This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Coagadex 250 IU powder and solvent for solution for injection.

Coagadex 500 IU powder and solvent for solution for injection.

2. Qualitative and quantitative composition

Each vial contains nominally 250 IU or 500 IU human coagulation factor X.

Coagadex contains approximately 100 IU/mL human coagulation factor X after reconstitution with 2.5 mL (250 IU) or 5 mL (500 IU) sterilised water for injections.

Produced from the plasma of human donors.

Excipients with known effect:

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection.

Powder vial containing white or off-white powder.

Solvent vial containing clear colourless liquid.

4. Clinical particulars
4.1 Therapeutic indications

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

Coagadex is indicated in all age groups

4.2 Posology and method of administration

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

Posology

The dose and duration of the treatment depend on the severity of the factor X deficiency (i.e. the patient's baseline 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-threatening bleeding 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 expressed as 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 appropriate dose 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 their pharmacokinetic (e.g. half-life, in vivo recovery) and clinical responses to Coagadex. Although the dose can be 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 should be 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. Judge each individual bleed on its own severity.

For secondary prophylaxis against re-bleeding or short-term prophylaxis prior to anticipated physical activity or 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 be monitored at intervals, especially in the first weeks of therapy or after dosage changes. Adjust dosage regimen 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 data available on routine prophylaxis in paediatric patients aged >12 to <18 years. 25 IU/kg twice weekly is the proposed starting dose for prophylaxis in patients >12 years of age with dose levels and dosing intervals to be adjusted as clinically indicated. Depending on individual clinical response, longer intervals, e.g. once weekly, 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 control of 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 the subject 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 after surgery, to ensure that haemostatic levels are obtained and maintained.

Elderly

No dose adjustment is necessary.

Renal impairment

No dose adjustment is necessary.

Hepatic impairment

No dose adjustment is necessary.

Paediatric population (less than 12 years of age)

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

For secondary prophylaxis against re-bleeding or short-term prophylaxis prior to anticipated physical activity or 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 be monitored at intervals, especially in the first weeks of therapy or after dosage changes. Adjust dosage regimen to clinical response and trough levels of Factor X of at least 5 IU/dL. Some patients may achieve desired 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 of treatment 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 estimated using 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 the subject 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 after surgery, to ensure that haemostatic levels are obtained and maintained.

Method of administration

Intravenous use.

After reconstitution, the product should be administered by the intravenous route at a suggested rate of 10 mL/min, but no 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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Hypersensitivity

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

Inhibitors

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

In general, all patients treated with Coagadex should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If expected factor X activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor X inhibitor concentration.

Transmissible Agents

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

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-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.

It is strongly recommended that every time that Coagadex is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Sodium Content

Coagadex contains up to 0.4 mmol/mL (9.2 mg/mL) of sodium. To be taken into consideration for patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

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

Fertility

Animal reproduction studies have not been conducted with Coagadex.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

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

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely with treatment of other 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 clinical trials.

Tabulated list of adverse reactions

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 (≥1/10 subjects); 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.

List of adverse reactions (ADRs) in 27 treated subjects

MedDRA System Organ Class

Adverse reaction

Frequency

Musculoskeletal and connective tissue disorders

Back pain

Common

General disorders and administration site conditions

Infusion site erythema

Fatigue

Infusion site pain

Common

Paediatric population

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

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

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

One case of accidental overdose was reported in the clinical trials, in which a subject received approximately 80 IU/kg Coagadex to treat a bleed. No adverse events were reported relating to this overdose. There is a potential for thromboembolism with overdose.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-haemorrhagics, vitamin K and other haemostatics, coagulation factor X, ATC code: B02BD13.

Mechanism of action

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) by the cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with factor Va on a phospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in the presence of calcium ions. Thrombin then acts upon soluble fibrinogen and factor XIII to generate a cross-linked fibrin clot.

Pharmacodynamic effects

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.

Clinical efficacy

In a multicentre, open-label, non-randomised clinical trial to evaluate the pharmacokinetics, safety and efficacy of 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 menorrhagic bleeding episodes.

The efficacy of Coagadex in treating bleeding episodes was assessed by the subject and/or investigator for each new bleeding episode, using a pre-determined bleed-specific ordinal rating scale of excellent, good, poor and unassessable. Of the 208 bleeding episodes treated with Coagadex, 187 bleeding episodes in 15 subjects were evaluated for efficacy. Ninety eight (53%) were major bleeding episodes, and 88 (47%) were minor bleeds (one bleed was not assessed). Coagadex was considered to be good (7%) or excellent (91%) in treating 98% of bleeding episodes. Of the 187 bleeding episodes in the efficacy analysis, 155 bleeds (83%) were treated with 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 recommended dose of 25 IU/kg Coagadex to treat a bleed was maintained during the study for 14 of the 16 subjects. The other 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 used by two subjects. One subject, aged 58 years, used 28 IU/kg once weekly for 8 weeks and, later, 25 IU/kg every 2 weeks for more than 5 months. The other subject, aged 22 years, used 24.6 IU/kg once weekly for 8.5 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 children aged less than 12 years of age. The mean age was 7.3 (range 2.6 to 11.9) years. Eight subjects had severe FX deficiency, the other had moderate deficiency. Four subjects were aged 0 to 5 years and five were aged 6 to 11 years inclusive. Routine prophylaxis was started with unit doses of 40-50 IU/kg and during the first 6 weeks trough levels of Factor X were measured to adjust the dosage 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 median prophylactic 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 and mean dose was 37.7 IU/kg (95% CI: 23.42, 51.91). The median dosing interval for all of the nine children was 3 days (range 2 to 8 days). Six children (66.7%) remained free of bleeds during routine prophylaxis. Three children (33.3%), one in the 0-5 years age group and two in the 6-11 years age group had a total of 10 bleeds due to epistaxes, trauma or menorrhagia. All were treated with a single infusion of Coagadex; mean and median doses 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 to 59 years with mild (n=2), moderate (n=1), and severe (n=2) disease, who underwent a total of seven surgical procedures.

For all surgical procedures, Coagadex was assessed as excellent (no post-operative bleeding, no requirement of blood transfusions, and blood loss was no more than 'as expected') in controlling blood loss during and after surgery. For major surgery, a median of 13 infusions (range 2 to 15 infusions) and a median cumulative dose of 181 IU/kg (range 45 to 210 IU/kg) were required to maintain haemostasis. For minor surgery, a median of 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.

5.2 Pharmacokinetic properties

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 of 25 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 baseline visit (n=16) and the Repeat PK assessment (n=15) gave an overall geometric mean IR of 2.07 IU/dL per IU/kg administered (n=31). Similarly, combining t½ values at the Baseline Visit and the Repeat PK assessment gave an overall geometric mean t½ of 29.36 hours. Systemic exposure to FX:C at the Repeat PK visit (at least 6 months later) was equivalent to that at baseline, since repeat/baseline ratios for all PK parameters were within the 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 of distribution (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 was 1.35 (21.7) mL/kg/hr.

Renal impairment

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

Hepatic impairment

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

Elderly

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

Paediatric population

Pharmacokinetic studies have not been performed in children under the age of 12 years. The study in young children (see section 5.1) measured incremental recovery at 30 min (IR30min) after the first dose and after the last dose in the study (approximately 6 months later) (see section 5.1) Combining IR30min values for FX:C at the baseline visit (n=9) and the Repeat PK assessment (n=9) gave an overall geometric mean IR of 1.74 (range 1.3-2.2) 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) was 1.53range 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 dosage regimen and 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.

5.3 Preclinical safety data

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 been conducted since human plasma coagulation factor X (as contained in Coagadex) is an endogenous protein.

6. Pharmaceutical particulars
6.1 List of excipients

Powder

Citric acid

Sodium hydroxide (for pH adjustment)

Disodium phosphate dihydrate

Sodium chloride

Sucrose

Solvent

Water for injections

6.2 Incompatibilities

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

The product should only be reconstituted using the Mix2Vial that is provided in the pack.

6.3 Shelf life

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 to 25°C +/-2°C).

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

Immediate containers

Powder vial: 250 IU or 500 IU of human coagulation factor X in a type I glass vial stoppered with a halobutyl rubber 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 an overseal.

Transfer Device (Mix2Vial).

Pack sizes

Coagadex 250 IU

1 vial 250 IU human coagulation factor X powder for solution for injection

1 vial 2.5 mL water for injections

1 Transfer Device (Mix2Vial)

Coagadex 500 IU

1 vial 500 IU human coagulation factor X powder for solution for injection

1 vial 5 mL water for injections

1 Transfer Device (Mix2Vial)

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The powder should only be reconstituted with the water for injections provided in the pack. The 250 IU and 500 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 30°C) prior to the removal of the snap-off cap closure from the powder vial.

Step 1: Remove the cap from the powder vial and clean the top of the stopper with an 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 push straight down until the spike penetrates the rubber stopper and snaps into place.

Remove the plastic outer packaging from the transfer device and discard it, taking care 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 down until the spike penetrates the rubber stopper and snaps into place.

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

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

A clear or slightly pearl-like solution should be obtained, usually in less than 1 minute (5 minutes maximum).

Step 5: Separate the empty solvent vial and blue part from the clear part by unscrewing anti-clockwise.

Draw air into the syringe by pulling the plunger to the volume of water added. Connect the syringe to 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 the syringe.

Disconnect the filled syringe from the device.

Follow the normal safety practices to administer the medicine.

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

The transfer device supplied with the product is sterile and cannot be used more than once. When the reconstitution 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 that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discolouration prior to administration.

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

7. Marketing authorisation holder

BPL Bioproducts Laboratory GmbH

Dornhofstraße, 63263 Neu-Isenburg

Germany

8. Marketing authorisation number(s)

EU/1/16/1087/001

EU/1/16/1087/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 16 March 2016

10. Date of revision of the text

03/2019

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu