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:

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. Each individual bleed should be judged 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 dose changes. Dose regimen should be adjusted 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

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. Each individual bleed should be judged 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 dose changes. Dose regimen should be adjusted 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:

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 intravenously 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

Traceability

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

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 human coagulation factor X 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.

Factor Xa inhibitors

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.

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.

Sodium content

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.

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 (see section 4.4).

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 (ADRs) 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.

Tabulated list of adverse reactions

MedDRA System Organ Class

Adverse reaction

Frequency

Musculoskeletal and connective tissue disorders

Back pain

Common

General disorders and administration site conditions

Infusion site erythema Infusion site pain Fatigue

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. However, there is a potential for thromboembolism with overdose which is likely to be associated with a reduced prothrombin time below the normal range. Careful clinical assessment by an experienced clinician is recommended with or without 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.