Leaflet REFIXIA 2000UI powder+solvent for injection
Indicated for: hemophilia B
Route of administration: injectable
Substance: nonacog beta pegol (coagulation factor)
ATC: B02BD04 (Blood and blood forming organs | Vitamin k and other hemostatics | Blood coagulation factors)
Risk of severe allergic reaction. Seek urgent medical help if serious symptoms occur.
This medicine is subject to additional monitoring.
Store in the refrigerator as instructed in the leaflet.
Nonacog beta pegol is a long-acting recombinant factor IX used in the treatment and prevention of bleeding episodes in patients with hemophilia B. It provides extended protection against bleeding due to its molecular modification.
The medication is administered intravenously, as directed by a doctor, usually at longer intervals than conventional factor IX products. It is important for patients to follow the treatment regimen and undergo regular tests to monitor factor IX levels.
Patients should be aware of potential side effects, such as injection site reactions, headaches, or fatigue. It is important to inform the doctor of any unusual symptoms.
Common side effects include injection site reactions, headaches, and fatigue. In rare cases, severe reactions such as allergic reactions or the development of factor IX inhibitors may occur. Patients should be informed of these risks before use.
General data about REFIXIA 2000UI
- Substance: nonacog beta pegol
- Date of last drug list: 01-04-2023
- Commercial code: W69456001
- Concentration: 2000UI
- Pharmaceutical form: powder+solvent for injection
- Quantity: 1
- Product type: original
- Prescription restrictions: P-RF - Medicines prescription that is retained in the pharmacy (not renewable).
Concentrations available for nonacog beta pegol
- 1000UI
- 2000UI
- 3000UI
- 500UI
Leaflet REFIXIA 2000UI
Contents of the package leaflet for the medicine REFIXIA 2000UI powder+solvent for injection
1. NAME OF THE MEDICINAL PRODUCT
Refixia 500 IU powder and solvent for solution for injection
Refixia 1 000 IU powder and solvent for solution for injection
Refixia 2 000 IU powder and solvent for solution for injection
Refixia 3 000 IU powder and solvent for solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Refixia 500 IU powder and solvent for solution for injection
Each vial contains nominally 500 IU nonacog beta pegol*.
After reconstitution, 1 ml of Refixia contains approximately 125 IU nonacog beta pegol.
Refixia 1 000 IU powder and solvent for solution for injection
Each vial contains nominally 1 000 IU nonacog beta pegol*.
After reconstitution, 1 ml of Refixia contains approximately 250 IU nonacog beta pegol.
Refixia 2 000 IU powder and solvent for solution for injection
Each vial contains nominally 2 000 IU nonacog beta pegol*.
After reconstitution, 1 ml of Refixia contains approximately 500 IU nonacog beta pegol.
Refixia 3 000 IU powder and solvent for solution for injection
Each vial contains nominally 3 000 IU nonacog beta pegol*.
After reconstitution, 1 ml of Refixia contains approximately 750 IU nonacog beta pegol.
*recombinant human factor IX, produced in Chinese Hamster Ovary (CHO) cells by recombinant
DNA technology, covalently conjugated to a 40 kDa polyethylene-glycol (PEG).
The potency (IU) is determined using the European Pharmacopoeia one-stage clotting test. Thespecific activity of Refixia is approximately 144 IU/mg protein.
Refixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG)selectively attached to specific N-linked glycans in the rFIX activation peptide. Upon activation of
Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leavingthe native activated factor IX molecule. The primary amino acid sequence of the rFIX in Refixia isidentical to the Ala148 allelic form of human plasma-derived factor IX. No additives of human oranimal origin are used in the cell culture, purification, conjugation, or formulation of Refixia.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
The powder is white to off-white.
The solvent is clear and colourless.
pH: 6.4.
Osmolality: 272 mOsmol/kg.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IXdeficiency).
Refixia can be used for all age groups.
4.2 Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
Treatment monitoringRoutine monitoring of factor IX activity levels for the purpose of dose adjustment is not necessary. Inthe clinical trial programme, dose adjustment was not performed. Mean steady state factor IX troughlevels ≥ 15% were observed for all age groups, see section 5.2 for details.
Due to the interference of polyethylene glycol (PEG) in the one-stage clotting assay with various aPTTreagents, it is recommended to use a chromogenic assay (e.g. Rox Factor IX or Biophen) whenmonitoring is needed. If a chromogenic assay is not available, it is recommended to use a one-stageclotting assay with an aPTT reagent (e.g. Cephascreen) qualified for use with Refixia. For modifiedlong-acting factor products, it is known that the one-stage clotting assay results are highly dependenton the aPTT reagent and reference standard used. For Refixia, some reagents will causeunderestimation (30-50%), while most silica containing reagents will cause severe overestimation ofthe factor IX activity (more than 400%). Therefore, silica based reagents should be avoided. Use of areference laboratory is recommended when a chromogenic assay or a qualified one-stage clottingassay is not available locally.
PosologyThe number of units of factor IX administered is expressed in International Units (IU), which arerelated to the current WHO standard for factor IX products. Factor IX activity in plasma is expressedeither as a percentage (relative to normal human plasma) or in International Units (relative to an
International Standard for factor IX in plasma).
Prophylaxis40 IU/kg body weight once weekly.
Adjustments of doses and administration intervals may be considered based on achieved FIX levelsand individual bleeding tendency. The trough levels achieved with the weekly 40 IU/kg dosingregimen are summarised in section 5.2.
Patients on prophylaxis who forget a dose are advised to take their dose upon discovery and thereaftercontinue with the usual once weekly dosing schedule. A double dose should be avoided.
On-demand treatment
Dose and duration of the substitution therapy depend on the location and severity of the bleeding, see
Table 1 for dosing guidance in bleeding episodes.
Table 1 Treatment of bleeding episodes with Refixia
Degree of Recommended Dosing recommendationshaemorrhage dose IU/kg of
Refixia
Early 40 A single dose is recommended.haemarthrosis,muscle bleeding ororal bleeding.
More extensivehaemarthrosis,muscle bleeding orhaematoma.
Severe or life 80 Additional doses of 40 IU/kg can bethreatening given.haemorrhages.
SurgeryThe dose level and dosing intervals for surgery depend on the procedure and local practice. Generalrecommendations are provided in Table 2.
Table 2 Treatment in surgery with Refixia
Type of surgical Recommended Dosing recommendationsprocedure dose IU/kg bodyweight
Minor surgery 40 Additional doses can be given if needed.including toothextraction.
Major surgery. 80 Pre-operative dose.
40 Consider two repeated doses of 40 IU/kg(in 1-3 day intervals) within the firstweek after surgery.
Due to the long half-life of Refixia, thefrequency of dosing in the post-surgicalperiod may be extended to once weeklyafter the first week until bleeding stopsand healing is achieved.
Paediatric populationThe dose recommendations in children are the same as for adults (for more details on paediatrics seesections 5.1 and 5.2).
Method of administrationIntravenous use.
Refixia is administered by intravenous bolus injection over several minutes after reconstitution of thepowder for injection with the histidine solvent. The rate of administration should be determined by thepatient’s comfort level up to a maximum injection rate of 4 ml/min.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
In case of self-administration or administration by caregiver appropriate training is needed.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known allergic reaction to hamster protein.
4.4 Special warnings and precautions for use
In order to improve traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.
HypersensitivityAllergic type hypersensitivity reactions are possible with Refixia. The product contains traces ofhamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue useof the medicinal product immediately and contact their physician. Patients should be informed of theearly signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest,wheezing, hypotension, and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
InhibitorsAfter repeated treatment with human coagulation factor IX products, patients should be monitored forthe development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units(BU) using appropriate biological testing.
There have been reports in the literature showing a correlation between the occurrence of a factor IXinhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluatedfor the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at anincreased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IXshould, according to the treating physician’s judgement, be performed under medical observationwhere proper medical care for allergic reactions could be provided.
In case of residual FIX activity levels, there is a risk of interference when performing the Nijmegenmodified Bethesda assay for inhibitor testing. Therefore a pre-heating step or a wash-out isrecommended in order to ensure detection of low-titre inhibitors.
Thromboembolism
Because of the potential risk of thrombotic complications, clinical surveillance for early signs ofthrombotic and consumptive coagulopathy should be initiated with appropriate biological testing whenadministering this product to patients with liver disease, to patients post-operatively, to new-borninfants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefitof treatment with Refixia should be weighed against the risk of these complications.
Cardiovascular event
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase thecardiovascular risk.
Catheter-related complicationsIf a central venous access device (CVAD) is required, risk of CVAD-related complications includinglocal infections, bacteraemia and catheter site thrombosis should be considered.
Paediatric populationThe listed warnings and precautions apply both to children and adults.
Sodium contentThis medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially“sodium-free”. In case of treatment with multiple vials, the total sodium content should be taken intoconsideration.
4.5 Interaction with other medicinal products and other forms of interaction
No interactions of human coagulation factor IX (rDNA) products with other medicinal products havebeen reported.
4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence ofhaemophilia B in women, experience regarding the use of factor IX during pregnancy andbreastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation onlyif clearly indicated.
4.7 Effects on ability to drive and use machines
Refixia has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observedrarely with recombinant factor IX products and may in some cases progress to severe anaphylaxis(including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they haveoccurred in close temporal association with development of factor IX inhibitors (see also section 4.4).
Nephrotic syndrome has been reported following attempted immune tolerance induction inhaemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Very rarely development of antibodies to hamster protein with related hypersensitivity reactions hasbeen observed.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If suchinhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, itis recommended that a specialised haemophilia centre is contacted.
There is a potential risk of thromboembolic episodes following the administration of factor IXproducts, with a higher risk for low purity preparations. The use of low purity factor IX products hasbeen associated with instances of myocardial infarction, disseminated intravascular coagulation,venous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia israrely associated with such adverse reactions.
Tabulated list of adverse reactionsThe table presented below is according to the MedDRA system organ classification (SOC and
Preferred Term Level).
Frequencies have been evaluated 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); veryrare (< 1/10 000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
A total of 115 previously treated patients (PTPs) and 54 previously untreated patients (PUPs) withmoderate or severe haemophilia B have been exposed to Refixia for a total of 543 patient years in thecompleted clinical trials.
Table 3 Frequency of adverse reactions in clinical trials
System Organ Class Adverse reaction Frequency
Blood and lymphatic system Factor IX inhibition Common*disorders
Immune system disorders Hypersensitivity Common
Anaphylactic reaction Common*
Cardiac disorders Palpitations Uncommon
Gastrointestinal disorders Nausea Common
Skin and subcutaneous tissue Pruritus** Commondisorders Rash Common
General disorders and Fatigue Commonadministration site conditions Hot flush Uncommon
Injection site reactions*** Common
* Frequency based on occurrence in PUP trial (N=54)
**Pruritus includes the terms pruritus and ear pruritus
***Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema andinjection site rash.
Description of selected adverse reactionsFactor IX inhibition and anaphylactic reactions have not been observed in PTPs, and frequencies aretherefore based on a PUP trial with 54 patients. In this trial, Factor IX inhibition occurred in 4/54 (8%)and anaphylactic reaction occurred in 1/54 (2%) categorising these events as common. The case withanaphylactic reaction occurred in a patient that also developed Factor IX inhibition.
Paediatric populationFrequency, type and severity of adverse reactions in children are expected to be similar as in adults. .
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Overdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated withoverdoses have been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04.
Mechanism of actionRefixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG)conjugated to the protein. The average molecular weight of Refixia is approximately 98 kDa and themolecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activationpeptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activatedfactor IX molecule.
Factor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it issynthesised in the liver. Factor IX is activated by factor XIa and by factor VII/tissue factor complex.
Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor Xconverts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot isformed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreasedlevels of factor IX and results in profuse bleeding into joints, muscles, or internal organs, eitherspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levelsof factor IX are increased, thereby enabling a temporary correction of the factor deficiency andcorrection of the bleeding tendencies.
Clinical efficacyThe clinical trial programme included one phase 1 trial and five phase 3 multicentre, non-controlledtrials. All patients had severe (factor IX level < 1%) or moderately severe (factor IX level ≤ 2%)haemophilia B.
Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates andbetween different clinical trials.
ProphylaxisOne hundred one of the previously treated patients and previously untreated patients across all age-groups were treated with a weekly prophylactic dose of 40 IU/kg where 40 (40%) of these patients hadno bleeding episodes (see details below).
Pivotal trial
The pivotal trial included 74 adolescent (13-17 years) and adult (18-65 years) previously treatedpatients (PTPs). The trial included one open-label on-demand arm with treatment for approximately28 weeks and two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or40 IU/kg once-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kgtreatments, the annualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lowerthan the bleeding rate (95% CI: 5%;73%) for patients in the 10 IU/kg arm (p<0.05).
The median (IQR) overall ABR in patients (13-65 years) treated with a prophylactic dose of 40 IU/kgonce weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00 (0.00; 2.05), joint ABR was0.97 (0.00; 2.07) and spontaneous ABR was 0.00 (0.00; 0.99).
In this pivotal trial in adolescent and adult patients, there were 70 breakthrough bleeding episodes for16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment ofbreakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70bleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at40 IU/kg for mild or moderate bleeds.
In 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one yearwith a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longerconsidered target joints at the end of the trial.
On-demand treatment
In the pivotal trial there was a non-randomised arm where 15 patients were treated in an on-demandregimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overallsuccess rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleedstreated with one or two injections.
Paediatric populationPreviously treated patients (PTPs)
The efficacy and safety of Refixia for prophylaxis and treatment of bleeds were evaluated in an open-label, single arm, non-controlled phase 3 trial. In the main phase of the paediatric PTP trial, 25 patientsinitially enrolled at 0 to 12 years of age received routine prophylactic administration of Refixia40 IU/kg once weekly for 52 weeks. The patients were stratified into two age groups; 12 patients were0 to 6 years and 13 patients 7 to 12 years at the time of signing informed consent. Twenty-two patientscontinued on to the extension phase and out of those, 12 patients had up to 8 years of routineprophylactic treatment.Main efficacy results in patients ≤ 12 years separated by main and extensionphase are summarised in table 4 according to the age at randomization.
Table 4: Annualised Bleeding Rate (ABR) in the Paediatric PTP Trial - Main & Extension Phase
Main Phase Extension Phase
Age of patient ≤ 6 years 7-12 years ≤ 6 years 7-12 years
N=12 N=13 N=11 N=11
Mean treatment 1.05 1.27 7.71 6.85period (years)
Total ABR
Poisson-estimated 0.87 (0.38; 2.01) 1.88 (1.14; 3.09) 0.62 (0.30; 1.32) 0.78 (0.34; 1.80)mean (95% CI)
Median (IQR) 0.00 (0.00; 3.00) 2.00(0.00; 6.51) 0.31 (0.00; 1.40) 0.40 (0.14; 1.55)
Due to the long trial duration several patients crossed age-groups and 10 patients that were initiallyenrolled as ≤ 6 years also contributed to the age category of 7-12 years. In the 7‑12 years age group,10 patients transitioned to the 13‑17 years age group. Of these 3 patients further transitioned to the ≥18years age group. Considering this actual age for the main and extension phase of the trial together, theoverall median/poisson-estimated ABR was 0.55/1.02 (95% CI: 0.68; 1.54) in patients ≤ 6 years and0.52/0.92 (95% CI: 0.47; 1.78) in patients 7-12 years. The median/poisson-estimated ABR was0.00/0.20 (95% CI: 0.09; 0.47) and 0.00/0.22 (95% CI: 0.05; 0.92) for spontaneous bleeds as well as0.53/0.82 (95% CI: 0.55; 1.23) and 0.33/0.64 (95% CI: 0.31; 1.31) for traumatic bleeds in patients≤ 6 years and patients 7-12 years, respectively. Treatment success (defined as excellent or goodresponse) was concluded for 88.6% and 92.0% of bleeding episodes that occurred during prophylaxisin patients ≤ 6 years and patients 7-12 years, respectively. Four out of 25 patients (16%) did not haveany bleeds throughout the trial. The mean annual consumption for prophylaxis was 2209.3 (SD:79.3) IU/kg and 2324.9 (SD: 83.5) IU/kg for patients ≤ 6 years and patients 7-12 years, respectively.
Two patients had target joints at baseline, which were considered resolved during the main phase.
None of the patients developed new target joints in the trial.
Previously untreated patients (PUPs)
The efficacy and safety of Refixia for prophylaxis and treatment of bleeds were evaluated in an open-label, single-arm multicentre non-controlled phase 3 trial. , . Of the 54 exposed patients (< 6 yearsold), 47 patients (87%) completed the main phase, and 42 patients (77.8%) completed the extensionphase.Main efficacy results separated by main and extension phase are summarised in table 5.
Table 5: Annualised Bleeding Rate (ABR) in the Paediatric PUP Trial - Main and Extension
Phase
Main Phase Extension Phase
N=51 N=46
Mean treatment period (years) 0.78 3.34
Total ABR
Poisson-estimated mean (95% CI) 0.78 (0.33; 1.82) 0.69 (0.41; 1.15)
Median (IQR) 0.00 (0.00 ; 1.02) 0.20 (0.00; 0.71)
The overall median ABR was 0.00 for spontaneous, traumatic, and joint bleeding episodes for mainphase and 0.20 for extension phase. For the trials main and extension phase the median/poisson-estimated ABR was 0.33/0.71 (95% CI: 0.41; 1.22) for PUPs on prophylaxis. The poisson-estimated
ABRs for spontaneous and traumatic bleeds were 0.13 (95% CI: 0.05; 0.37) and 0.56 (95% CI: 0.32;0.98) throughout the trial period, respectively (the median ABRs was 0 for both). 47.8% of PUPs didnot experience any bleeding events. None of the paediatric patients developed target joints in the trial.. Out of 200 bleeds, 194 (97.0%) were successfully treated, achieving an excellent or good outcomeand 182 (91.0%) were treated with a single injection. Of the 194 successfully treated bleeds, 92.8%required only one injection of Refixia for successful treatment.
Overall haemostatic efficacy
Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg forsevere bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacywas performed by the patient or caretaker (for home treatment) or study site investigator (for treatmentunder health care professional supervision) using a 4-point scale of excellent, good, moderate, or poor.
The overall success rate (defined as excellent or good) for treatment of bleeds in previously treatedpatients was 91.6% (645 out of 704). Of the 704 treated bleeds observed in 85 (80.9%) of the 105patients, 608 (86.4%) of the bleeds were resolved with 1 injection and 72 (10.2%) of the bleeds wereresolved with 2 injections of Refixia.
The success rate and dose needed for treatment of the bleeding episodes were independent of thelocalisation of the bleed. The success rate for treatment of bleeding episodes was also independent ofwhether the bleed was traumatic or spontaneous of nature.
SurgeryFive trials, of which one trial was a dedicated surgery trial, included in total 20 major and 105 minorsurgery procedures. Haemostatic effect of Refixia during surgery was confirmed with a success rate of100% in the 20 major surgeries in the trials. All evaluated minor surgeries were performedsuccessfully.
In a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1gastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In thepost-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg dosesadministered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and aftersurgery was 241 IU/kg (range: 81-460 IU/kg).
5.2 Pharmacokinetic properties
Refixia has a prolonged half-life compared to unmodified factor IX. All pharmacokinetic studies with
Refixia were conducted in previously treated patients with haemophilia B (factor IX ≤2%). Theanalysis of plasma samples was conducted using the one-stage clotting assay.
Steady state pharmacokinetic parameters for adolescents and adults are shown in Table 6
Table 6 Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescent andadult PTPs (geometric mean (CV%))
PK Parameter 13-17 years ≥ 18 years
N=3 N=6
Half-life (t1/2) (hours) 103 (14) 115 (10)
Incremental Recovery (IR) (IU/ml per 0.018 (28) 0.019 (20)
IU/kg)
Area under the curve (AUC)0-168h 91 (22) 93 (15)(IU*hours/ml)
Clearance (CL) (ml/hour/kg) 0.4 (17) 0.4 (11)
Mean residence time (MRT) (hours) 144 (15) 158 (10)
Volume of distribution (Vss) (ml/kg) 61 (31) 66 (12)
Factor IX activity 168 h post dosing 0.29 (19) 0.32 (17)(IU/ml)
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume ofdistribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation.
All patients assessed in the steady state pharmacokinetic session had factor IX activity levels above0.24 IU/ml at 168 hours post dosing with a weekly dose of 40 IU/kg.
Single-dose pharmacokinetic parameters of Refixia are listed by age in Table 7.
Table 7 Single-dose pharmacokinetic parameters of Refixia (40 IU/kg) in PTPs by age(geometric mean (CV%))
PK Parameter 0-6 years 7-12 years 13-17 years N=3 ≥ 18 years N=6
N=12 N=13
Half-life (t1/2) (hours) 70 (16) 76 (26) 89 (24) 83 (23)
Incremental Recovery 0.015 (7) 0.016 (16) 0.020 (15) 0.023 (11)(IR) (IU/ml per IU/kg)
Area under the curve 46 (14) 56 (19) 80 (35) 91 (16)(AUC)inf (IU*hours/ml)
Clearance CL 0.8 (13) 0.6 (22) 0.5 (30) 0.4 (15)(ml/hour/kg)
Mean residence time 95 (15) 105 (24) 124 (24) 116 (22)(MRT) (hours)
Volume of distribution 72 (15) 68 (22) 59 (8) 47 (16)(Vss) (ml/kg)
Factor IX activity 168 h 0.08 (16) 0.11 (19) 0.15 (60) 0.17 (31)post dosing (IU/ml)
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume ofdistribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation.
As expected, body weight adjusted clearance in paediatric and adolescent patients was highercompared to adults. No dose adjustment was required for paediatric or adolescent patients in clinicaltrials.
The mean trough levels at steady state are presented in Table 8; based on all pre-dose measurementstaken every 8 weeks at steady state for all patients on once weekly dosing of 40 IU/kg.
Table 8 Mean of trough levels* of Refixia (40 IU/kg) at steady state0-6 years 7-12 years 13-17 years 18-65 years 0-5 years(PTP) (PTP) (PTP) (PTP) (PUP)
N=12 N=13 N=9 N=20 N=51
Estimated 0.15 0.19 0.24 0.29 0.17mean (0.13;0.18) (0.16;0.22) (0.20;0.28) (0.26;0.33) (0.16; 0.18)factor IXtrough levels
IU/ml(95% CI)
* Factor IX trough levels = factor IX activity measured prior to next weekly dose (5 to 10 days post dosing) at steady state.
Pharmacokinetics were investigated in 16 adult and adolescent patients of which 6 were normal weight(BMI 18.5-24.9 kg/m2) and 10 were overweight (BMI 25-29.9 kg/m2). There were no apparentdifferences in the pharmacokinetic profiles between normal weight and overweight patients.
In the paediatric PTP and PUP trial, the Factor IX mean trough levels at steady state were within therange of mild haemophilia (i.e. 0.05-0.4 IU/ml), independent of age.
5.3 Preclinical safety data
A juvenile animal neurotoxicity study was conducted to evaluate the potential neurotoxicity of Refixiawhen intravenously administered 120-1 200 IU/kg/twice weekly in immature male rats from 3 to13 weeks of age (corresponding to 2 to 16 years of age in humans), followed by a 13-week treatment-free period. The doses were 6-60 times higher than the weekly clinical dose of 40 IU/kg. PEG wasdetected by immunohistochemical staining in the choroid plexus, pituitary, circumventricular organs,and cranial motor neurons. Dosing Refixia to juvenile rats did not result in any functional orpathological effects, as measured by neurobehavioural/neurocognitive tests, including motor activity,sensory function, learning and memory as well as growth, sexual maturation, and fertility.
In a repeat dose toxicity study in monkeys, mild and transient body tremors were seen 3 hours postdosing and abated within 1 hour. These body tremors were seen at doses of Refixia (3 750 IU/kg),which were more than 90 times higher than the recommended dose for humans (40 IU/kg). Nomechanism behind the tremors was identified. Tremors have not been reported in the clinical trials.
Non-clinical data reveal no concern for humans based on conventional safety pharmacology andrepeated dose toxicity studies in rats and monkeys.
In repeat dose toxicity studies in rats and monkeys, 40 kDa polyethylene-glycol (PEG) was detectedby immunohistochemical staining in epithelial cells of choroid plexus in the brain. This finding wasnot associated with tissue damage or abnormal clinical signs.
In distribution and excretion studies in mice and rats, the 40 kDa polyethylene-glycol (PEG) moiety of
Refixia was shown to be widely distributed to and eliminated from organs, and excreted via plasma inurine (42-56%) and faeces (28-50%). Based on modelled data using observed terminal half-lives (15-49 days) in rat tissue distribution studies, the 40 kDa polyethylene-glycol (PEG) moiety will reachsteady state levels in all human tissues within 1-4.5 years of treatment.
The exposure ratios for PEG in the choroid plexus, measured in animals at the no observed adverseeffect level (NOAEL) versus predicted clinical PEG-exposure, ranged from 5-fold in the juvenile ratneurotoxicity study to 6-fold in the 26-week repeat dose toxicity study in adult rats.
Long-term studies in animals to evaluate the carcinogenic potential of Refixia, or studies to determinethe effects of Refixia on genotoxicity, fertility, development, or reproduction have not been performed.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Histidine
Sucrose (E 473)
Polysorbate 80 (E 433)
Mannitol (E 421)
Sodium hydroxide (for pH adjustment) (E 524)
Hydrochloric acid (for pH adjustment) (E 507)
SolventHistidine
Water for injections
Sodium hydroxide (for pH adjustment) (E 524)
Hydrochloric acid (for pH adjustment) (E 507)
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts or reconstituted with infusion solutions other than the provided histidine solvent.
6.3 Shelf life
Unopened30 months. During the shelf life Refixia may be stored up to 30 °C for a single period not exceeding 1year. Once the product has been taken out of the refrigerator the product must not be returned to therefrigerator. Please record the beginning of storage at room temperature on the product carton.
After reconstitutionChemical and physical in-use stability have been demonstrated for 24 hours stored in a refrigerator(2 °C - 8 °C) and 4 hours stored at room temperature (≤ 30 °C) protected from light.
From a microbiological point of view, the reconstituted product should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the usersand would normally not be recommended for longer than 4 hours stored at room temperature (≤ 30 °C)or 24 hours in a refrigerator (2 °C - 8 °C), unless reconstitution has taken place under controlled andvalidated aseptic conditions. Store the reconstituted medicinal product in the vial.
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage at room temperature and storage conditions after reconstitution of the medicinal product,see section 6.3.
6.5 Nature and contents of container
Each pack contains:- 1 glass vial (type I) with powder and chlorobutyl rubber stopper- 1 sterile vial adapter for reconstitution- 1 pre-filled syringe of 4 ml histidine solvent with backstop (polypropylene), a rubber plunger(bromobutyl) and a tip cap with a stopper (bromobutyl)- 1 plunger rod (polypropylene).
Pack size of 1.
6.6 Special precautions for disposal and other handling
Refixia is to be administered intravenously after reconstitution of the powder with the solvent suppliedin the syringe. After reconstitution the solution appears as a clear and colourless to slightly yellowliquid, free of visible particles. Reconstituted medicinal product should be inspected visually forparticulate matter and discoloration prior to administration. Do not use solutions that are cloudy orhave deposits. Store the reconstituted medicinal product in the vial.
For instructions on reconstitution of the medicinal product before administration, see the packageleaflet.
The rate of administration should be determined by the patient’s comfort level up to a maximuminjection rate of 4 ml/min.
An infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters will alsobe needed. These devices are not included in the Refixia package.
Always use an aseptic technique.
DisposalAfter injection, safely dispose of the syringe with the infusion set and the vial with the vial adapter.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.