NovoThirteen

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
NovoThirteen 2500 IU powder and solvent for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial contains catridecacog (recombinant coagulation factor XIII) (rDNA): 2500 IU per 3 ml, after 
reconstitution corresponding to a concentration of 833 IU/ml. The specific activity of NovoThirteen is 
approximately 165 IU/mg protein. 
 
The active substance is produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA 
technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for solution for injection. 
 
The powder is white and the solvent is clear and colourless. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Long term prophylactic treatment of bleeding in patients with congenital factor XIII A-subunit 
deficiency. 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). 
 
The recommended dose is 35 IU/kg body weight (bw) once monthly (every 28 days ± 2 days), 
administered as an intravenous bolus injection. 
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 bw (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. 
 



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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 (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 section 4.8, 5.1 and 5.2. 
 
Method of administration 
Intravenous use. 
 
The preparation should be administered as a slow bolus intravenous injection at a rate not higher than 
2 ml/minute. 
 
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). 
 
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 
The on-demand treatment of acute bleeds or breakthrough bleeds with NovoThirteen was allowed per 
protocol in the late phase clinical development programme. One patient was treated on demand in a 
phase 3b extension study (F13CD-3720). Also, on-demand treatment is followed in a non-
interventional post-authorisation safety study (NN1841-3868). Until further results are available, 
alternative treatment should be considered in such situations. 
 
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. 



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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 clinical data on the use of NovoThirteen in pregnant women. Animal studies are 
insufficient with respect to reproductive toxicity (see section 5.3) as NovoThirteen has not been 
studied in pregnant animals. The risk to humans is not known. However, based on the therapeutic 
need the use of NovoThirteen may be considered during pregnancy. 
 
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 



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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 



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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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antihaemorrhagics, Blood Coagulation factor, ATC code: B02BD11. 
 
Mechanism of action 
In plasma, FXIII circulates as a heterotetramer [A2B2] composed of 2 FXIII A-subunits and 2 FXIII B-
subunits held together by strong non-covalent interactions. The FXIII B-subunit acts as a carrier 
molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When the FXIII A-
subunit is bound to the FXIII B-subunit [A2B2], the half-life of the FXIII A-subunit [A2] is prolonged. 
FXIII is a pro-enzyme (pro-transglutaminase), which is activated by thrombin in the presence of Ca2+. 
The enzymatic activity resides with the FXIII A-subunit. Upon activation, the FXIII A-subunit 
dissociates from the FXIII B-subunit and thereby exposes the active site of the FXIII A-subunit. The 
active transglutaminase cross-links fibrin and other proteins resulting in increased mechanical 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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strength and resistance to fibrinolysis of the fibrin clot and contributes to enhanced platelet and clot 
adhesion to the injured tissue. 
 
NovoThirteen is a recombinant coagulation factor XIII A-subunit produced in yeast cells 
(Saccharomyces cerevisiae) by recombinant DNA technology. It is structurally identical to the human 
FXIII A-subunit [A2]. NovoThirteen (A-subunit) binds to free human FXIII B-subunit resulting in a 
heterotetramer [rA2B2] with a similar half-life to endogenous [A2B2].  
 
Pharmacodynamic effects 
At present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII. 
The results of standard coagulation tests are normal, as it is the quality of the clot that is affected. A 
clot solubility assay is widely used as an indicator of FXIII deficiency, but the assay is qualitative, and 
when performed correctly the test is positive only when the FXIII activity in the sample is close to 
zero. 
 
NovoThirteen has been shown to have the same pharmacodynamic properties in plasma as 
endogenous FXIII. 
 
Clinical efficacy and safety 
A pivotal prospective, open-label, single-arm phase 3 trial (F13CD-1725) including 41 patients with 
FXIII A-subunit deficiency was conducted to investigate the haemostatic efficacy of rFXIII in patients 
with congenital FXIII deficiency as reflected by the rate of bleeding episodes requiring treatment with 
a FXIII-containing product. The dosing scheme used was 35 IU/kg/month (every 28 days ± 2 days). 
Five bleeding episodes requiring treatment with a FXIII-containing product have been observed in 
four patients during treatment with rFXIII in the trial. 
 
The mean rate of treatment-requiring bleeds was determined to 0.138 per subject year. In the primary 
endpoint analysis covering the referred period, the age-adjusted rate (number per subject year) of 
treatment-requiring bleeds during the rFXIII treatment period was 0.048/year (95% CI: 0.009 - 0.250; 
model-based estimate corresponding to the mean age of 26.4 years for the 41 patients). 
 
In the F13CD-1725 extension trial F13CD-3720, the age-adjusted rate of bleeds that required 
treatment with a FXIII-containing product was estimated to be 0.021 bleeds per subject year with a 
95% CI of [0.0062; 0.073] (model-based estimate corresponding to a mean age of the trial population 
of 31.0 years).  
 
The crude bleeding rates in the two trials, F13CD-1725 and F13CD-3720, not adjusted for age, were 
0.138 and 0.043 respectively, corresponding to a total of 13 bleeds over 223 subject-years and a 
pooled rate of 0.058.  
 
Paediatric population 
Analyses of data from paediatric patients included in clinical trials have not identified differences in 
treatment response according to age. 
 
Twenty-one children between the age of 6 to less than 18 years old and six children less than 6 years 
old have been treated with NovoThirteen for a total of 986 exposures.  
Children above 6 years were investigated through the pivotal phase 3 trial (F13CD-1725) and the  
extension study (F13CD-3720) assessing the safety of monthly replacement therapy with 
NovoThirteen. 
 
The 6 patients below 6 years were investigated through a single dose pharmacokinetic phase 3b trial 
(F13CD-3760) and then, included in the long-term follow-up trial (F13CD-3835) assessing the safety 
and the efficacy of monthly replacement therapy with NovoThirteen. No treatment requiring bleeding 
episodes have been detected in patients below 6 years during 17 years of cumulative follow-up, 
representing a total of 214 doses. The suggested dose of 35 IU/kg has shown to be appropriate to 
provide haemostatic coverage in this young population. 



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5.2 Pharmacokinetic properties 
 
The half-life of NovoThirteen was assessed in the F13CD-1725 trial from a limited blood sampling 
scheme at 1 hour, 14 and 28 days post dose. Based on FXIII activity measured by the Berichrom assay 
in patients with congenital FXIII deficiency, a geometric mean half-life of 11.8 days was estimated. 
This is in agreement with the elimination pharmacokinetics estimated from a clinical pharmacology 
trial in healthy subjects, which determined the half-life to be 11.8 days. In this trial the mean volume 
of distribution at steady state was 47 ml/kg, mean residence time was 15.5 days and mean clearance 
was 0.13 ml/kg. 
 
Paediatric population 
In a pharmacokinetic trial 6 children (age 1 to less than 6 years old) with congenital FXIII A-subunit 
deficiency were exposed to one single i.v. dose of NovoThirteen 35 IU/kg. The mean t½ of FXIII was 
approximately 15 days (range: 10 to 25 days). In this trial, the mean clearance in children was 
0.15 ml/h/kg.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology and 
repeated dose toxicity. All findings in the non-clinical safety programme have been related to 
expected exaggerated pharmacology (general thrombosis, ischaemic necrosis and ultimately 
mortality) of rFXIII and non-proteolytically activated recombinant FXIII at dose levels in excess 
(>48 fold) of the maximum recommended clinical dose of 35 IU/kg. 
 
A potential synergistic effect of combined treatment with rFXIII and rFVIIa in an advanced 
cardiovascular model in cynomolgus monkey resulted in exaggerated pharmacology (thrombosis and 
death) at a lower dose level than when administering the individual compounds. 
 
Animal reproductive or developmental toxicity studies have not been performed. No effects on 
reproductive organs were noted in the repeated dose toxicity studies. 
Genotoxic potential or carcinogenicity has not been studied since rFXIII is an endogenous protein. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder: 
Sodium chloride 
Sucrose 
Polysorbate 20 
L-histidine 
Hydrochloric acid (for pH-adjustment) 
Sodium hydroxide (for pH-adjustment) 
 
Solvent: 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products. 
Following reconstitution the product should be administered separately and not mixed with infusion 
solutions nor be given in a drip. 
 



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6.3 Shelf life 
 
2 years. 
 
After reconstitution, the medicinal product should be used immediately due to the risk of 
microbiological contamination.  
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C–8°C). 
Store in the original package in order to protect from light. 
Do not freeze. 
For storage conditions of the reconstituted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Powder (2500 IU) in a vial (glass type I) with rubber stopper (chlorobutyl) and 3.2 ml solvent in a vial 
(glass type I) with rubber stopper (bromobutyl) and a vial adapter for reconstitution. 
Pack size of 1. 
 
6.6 Special precautions for disposal and other handling 
 
NovoThirteen user instructions 
To reconstitute and administer this product the following tools are needed: a 10 ml syringe or a 
syringe of a convenient size according to injection volume, alcohol swabs, the included vial adapter 
and an infusion set (tubing, butterfly needle). 
 
Preparing the solution 
 
Always use an aseptic technique. Before starting, the hands should be washed. Bring the powder and 
solvent vials to a temperature not above 25°C by holding them in the hands. Clean the rubber stoppers 
on the vials with alcohol swabs and allow them to dry before use. 
 
The product is reconstituted using the vial adapter included. 
Attach the vial adapter to the solvent vial (water for injections). Take care not to touch the spike on 
the vial adapter. 
 
Pull the plunger to draw in a volume of air equal to the total amount of solvent in the solvent vial. 
 
Screw the syringe tightly onto the vial adapter on the solvent vial. Inject air into the vial by pushing 
the plunger until you feel a clear resistance. 
 
Hold the syringe with the solvent vial upside down. Pull the plunger to draw the solvent into the 
syringe. 
 
Remove the empty solvent vial by tipping the syringe with the vial adapter. 
 
Click the vial adapter, still attached to the syringe onto the powder vial. Push the plunger slowly to 
inject the solvent into the powder vial. Make sure not to aim the stream of solvent directly at the 
powder as this will cause foaming. 
 
Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause 
foaming. NovoThirteen should be inspected visually for extraneous (for any foreign) particulate 
matter and discoloration prior to administration. In the event of either being observed, discard the 
medicinal product.  
 



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Reconstituted NovoThirteen is a clear, colourless solution. 
 
If a larger dose is needed, repeat the procedure in a separate syringe until the required dose is reached. 
 
If the patient weighs less than 24 kg, the reconstituted NovoThirteen should be diluted with 6 ml of 
sodium chloride 0.9%, solution for injection (refer to the section Use in the paediatric population for 
further detailed instructions on the dilution step).  
 
Important information 
 
Once prepared, NovoThirteen for injection should be used immediately. 
 
Injecting the solution 
 
Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have 
been pushed out by the pressure in the vial). Hold the syringe with the vial upside down and pull the 
plunger to draw up the amount calculated for the injection. 
 
Unscrew the vial adapter with the vial. 
 
The product is now ready for injection. 
 
Safely dispose of the syringe, vial adapter, infusion set and vials. Any unused medicinal product or 
waste material should be disposed of in accordance with local requirements. 
 
Use in the paediatric population 
 
Dilution of the reconstituted product with sodium chloride 0.9%, solution for injection 
 
If the paediatric patient weighs less than 24 kg, the reconstituted NovoThirteen should be diluted with 
6 ml of sodium chloride 0.9%, solution for injection to be able to handle the dosing of small children 
(see section 4.2 ‘Posology and method of administration – Paediatric population’). 
 
To dilute the reconstituted NovoThirteen the following tools are needed: a vial containing sodium 
chloride 0.9%, solution for injection, a 10 ml syringe and alcohol swabs. 
 
General instructions for dilution 
The dilution should be performed in accordance with aseptic rules.  
Carefully draw exactly 6 ml sodium chloride 0.9%, solution for injection, into the 10 ml syringe. 
Slowly inject the 6 ml sodium chloride 0.9%, solution for injection, into the reconstituted 
NovoThirteen vial. 
Gently swirl the vial to mix the solution. 
The diluted solution is a clear, colourless solution. Check the injection solution for particulate matter 
and for discolouration. If either is noticed, please discard. 
 
After dilution proceed to the step ‘Injecting the solution’. 
 
Any residual material of the diluted product has to be discarded immediately. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 



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8. MARKETING AUTHORISATION NUMBER  
 
EU/1/12/775/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 03 September 2012 
Date of latest renewal:  
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/. 

 

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


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ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE  

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



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A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substance  
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
Novo Nordisk A/S 
Hagedornsvej 1 
DK-2820 Gentofte 
Denmark 
 
Name and address of the manufacturer responsible for batch release 
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.  
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or within 60 days 
as a result of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 



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The Marketing Authorisation Holder (MAH) shall ensure that, at launch, a letter is sent to all 
expected and actual prescribers of NovoThirteen with an Educational Pack containing the following: 
1. Physician brochure 
2. Patient brochure 
 
Both documents are to be used as part of an educational plan aiming to minimise risks of medication 
errors, risk of thromboembolic events due to increased levels of non-proteolytically activated rFXIII 
in connection with incorrect storage, and risk of off-label use for treatment of breakthrough bleeding. 
The MAH should ensure harmonisation between terminology used in the brochures and the product 
information. 
 
The physician brochure should contain the following key elements and item: 
• Indication of the product 
• The risks of off-label use within FXIII congenital deficiency 
• Appropriate diagnostic procedures to confirm FXIII A-subunit deficiency 
• Warning of the difference of both posology and concentration between NovoThirteen and other 

FXIII containing products (the recommended dose of NovoThirteen is 35 IU/kg body weight 
(bw) once monthly, administered as an intravenous bolus injection. The dose volume in 
millilitres should be calculated based on body weight for each patient using the following 
formula: Dose volume in ml = 0.042 x subject bw (kg) if bw > 24 kg or dose volume in 
ml = 0.117 x bw (kg) if bw < 24 kg). 

• Correct handling and the risks associated with mishandling 
• Embolic and thrombotic events including the increased risk of vessel occlusion in patients at 

risk of thrombosis 
• What to do in the event of incorrect storage, thrombosis or embolism 
• Contraindication of hypersensitivity 
• Warning and precautions regarding anaphylaxis 
• The importance of collecting safety data and how to enrol patients in the PASS and other 

registries 
• Distribution and use of the patient brochure and the need to ensure that the patient has read and 

understood the brochure 
• Summary of Product Characteristics. 
 
The patient brochure, to be distributed to patients by the prescribers, should contain the following key 
elements and item: 
• Indication of the product 
• The risks of off-label use within FXIII congenital deficiency 
• How to safely store, handle, reconstitute and administer the product 
• The risks associated with incorrect storage and mishandling 
• How to recognise the potential side effects (thrombosis and embolism)  
• What to do in the event of incorrect storage, thrombosis or embolism 
• Package Leaflet. 
 
The Marketing Authorisation Holder must implement this educational plan nationally, prior to 
marketing. The final content, format and distribution modalities of both documents should be agreed 
with the national competent authority in each Member State. 
 



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 



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A. LABELLING 
 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NovoThirteen 2500 IU powder and solvent for solution for injection 
catridecacog (rDNA factor XIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One vial contains catridecacog (recombinant coagulation factor XIII) (rDNA) 2500 IU per 3 ml, after 
reconstitution corresponding to a concentration of 833 IU/ml. 
 
 
3. LIST OF EXCIPIENTS 
 
Powder: Sodium chloride, sucrose, polysorbate 20, L-histidine, hydrochloric acid, sodium hydroxide 
Solvent: water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection  
2500 IU powder in a vial, 
3.2 ml solvent in a vial, 
1 vial adapter  
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Intravenous use 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNINGS, IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After reconstitution, use the medicine immediately due to the risk of microbiological contamination. 
 
 
9. SPECIAL STORAGE CONDITIONS 



18 

 
Store in a refrigerator. 
Store in the original package in order to protect from light. 
Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER  
 
EU/1/12/775/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NovoThirteen 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



19 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Label for powder vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
NovoThirteen 2500 IU 
powder for injection 
catridecacog 
IV use after reconstitution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2500 IU 
 
 
6. OTHER 
 
Novo Nordisk A/S 



20 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Label for solvent vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Solvent for NovoThirteen  
Water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3.2 ml  
 
 
6. OTHER 
 
For reconstitution 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



22 

Package leaflet: Information for the user 
 

NovoThirteen 2500 IU powder and solvent for solution for injection 
 

catridecacog (recombinant coagulation factor XIII) 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
– Keep this leaflet. You may need to read it again. 
– If you have any further questions, ask your doctor. 
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
– If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What NovoThirteen is and what it is used for 
2. What you need to know before you use NovoThirteen 
3. How to use NovoThirteen 
4. Possible side effects 
5. How to store NovoThirteen 
6. Contents of the pack and other information. 
 
 
1. What NovoThirteen is and what it is used for 
 
What NovoThirteen is 
NovoThirteen contains the active substance catridecacog, which is identical to human coagulation 
factor XIII, an enzyme necessary for blood clotting. NovoThirteen replaces the missing factor XIII 
and helps to stabilise the initial blood clot by producing a mesh around the clot. 
 
What NovoThirteen is used for 
NovoThirteen is used to prevent bleeding in patients who do not have enough or are missing part of 
factor XIII (that is called A-subunit). 
 
 
2. What you need to know before you use NovoThirteen 
 
Do not use NovoThirteen 
• If you are allergic to catridecacog or any of the other ingredients of this medicine (listed in 

section 6). 
 
If you are not sure, ask your doctor before using this medicine. 
 
Warnings and precautions 
Talk to your doctor before using NovoThirteen: 
• If you have or have ever had a higher risk of blood clots forming (thrombosis), as NovoThirteen 

may increase the severity of a pre-existing blood clot. 
• If you have or have ever had liver damage. 
 
Contact your doctor immediately: 
• If you experience bleeding during your treatment with NovoThirteen occurring spontaneously 

and/or requiring treatment. In this last case your doctor will prescribe an alternative treatment 
to treat the bleeding. 



23 

• If you experience an allergic reaction to NovoThirteen. The signs may include: hives, itching, 
swelling, difficulty breathing, low blood pressure (signs include paleness and coldness of skin, 
rapid heartbeat), feeling dizzy and sweating. 

 
Other medicines and NovoThirteen 
Tell your doctor if you are using, have recently used or might use any other medicines. 
It is not recommended to use NovoThirteen and recombinant coagulation factor VIIa (another blood 
clotting factor) together. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, or if you think you may be pregnant or are planning to have a 
baby, ask your doctor for advice before taking this medicine. 
 
NovoThirteen contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially ‘sodium-free’. 
 
 
3. How to use NovoThirteen 
 
Your treatment with NovoThirteen should be initiated by a doctor experienced in the treatment of rare 
bleeding disorders. 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Before you can use NovoThirteen for injection you need to reconstitute the product. Please see 
NovoThirteen user instructions. 
 
NovoThirteen is given as an injection into a vein. Your dose will depend on your body weight. The 
usual dose is 35 IU for each kilogram of body weight. The injections are given once a month (every 
28 ± 2 days).  
NovoThirteen should be injected at a rate not higher than 2 ml/minute. 
 
Based on the concentration of NovoThirteen solution, the dose volume to be injected (in millilitres) 
can be calculated from this formula:  
Dose volume in millilitres = 0.042 x your body weight in kilograms. 
 
You should only use the prescribed dose calculated by your doctor from this formula considering that 
the usual dose and the concentration of NovoThirteen are different from those of the other products 
which contain factor XIII.  
Your doctor may adapt the dose if this is deemed necessary. 
 
Use in small children 
For children weighing less than 24 kg the reconstituted NovoThirteen should be further diluted with 
6 ml of sodium chloride 0.9%, solution for injection to be able to handle the dosing of small children. 
For more information see section ‘NovoThirteen user instructions – Instructions of how to dilute the 
reconstituted NovoThirteen’. 
 
The dose volume for the reconstituted NovoThirteen diluted with 6 ml sodium chloride 0.9%, solution 
for injection can be calculated from this formula: 
 
Dose volume in millilitres = 0.117 x body weight in kilograms. 
 
Use in children and adolescents (weighing more than 24 kg) 
NovoThirteen can be used in children and adolescents in the same way as in adults. 
 
If you use more NovoThirteen than you should 



24 

There is limited information on overdose with NovoThirteen. None of the reported cases have shown 
any signs of illness. Contact your doctor if you have injected more NovoThirteen than you have been 
instructed. 
 
If you forget to use NovoThirteen 
If you forget an injection of NovoThirteen, talk to your doctor. Do not take a double dose to make up 
for a forgotten dose. 
 
If you stop using NovoThirteen 
If you stop using NovoThirteen, you are not protected against bleeding. Do not stop using 
NovoThirteen without talking to your doctor. Your doctor will explain what might happen if you stop 
treatment and discuss other options with you. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Side effects include: 
Common (may affect up to 1 in 10 people): 
• Headache (most common side effect) 
• Pain where the injection is given 
• Pain in the legs and arms 
• Increased amount of small protein fragments caused by break down of blood clots 
• A drop in the number of some types of white blood cells. This means your body may be more 

prone to infections 
• Development of antibodies against factor XIII which have no influence on the effect of the 

drug. 
 
Side effects in children: 
The side effects observed in children are the same as also observed in adults but the side effects may 
be more common in children than in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store NovoThirteen 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the label and the outer carton after 
‘EXP.’. The expiry date refers to the last day of that month. 
Store in a refrigerator (2°C–8°C). 
Do not freeze. 
 
Store in the original package in order to protect from light. 
 
Once prepared, NovoThirteen for injection should be used immediately. 
 
The solution is clear and colourless. Do not use this medicine if there are particles in it or it is 
discoloured when reconstituted. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


25 

 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What NovoThirteen contains 
• The active substance is catridecacog (recombinant coagulation factor XIII: 2500 IU/3 ml, after 

reconstitution, corresponding to a concentration of 833 IU/ml. 
• The other ingredients are for the powder sodium chloride, sucrose and polysorbate 20, 

L-histidine, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH adjustment) and 
for the solvent water for injections. 

 
What NovoThirteen looks like and contents of the pack 
NovoThirteen is supplied as a powder and solvent for solution for injection (2500 IU powder in a vial 
and 3.2 ml solvent in a vial, with a vial adapter). 
Pack size of 1. 
 
The powder is white and the solvent is clear and colourless. 
 
Marketing Authorisation Holder and Manufacturer 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
This leaflet was last revised in  
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  
 

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


26 

NovoThirteen user instructions 
 
To reconstitute and administer this product the following tools are needed: a 10 ml syringe or a 
syringe of a convenient size according to injection volume, alcohol swabs, the included vial adapter 
and an infusion set (tubing, butterfly needle). 
 

 
 
Preparing the solution 
 
Always use an aseptic technique. Before starting, the hands should be washed. Bring the powder and 
solvent vials to a temperature not above 25°C, by holding them in the hands until they feel as warm as 
your hands. Remove the plastic caps from the 2 vials. If the caps are loose or missing, do not use the 
vials. Clean the rubber stoppers on the vials with alcohol swabs and allow them to dry before use. 
 

 
 
The product is reconstituted using the vial adapter included. 
Remove the protective paper from the vial adapter without taking the vial adapter out of the protective 
cap. Attach the vial adapter to the solvent vial (water for injections). Take care not to touch the spike 
on the vial adapter. 
 
Once attached, remove the protective cap from the vial adapter. 
 



27 

 
 
Pull the plunger to draw in a volume of air equal to the total amount of solvent in the solvent vial. 
 

 
 
Screw the syringe tightly onto the vial adapter on the solvent vial. Inject air into the vial by pushing the 
plunger until you feel a clear resistance. 
 

 
 
Hold the syringe with the solvent vial upside down. Pull the plunger to draw the solvent into the 
syringe. 
 



28 

 
 
Remove the empty solvent vial by tipping the syringe with the vial adapter. 
 

 
 
Click the vial adapter, still attached to the syringe onto the powder vial. Hold the syringe slightly 
tilted with the vial facing downwards. Push the plunger slowly to inject the solvent into the powder 
vial. Make sure not to aim the stream of solvent directly at the powder as this will cause foaming. 
 

 
 
Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause 
foaming. 
 
NovoThirteen should be inspected visually for extraneous (for any foreign) particulate matter and 
discoloration prior to administration. In the event of either being observed, discard the medicinal 
product. 
 
Reconstituted NovoThirteen is a clear, colourless solution. 
If a larger dose is needed, repeat the procedure in a separate syringe until the required dose is reached. 
 
Important information 



29 

 
Once prepared, NovoThirteen for injection should be used immediately. 
 
In case a dilution of the reconstituted NovoThirteen is needed proceed to the section ‘Dilution of the 
reconstituted product with sodium chloride 0.9%, solution for injection’.  
 

 
 
Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have 
been pushed out by the pressure in the vial). Hold the syringe with the vial upside down and pull the 
plunger to draw up the amount calculated for the injection. 
 

 
 
Unscrew the vial adapter with the vial. 
 
The product is now ready for injection in the vein. Follow the injection procedure as instructed by 
your doctor. 
 
After the injection 
 

 
 



30 

Safely dispose of the syringe, vial adapter, infusion set and vials. Any unused medicinal product or 
waste material should be disposed of in accordance with local requirements. 
 
Instructions of how to dilute the reconstituted NovoThirteen 
 
To dilute the reconstituted NovoThirteen the following tools are needed: a vial containing sodium 
chloride 0.9%, solution for injection, a 10 ml syringe and alcohol swabs. 
 
General instructions for dilution 
 
The dilution should be performed in accordance with aseptic rules.  
Carefully draw exactly 6 ml sodium chloride 0.9%, solution for injection, into the 10 ml syringe. 
Slowly inject the 6 ml sodium chloride 0.9%, solution for injection, into the reconstituted 
NovoThirteen vial. 
Gently swirl the vial to mix the solution. 
The diluted solution is a clear, colourless solution. Check the injection solution for particulate matter 
and for discolouration. If either is noticed, please discard. 
 
After dilution proceed to step H. 
 
Any residual material of the diluted product has to be discarded immediately. 
 
In case of any questions ask your doctor or nurse. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET