4.1. Therapeutic indications

Long term prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency.

Treatment of breakthrough bleeding episodes during regular prophylaxis.

NovoThirteen can be used for all age groups.

4.2. Posology and method of administration

Treatment should be initiated under the supervision of a doctor experienced in the treatment of rare bleeding disorders. The congenital factor XIII A-subunit deficiency should be confirmed by appropriate diagnostic procedures including factor XIII activity and immunoassay and if applicable genotyping.

Posology

The potency of this medicinal product is expressed in international units (IU).

Although expressed in the same unit (IU), the posology of NovoThirteen is different from the dosing schedule of the other FXIII containing products (see section 4.4).

Prophylaxis

The recommended dose for prophylactic treatment is 35 IU/kg body weight once monthly (every 28 days ± 2 days), administered as an intravenous bolus injection.

Treatment of bleeds

If a breakthrough bleed occurs during regular prophylaxis, it is recommended to treat with a single dose of 35 IU/kg body weight administered as an intravenous bolus injection.

If bleeds occur in a patient who is not on regular prophylaxis, a single dose of 35 IU/kg body weight as an intravenous bolus injection may be administered at the discretion of the treating physician in order to control the bleed (see section 4.4 'On-demand treatment').

Based on the actual concentration of NovoThirteen, the volume (in millilitres) to be administered to patients weighing at least 24 kg can be calculated from the formula below:

Dose volume in ml = 0.042 x subject body weight (kg)

Dose adjustment can be considered necessary by the physician in certain situations where the prevention of bleeding is not appropriately covered by the recommended 35 IU/kg/month dose.

This dose adjustment should be based on FXIII activity levels.

Monitoring NovoThirteen activity levels using a standard FXIII activity assay is recommended.

Minor surgery

It is recommended that minor surgery, including tooth extraction is done in connection with prophylactic dosing. Otherwise, an additional dose can be given if needed. The dose should be based on the FXIII activity levels.

Paediatric population

No dose adjustment is required when NovoThirteen is used in paediatric patients and the dose of 35 IU/kg body weight should be used for both prophylaxis and treatment of bleeds (see section 5.2 'Paediatric population').

However, if the paediatric patient weighs less than 24 kg, the reconstituted NovoThirteen should be further diluted with 6 ml of sodium chloride 0.9%, solution for injection to handle the dosing of small children (see section 6.6 'Special precautions for disposal and other handling – Use in the paediatric population').

The dose volume for small children can then be calculated by using the below formula:

Dose volume in ml = 0.117 x body weight in kilograms.

The calculation of the correction factor 0.117 is related to the exact quantity of the product and not the nominal value of the product.

Currently available data are described in sections 4.8, 5.1 and 5.2.

Method of administration

Intravenous use.

The preparation should be administered immediately after reconstitution as a slow bolus intravenous injection at a rate not higher than 2 ml/minute, see section 4.4.

For instructions on reconstitution of the medicinal product prior to 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

Considering that the posology and the FXIII concentration in NovoThirteen are different from those of the other FXIII containing products, careful attention should be paid to the calculation of the appropriate dose for the individual patient (see dose volume formula provided in section 4.2).

Traceability

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

Congenital FXIII B-subunit deficiency

In patients with FXIII deficiency, NovoThirteen is not effective if used for monthly prophylactic treatment of bleeding in patients with congenital FXIII B-subunit deficiency. FXIII B-subunit deficiency is associated with a much reduced half-life of the administered pharmacologically active A-subunit. The subunit deficiency of patients should be determined prior to treatment by appropriate diagnostic procedures including factor XIII activity and immunoassay and if applicable genotyping.

On-demand treatment

On-demand treatment of patients not on prophylactic treatment was not studied in clinical development programme.

Allergic reactions

As NovoThirteen contains a recombinant protein it may cause allergic reactions including anaphylactic reactions. Patients should be informed of the early signs of hypersensitivity reactions (including hives, generalised urticaria, tightness of the chest, wheezing, hypotension) and anaphylaxis. If allergic or anaphylactic-type reactions occur, the administration should be immediately discontinued and further treatment with NovoThirteen should not be given.

Inhibitor formation:

Inhibitor formation to NovoThirteen therapy has not been detected in clinical trials. Inhibitors may be suspected in the event of lack of therapeutic response which is observed as bleeding or demonstrated by laboratory findings including FXIII activity that fails to reach expected levels. In the event that inhibitors are suspected analysis for antibodies should be performed.

Patients known to have neutralising antibodies to FXIII should not be treated with NovoThirteen without close monitoring.

Thromboembolic risk:

The reconstituted product must be handled in accordance with section 6.3.

Incorrect storage of the product after reconstitution must be avoided as it may result in loss of sterility and in increased levels of non-proteolytically activated NovoThirteen. Increased levels of activated NovoThirteen may increase the risk of thrombosis.

In case of predisposition to conditions of thrombosis, caution should be exercised due to the fibrin-stabilising effect of NovoThirteen. A stabilisation of the thrombus might occur, resulting in increased risk of vessel occlusions.

Hepatic impairment

Patients with hepatic impairment have not been studied. NovoThirteen may not be effective in patients with hepatic impairment if the hepatic impairment is severe enough to result in decreased levels of FXIII B-subunits. FXIII activity levels should be monitored in patients with severe hepatic impairment.

Elderly patients

There is limited clinical experience in administering NovoThirteen to elderly patients with congenital FXIII deficiency.

Renal insufficiency

Patients with renal insufficiency requiring dialysis have not been studied in clinical trials.

Sodium content

The medicinal product contains less than 1 mmol sodium (23 mg) per injection, indicating that it is essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

There are no clinical data available on interaction between NovoThirteen and other medicinal products.

Based on the non-clinical study (see section 5.3) it is not recommended to combine NovoThirteen and recombinant activated FVII (rFVIIa).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no studies in pregnant women investigating drug associated risks. There are limited amount of data from the clinical use of NovoThirteen in pregnant women and available data do not show any negative effects on the health of the foetus/new-born child or for the pregnant woman. The use of NovoThirteen may be considered during pregnancy only if clearly indicated.

Animal reproduction studies have not been conducted with NovoThirteen (see section 5.3).

Breast-feeding

It is unknown whether rFXIII is excreted in human breast milk. The excretion of rFXIII in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with NovoThirteen should be made taking into account the benefit of breast-feeding to the child and the benefit of NovoThirteen therapy to the mother.

Fertility

No effects on reproductive organs have been seen in non-clinical studies. There are no human data on potential effects on fertility.

4.7. Effects on ability to drive and use machines

NovoThirteen has no influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most frequent adverse reaction is 'headache' reported in 37% of patients.

Tabulated list of adverse reactions

In clinical trials, NovoThirteen has been administered to 82 patients with congenital factor XIII A- subunit deficiency (3112 doses of NovoThirteen).

Frequency descriptions of all adverse reactions identified from 82 patients with congenital FXIII deficiency exposed in clinical trials are presented in the below table by system organ class.

Frequency categories are defined according to the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Common (≥ 1/100 to < 1/10)

Leucopenia and aggravated neutropenia

Nervous system disorders

Common (≥ 1/100 to < 1/10)

Headache

Musculoskeletal and connective tissue disorders

Common (≥ 1/100 to < 1/10)

Pain in extremity

General disorders and administration site conditions

Common (≥ 1/100 to < 1/10)

Injection site pain

Investigations

Common (≥ 1/100 to < 1/10)

Common (≥ 1/100 to < 1/10)

Non-neutralising antibodies

Fibrin D-dimer increased

Description of selected adverse reactions

One patient with pre-existing neutropenia experienced a mild aggravation of neutropenia and leucopenia during treatment with NovoThirteen. Following discontinuation of NovoThirteen the patient's neutrophil count returned to levels similar to those prior to treatment with NovoThirteen.

Non-neutralising antibodies have been seen in 4 of the 82 exposed patients with congenital FXIII deficiency. The four events of non-neutralising antibodies occurred in patients below the age of 18 (age 8, 8, 14 and 16). These antibodies were seen at the start of treatment with NovoThirteen. All 4 patients received at least 2 doses of NovoThirteen. 3 of the patients discontinued the study and returned to their previous treatment. One continued to receive rFXIII and the antibodies decreased below detection limit. The antibodies had no inhibitory action and the patients did not experience any adverse events or bleeding in association with these antibodies. Antibodies were transient in all patients.

One healthy subject developed low-titer, transient non-neutralising antibodies after receiving the first dose of NovoThirteen. The antibodies had no inhibitory activity, and the subject did not experience any adverse events or bleeding in association with these antibodies. The antibodies disappeared in the 6-month follow up.

In all cases, the non-neutralising antibodies were found to be of no clinical significance.

In a post-authorisation safety study transient non-neutralising antibodies were seen in a child with congenital FXIII deficiency after several years of treatment with NovoThirteen. No clinical findings were associated with these antibodies.

Paediatric population

21 patients were between the age of 6 to less than 18 years old and 6 patients were less than 6 years old (total of 986 exposures of NovoThirteen in paediatric subjects (less than 18 years old).

In clinical studies, adverse reactions were more frequently reported in patients aged from 6 to less than 18 years old than in adults. 3 patients (14%) aged between 6 and 18 years experienced serious adverse reactions in comparison to 0 patients over 18 years that experienced serious adverse reactions. Four cases of non-neutralising antibodies were reported at the start of the treatment in patients from 6 to 18 years of age. 3 of these patients discontinued the study due to the adverse reaction.

In patients below 6 years, no anti-rFXIII antibodies, no thromboembolic adverse events or other safety issues were reported.

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 national reporting system listed in Appendix V.

4.9. Overdose

In the reported cases of NovoThirteen overdose up to 2.3 times, no clinical symptoms have been observed.