adverse reactions have been reported in clinical studies involving 27 patients treated with

Coagadex. Frequencies have been evaluated according to the following convention: very common (≥1/10subjects); common (≥1/100 to <1/10). Frequencies of uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to<1/1,000) or very rare (<1/10,000) cannot be estimated from the available data.

MedDRA System Organ Class Adverse reaction Frequency

Musculoskeletal and connective tissue disorders Back pain Common

General disorders and administration site conditions Infusion site erythema Common

Infusion site pain

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults (seesection 5.1).

For safety information with respect to transmissible agents, see section 4.4.

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 system listed in

Appendix V.

One case of accidental overdose was reported in the clinical trials, in which a subject received approximately80 IU/kg Coagadex to treat a bleed. No adverse events were reported relating to this overdose. However, thereis a potential for thromboembolism with overdose which is likely to be associated with a reduced prothrombintime below the normal range. Careful clinical assessment by an experienced clinician is recommended with orwithout use of the Wells score, clinical laboratory tests of haemostasis and appropriate ultrasound imaging.

Treatment of proven or suspected DVT should follow the usual procedures but with monitoring FX.

Pharmacotherapeutic group: Anti-haemorrhagics, vitamin K and other haemostatics, coagulation factor X,

ATC code: B02BD13.

Factor X is an inactive zymogen, which can be activated by factor IXa (via the intrinsic pathway) or by factor

VIIa (via the extrinsic pathway). Factor X is converted from its inactive form to the active form (factor Xa) bythe cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with factor Va on aphospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in thepresence of calcium ions. Thrombin then acts upon soluble fibrinogen and factor XIII to generate a cross-linked fibrin clot.

Coagadex is derived from human plasma and used as a replacement for the naturally existing coagulation factor

X in patients with hereditary factor X deficiency.

In a multicentre, open-label, non-randomised clinical trial to evaluate the pharmacokinetics, safety and efficacyof Coagadex, 16 subjects (aged 12 years and above) with moderate to severe hereditary factor X deficiency(FX:C < 5 IU/dL) received a dose of 25 IU/kg Coagadex to treat spontaneous, traumatic and menorrhagicbleeding episodes.

The efficacy of Coagadex in treating bleeding episodes was assessed by the subject and/or investigator foreach new bleeding episode, using a pre-determined bleed-specific ordinal rating scale of excellent, good, poorand unassessable. Of the 208 bleeding episodes treated with Coagadex, 187 bleeding episodes in 15 subjectswere evaluated for efficacy. Ninety eight (53%) were major bleeding episodes, and 88 (47%) were minorbleeds (one bleed was not assessed). Coagadex was considered to be good (7%) or excellent (91%) in treating98% of bleeding episodes. Of the 187 bleeding episodes in the efficacy analysis, 155 bleeds (83%) were treatedwith one infusion, 28 bleeds (15%) with two infusions, 3 bleeds (2%) with three infusions and 1 bleed (0.5%)with four infusions. The mean dose per infusion and total dose of Coagadex were 25.4 IU/kg and 30.4 IU/kg,respectively. Four bleeding episodes in two subjects were considered treatment failures. The recommendeddose of 25 IU/kg Coagadex to treat a bleed was maintained during the study for 14 of the 16 subjects. Theother two subjects used doses up to 30 IU/kg and 33 IU/kg.

A total of 184 infusions of Coagadex were given as a preventative measure. Routine prophylaxis was usedby two subjects. One subject, aged 58 years, used 28 IU/kg once weekly for 8 weeks and, later, 25 IU/kgevery 2 weeks for more than 5 months. The other subject, aged 22 years, used 24.6 IU/kg once weekly for8.5 months. Neither subject had any bleeds during these periods.

Prophylaxis of Bleeding Episodes

The third study evaluated the use of Coagadex in routine prophylaxis of bleeding episodes in nine childrenaged less than 12 years of age. The mean age was 7.3 (range 2.6 to 11.9) years. Eight subjects had severe FXdeficiency, the other had moderate deficiency. Four subjects were aged 0 to 5 years and five were aged 6 to 11years inclusive. Routine prophylaxis was started with unit doses of 40-50 IU/kg and during the first 6 weekstrough levels of Factor X were measured to adjust the dose regimen to maintain a trough level of at least 5

IU/dL. A total of 537 (mean 59.7 per subject) prophylactic infusions were administered. The medianprophylactic dose per infusion per subject was 39.60 IU/kg (mean 38.76 IU/kg), and ranged from 18.0 to 47.3

IU/kg. Median and mean doses per infusion in the four children less than 6 years of age were both 40.1 IU/kg(95% CI 30.70, 49.57) and in the five children 6 to 11 years of age inclusive, median dose was 39.6 IU/kg andmean dose was 37.7 IU/kg (95% CI: 23.42, 51.91). The median dose interval for all of the nine children was 3days (range 2 to 8 days). Six children (66.7%) remained free of bleeds during routine prophylaxis. Threechildren (33.3%), one in the 0-5 years age group and two in the 6-11 years age group had a total of 10 bleedsdue to epistaxes, trauma or menorrhagia. All were treated with a single infusion of Coagadex; mean and mediandoses 31.7 IU/kg (range 24.6 to 38.8 IU/kg) and all recorded efficacy ratings were categorized as excellent.

There were no adverse drug reactions in this study in children less than 12 years of age.

Surgical haemostasis

The safety and efficacy of Coagadex for perioperative management was evaluated in five subjects aged 14 to59 years with mild (n=2), moderate (n=1), and severe (n=2) disease, who underwent a total of seven surgicalprocedures.

For all surgical procedures, Coagadex was assessed as excellent (no post-operative bleeding, no requirementof blood transfusions, and blood loss was no more than ‘as expected’) in controlling blood loss during andafter surgery. For major surgery, a median of 13 infusions (range 2 to 15 infusions) and a median cumulativedose of 181 IU/kg (range 45 to 210 IU/kg) were required to maintain haemostasis. For minor surgery, a medianof 2.5 infusions (range 1 to 4 infusions) and a median cumulative dose of 89 IU/kg (range 51 to 127 IU/kg)were used to maintain haemostasis.

In a clinical study of Coagadex in subjects with severe or moderate factor X deficiency (basal FX:C <5 IU/dL),the pharmacokinetics of Coagadex were assessed in 16 subjects after administration of a nominal dose of25 IU/kg. Pharmacokinetic (PK) parameters were calculated from plasma factor X:C (one-stage clotting assay)activity measurements after subtraction of the pre-dose value. Combining IR values for FX:C at the baselinevisit (n=16) and the Repeat PK assessment (n=15) gave an overall geometric mean IR of 2.07 IU/dL per IU/kgadministered (n=31). Similarly, combining t½ values at the Baseline Visit and the Repeat PK assessment gavean overall geometric mean t½ of 29.36 hours. Systemic exposure to FX:C at the Repeat PK visit (at least6 months later) was equivalent to that at baseline, since repeat/baseline ratios for all PK parameters were withinthe range of 90% to 110%.

The mean (CV%) for incremental recovery was 2.08 (18.1). The mean (CV%) maximum plasma concentration(Cmax) was 0.504 (17.2) IU/mL.

The mean (CV%) for area under the curve (AUC 0-144h) was 17.1 (21.0) IU.hr/mL.

Human coagulation factor X is largely retained within the vascular compartment: mean apparent volume ofdistribution (Vss) was 56.3 (24.0) mL/kg.

The mean (CV%) half-life of human coagulation factor X was 30.3 (22.8) hr and clearance was1.35 (21.7) mL/kg/hr.

No pharmacokinetic studies have been conducted but there is no anticipated effect of gender or renal functionon the pharmacokinetic profile of Coagadex.

No pharmacokinetic studies have been conducted but there is no anticipated effect of gender or hepatic functionon the pharmacokinetic profile of Coagadex.

No pharmacokinetic studies have been conducted but there is no anticipated effect of age on thepharmacokinetic profile of Coagadex.

Pharmacokinetic studies have not been performed in children under the age of 12 years. The study inchildren (see section 5.1) measured incremental recovery at 30 min (IR30min) after the first dose and after thelast dose in the study (approximately 6 months later) (see section 5.1) Combining IR30min values for FX:C atthe baseline visit (n=9) and the Repeat PK assessment (n=9) gave an overall geometric mean IR of 1.74 (range1.3-2.2) IU/dL per IU/kg administered (n=9). For the subgroup aged 6-11 years (n=5), the geometric mean

IR30min was 1.91 (range 1.6 -2.2) IU/mL per IU/kg and for the youngest subgroup, 0-5 years (n=4) was1.53range 1.3-1.8) IU/mL per IU/kg.

Trough levels of FX:C were measured during the first 6 weeks of the study to individualise the dose regimenand to maintain a trough level of at least 5 IU/dL. During the dose-adjustment phase, two trough levels were<5 IU/dL but thereafter none were below this threshold.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology,single and repeat-dose toxicity, thrombogenicity and local tolerability.

No investigations on genotoxicity, carcinogenicity and reproductive or developmental toxitcity have beenconducted since human plasma coagulation factor X (as contained in Coagadex) is an endogenous protein.

Citric acid

Sodium hydroxide (for pH adjustment)

Disodium phosphate dihydrate

Sodium chloride

Sucrose

Water for injections

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

The product should only be reconstituted using the Mix2Vial that is provided in the pack (see section 6.6).

3 years.

After reconstitution, from a microbiological point of view, the product should be used immediately.

However, chemical and physical in-use stability has been demonstrated for 1 hour at room temperature (up to25°C +/-2°C).

Do not store above 30°C.

Do not freeze.

Keep container in the outer carton in order to protect it from light.

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

Immediate containers

Powder vial: 250 IU or 500 IU of human coagulation factor X in a type I glass vial stoppered with a halobutylrubber stopper, oversealed with a snap-off polypropylene cap and aluminium lacquered skirt.

Solvent vial: 2.5 mL or 5 mL solution in a type I glass vial sealed with a halobutyl rubber stopper and anoverseal.

Transfer Device (Mix2Vial).

Coagadex 250 IU1 vial 250 IU human coagulation factor X powder for solution for injection1 vial 2.5 mL water for injections1 Transfer Device (Mix2Vial)

Coagadex 500 IU1 vial 500 IU human coagulation factor X powder for solution for injection1 vial 5 mL water for injections1 Transfer Device (Mix2Vial)

Not all pack sizes may be marketed.

The powder should only be reconstituted with the water for injections provided in the pack. The 250 IU and500 IU presentations should be reconstituted using 2.5 mL and 5 mL water for injections, respectively.

Do not use the water for injections if signs of particulate matter are visible.

The vials should be brought to room temperature (not above 30oC) prior to the removal of the snap-off capclosure from the powder vial.

Step 1: Remove the cap from the powder vial and clean the top of the stopper withan alcohol swab.

Repeat this step with the solvent vial.

Peel back the top of the transfer device package but leave the device in the package.

Step 2: Place the blue end of the transfer device on the solvent vial and pushstraight down until the spike penetrates the rubber stopper and snaps into place.

Remove the plastic outer packaging from the transfer device and discard it, takingcare not to touch the exposed end of the device.

Step 3: Turn the solvent vial upside down with the transfer device still attached.

Place the clear end of the transfer device on the powder vial and push straight downuntil the spike penetrates the rubber stopper and snaps into place.

Step 4: The solvent will be pulled into the powder vial by the vacuum containedwithin it.

Gently swirl the vial to make sure the powder is thoroughly mixed. Do not shake thevial.

A colourless, clear or slightly opalescent solution should be obtained, usually in lessthan 1 minute (5 minutes maximum).

Step 5: Separate the empty solvent vial and blue part of the transfer device fromthe clear part by unscrewing anti-clockwise.

Take an empty syringe (not provided in the Coagadex pack) and draw air into it bypulling the plunger to match the volume of water added in step 4. Connect the syringeto the clear part of the transfer device and push the air into the vial.

Step 6: Immediately invert the vial of solution, which will be drawn into thesyringe.

Disconnect the filled syringe from the device.

Follow the normal safety practices to administer the medicinal product.

Note: If you have more than one vial to make up your dose, repeat steps 1 through 6 withdrawing thesolution in the vial into the same syringe.

The transfer device supplied with the product is sterile and cannot be used more than once. When thereconstitution process is complete, the used transfer device should be disposed of it in the ‘sharps box’.

The solution should be colourless, clear or slightly opalescent when administered. Do not use solutions thatare cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter anddiscolouration prior to administration.

Any unused product or waste material should be disposed of in accordance with local requirements.

Kedrion S.p.A. - Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca), Italy.

EU/1/16/1087/001

EU/1/16/1087/002

Date of first authorisation: 16 March 2016

Date of latest renewal: 17 March 2021

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

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