- Approval Id
- ad00a68f5ab1a696
- Drug Approval Emc Name
- Refixia 1000 IU powder and solvent for solution for injection
- Drug Name
- Refixia 1000 IU powder and solvent for solution for injection
- Company Name
- Novo Nordisk Limited
- Company Address
- 3 City Place, Beehive Ring Road, Gatwick, West Sussex, RH6 0PA
- Company Website
- http://www.novonordisk.co.uk
- Company Telephone
- +44 (0)1293 613555
- Company Medical Info Direct Line
- +44 (0)800 023 2573
- Company Medical Info Email
- CustomerCare@novonordisk.com
- Company Customer Care Direct Line
- +44 (0)800 023 2573
- Atc Code
- B02BD04
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
- Authorisation Number
- PLGB 04668/0404
- Authorisation Date
- 16/05/2022
- Instruction Authorisation Holder
- Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd
Denmark
- Instruction Authorisation Number
- PLGB 04668/0404
- Instruction Authorisation Date
- 16/05/2022
- Instruction Dosage 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.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
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 monitoring\*\*
Routine monitoring of factor IX activity levels for the purpose of dose adjustment is not necessary. In the clinical trial programme, dose adjustment was not performed. Mean steady state factor IX trough levels ≥ 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 aPTT reagents, it is recommended to use a chromogenic assay (e.g. Rox Factor IX or Biophen) when monitoring is needed. If a chromogenic assay is not available, it is recommended to use a one-stage clotting assay with an aPTT reagent (e.g. Cephascreen) qualified for use with Refixia. For modified long-acting factor products, it is known that the one-stage clotting assay results are highly dependent on the aPTT reagent and reference standard used. For Refixia some reagents will cause underestimation (30–50%), while most silica containing reagents will cause severe overestimation of the factor IX activity (more than 400%). Therefore, silica based reagents should be avoided. Use of a reference laboratory is recommended when a chromogenic assay or a qualified one-stage clotting assay is not available locally.
\*\*Posology\*\*
The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma).
\*\*\*Prophylaxis\*\*\*
40 IU/kg body weight once weekly.
Adjustments of doses and administration intervals may be considered based on achieved FIX levels and individual bleeding tendency. The trough levels achieved with the weekly 40 IU/kg dosing regimen are summarised in section 5.2.
Patients on prophylaxis who forget a dose are advised to take their dose upon discovery and thereafter continue 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 haemorrhage\*\* | \*\*Recommended dose IU/kg of Refixia\*\* | \*\*Dosing recommendations\*\* |
| Early haemarthrosis, muscle bleeding or oral bleeding. More extensive haemarthrosis, muscle bleeding or haematoma. | 40 | A single dose is recommended. |
| Severe or life threatening haemorrhages. | 80 | Additional doses of 40 IU/kg can be given. |
\*\*\*Surgery\*\*\*
The dose level and dosing intervals for surgery depend on the procedure and local practice. General recommendations are provided in Table 2.
\*\*Table 2 Treatment in surgery with Refixia\*\*
| | | |
| --- | --- | --- |
| \*\*Type of surgical procedure\*\* | \*\*Recommended dose IU/kg body weight\*\* | \*\*Dosing recommendations\*\* |
| Minor surgery including tooth extraction. | 40 | Additional doses can be given if needed. |
| Major surgery. | 80 | Pre-operative dose. |
| 40 | Consider two repeated doses of 40 IU/kg (in 1–3 day intervals) within the first week after surgery. Due to the long half-life of Refixia, the frequency of dosing in the post-surgical period may be extended to once weekly after the first week until bleeding stops and healing is achieved. |
\*\*\*Paediatric population\*\*\*
The dose recommendations in children are the same as for adults: (for more details on paediatrics see sections 5.1 and 5.2).
\*\*Method of administration\*\*
Intravenous use.
Refixia is administered by intravenous bolus injection over several minutes after reconstitution of the powder for injection with the histidine solvent. The rate of administration should be determined by the patient'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
\*\*Traceability\*\*
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
\*\*Hypersensitivity\*\*
Allergic type hypersensitivity reactions are possible with Refixia. The product contains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early 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.
\*\*Inhibitors\*\*
After repeated treatment with human coagulation factor IX products, patients should be monitored for the 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 IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased 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 IX should, according to the treating physician's judgement, be performed under medical observation where 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 Nijmegen modified Bethesda assay for inhibitor testing. Therefore a pre-heating step or a wash-out is recommended in order to ensure detection of low-titre inhibitors.
\*\*Thromboembolism\*\*
Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of 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 the cardiovascular risk.
\*\*Catheter-related complications\*\*
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
\*\*Paediatric population\*\*
The listed warnings and precautions apply both to children and adults.
\*\*Sodium content\*\*
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium-free”.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 have been reported.4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only if 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
\*\*Summary of the safety profile\*\*
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely with 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 have occurred 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 in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre is contacted.
There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia is rarely associated with such adverse reactions.
\*\*Tabulated list of adverse reactions\*\*
The 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); very rare (< 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 50 previously untreated patients (PUPs) with moderate or severe haemophilia B have been exposed to Refixia for a total of 434 patient years in the completed and on-going clinical trials.
\*\*Table 3 Frequency of adverse reactions in clinical trials\*\*
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Adverse reaction\*\* | \*\*Frequency\*\* |
| Blood and lymphatic system disorders | Factor IX inhibition | Common\\* |
| Immune system disorders | Hypersensitivity Anaphylactic reaction | Common Common\\* |
| Cardiac disorders | Palpitations | Uncommon |
| Gastrointestinal disorders | Nausea | Common |
| Skin and subcutaneous tissue disorders | Pruritus\\*\\* Rash | Common Common |
| General disorders and administration site conditions | Fatigue Hot flush Injection site reactions\\*\\*\\* | Common Uncommon Common |
\\* Frequency based on occurrence in PUP trial (N=50)
\\*\\*Pruritus includes the terms pruritus and ear pruritus
\\*\\*\\*Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and injection site rash.
\*\*Description of selected adverse reactions\*\*
Factor IX inhibition and anaphylactic reactions have not been observed in PTPs, and frequencies are therefore based on an ongoing PUP trial with 50 patients. In this trial, Factor IX inhibition occurred in 4/50 (8%) and anaphylactic reaction occurred in 1/50 (2%) categorising these events as common. The case with anaphylactic reaction occurred in a patient that also developed Factor IX inhibition.
\*\*Paediatric population\*\*
Frequency, type and severity of adverse reactions in children are expected to be similar as in adults.
\*\*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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Overdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated with overdoses have been reported.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04.
\*\*Mechanism of action\*\*
Refixia 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 the molecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated factor IX molecule.
Factor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it is synthesised 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 X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
\*\*Clinical efficacy\*\*
The clinical trial programme included one phase 1 trial and five phase 3 multicentre, non-controlled trials. 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 and between different clinical trials.
\*\*\*Prophylaxis\*\*\*
One hundred and 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 had no bleeding episodes (see details below).
\*\*\*Pivotal trial\*\*\*
The pivotal trial included 74 adolescent (13–17 years) and adult (18–65 years) previously treated patients (PTPs). The trial included one open-label on-demand arm with treatment for approximately 28 weeks and two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or 40 IU/kg once-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kg treatments, the annualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lower than 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/kg once weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00 (0.00; 2.05), joint ABR was 0.97 (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 for 16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment of breakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70 bleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds.
In 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one year with a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longer considered 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-demand regimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overall success rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleeds treated with one or two injections.
\*\*Paediatric population\*\*
Previously 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 patients initially enrolled at 0 to 12 years of age received routine prophylactic administration of Refixia 40 IU/kg once weekly for 52 weeks. The patients were stratified into two age groups; 12 patients were 0 to 6 years and 13 patients 7 to 12 years at the time of signing informed consent. Twenty-two patients continued on to the extension phase and out of those, 12 patients had up to 8 years of routine prophylactic treatment. Due to the long trial duration several patients crossed age-groups and 10 patients that were initially enrolled as ≤ 6 years also contributed to the age category of 7-12 years. Main efficacy results in patients ≤ 12 years separated by main and extension phase are summarised in table 4.
\*\*Table 4: Annualised Bleeding Rate (ABR) in the Paediatric PTP Trial - Main & Extension Phase – actual age groups\*\*
| | | | | |
| --- | --- | --- | --- | --- |
| | \*\*Main Phase\*\* | | \*\*Extension Phase\*\* | |
| \*\*Age of patient\\*\*\* | \*\*≤ 6 years\*\* \*\*N=12\*\* | \*\*7-12 years\*\* \*\*N=14\*\* | \*\*≤ 6 years\*\* \*\*N=10\*\* | \*\*7-12 years\*\* \*\*N=20\*\* |
| \*\*Mean treatment period (years)\*\* | 0.86 | 0.92 | 2.39 | 3.09 |
| \*\*Total ABR\*\* | | | | |
| Poisson-estimated mean (95% CI) | 0.97 (0.50; 1.89) | 2.10 (1.34; 3.30) | 1.05 (0.65; 1.69 | 0.58 (0.21; 1.64) |
| Median (IQR) | 0.00 (0.00; 1.99) | 2.00 (0.00; 3.02) | 0.00 (0.00; 1.65) | 0.15 (0.00; 1.29) |
\\*Some patients contributed to both age groups.
For the main and extension phase of the trial together, the overall median/poisson-estimated ABR was 0.55/1.02 (95% CI: 0.68; 1.54) in patients ≤ 6 years and 0.52/0.84 (95% CI: 0.41; 1.75) in patients 7-12 years. The median/poisson-estimated ABR was 0/0.2 (95% CI: 0.09; 0.47) and 0/0.23 (95% CI: 0.05; 0.96) for spontaneous bleeds as well as 0.53/0.82 (95% CI: 0.55; 1.23) and 0.33/0.56 (95% CI: 0.25; 1.27) for traumatic bleeds in patients ≤ 6 years and patients 7-12 years, respectively. Treatment success (defined as excellent or good response) was concluded for 88.6% and 93.7% of bleeding episodes that occurred during prophylaxis in patients ≤ 6 years and patients 7-12 years, respectively. Five out of 25 patients (20%) did not have any bleeds throughout the trial.The mean annual consumption for prophylaxis was 2 208.6 (SD: 78.8) IU/kg and 2 324.8 (SD: 83.3) 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. In the main phase of the paediatric PUP trial, 47 out of 50 patients < 6 years old received 40 IU/kg once weekly and 38 patients continued on to the extension phase. 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\*\* \*\*N=47\*\* | \*\*Extension Phase\*\* \*\*N=38\*\* |
| \*\*Mean treatment period (years)\*\* | 0.75 | 2.23 |
| \*\*Total ABR\*\* | | |
| Poisson-estimated mean (95% CI) | 0.82 (0.34 ; 1.98) | 0.58 (0.35 ; 0.96) |
| Median (IQR) | 0.00 (0.00 ; 1.02) | 0.00 (0.00 ; 0.88) |
The overall median ABR was 0 for spontaneous, traumatic, and joint bleeding episodes. For the trials main and extension phase the median/poisson-estimated ABR was 0.25/0.65 (95% CI: 0.34; 1.25) for PUPs on prophylaxis. The poisson-estimated ABRs for spontaneous and traumatic bleeds were 0.14 (95% CI: 0.05; 0.43) and 0.2 (95% CI: 0.05; 0.81) throughout the trial period, respectively (the median ABRs was 0 for both).46.8% of PUPs did not experience any bleeding events. None of the paediatric patients developed target joints in the trial. The overall success rate (defined as excellent or good) for treatment of bleeds in previously untreated patients was 96% (135 out of 140). Of the 140 treated bleeds observed in 34 (68%) out of 50 patients, 124 (89%) of the bleeds were resolved with 1 injection and 13 (9%) of the bleeds were resolved with 2 injections of Refixia.
\*\*Overall haemostatic efficacy\*\*
Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg for severe bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacy was performed by the patient or caretaker (for home treatment) or study site investigator (for treatment under 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 treated patients was 92% (626 out of 683). Of the 677 treated bleeds observed in 84 (80%) of the 105 patients, 590 (86%) of the bleeds were resolved with 1 injection and 70 (10%) of the bleeds were resolved with 2 injections of Refixia
The success rate and dose needed for treatment of the bleeding episodes were independent of the localisation of the bleed. The success rate for treatment of bleeding episodes was also independent of whether the bleed was traumatic or spontaneous of nature.
\*\*Surgery\*\*
Three trials, of which one trial was a dedicated surgery trial, included in total 15 major and 26 minor surgery procedures (patients aged 13 to 56 years). Haemostatic effect of Refixia during surgery was confirmed with a success rate of 100% in the 15 major surgeries in the trials. All evaluated minor surgeries were performed successfully.
In a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in 13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1 gastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of 80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of 80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In the post-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg doses administered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and after surgery 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%). The analysis of plasma samples was conducted using the one-stage clotting assay.
Steady state pharmacokinetic parameters for adolescents and adults are shown in Table 4
\*\*Table 6 Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescent and adult PTPs (geometric mean (CV%))\*\*
| | | |
| --- | --- | --- |
| \*\*PK Parameter\*\* | \*\*13–17 years N=3\*\* | \*\*≥18 years N=6\*\* |
| Half-life (t1/2) (hours) | 103 (14) | 115 (10) |
| Incremental Recovery (IR) (IU/ml per IU/kg) | 0.018 (28) | 0.019 (20) |
| Area under the curve (AUC)0-168h (IU\\*hours/ml) | 91 (22) | 93 (15) |
| 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 (IU/ml) | 0.29 (19) | 0.32 (17) |
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = 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 above 0.24 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\*\* \*\*N=12\*\* | \*\*7–12 years\*\* \*\*N=13\*\* | \*\*13–17 years\*\* \*\*N=3\*\* | \*\*≥18 years\*\* \*\*N=6\*\* |
| Half-life (t1/2) (hours) | 70 (16) | 76 (26) | 89 (24) | 83 (23) |
| Incremental Recovery (IR) (IU/ml per IU/kg) | 0.015 (7) | 0.016 (16) | 0.020 (15) | 0.023 (11) |
| Area under the curve (AUC)inf (IU\\*hours/ml) | 46 (14) | 56 (19) | 80 (35) | 91 (16) |
| Clearance CL (ml/hour/kg) | 0.8 (13) | 0.6 (22) | 0.5 (30) | 0.4 (15) |
| Mean residence time (MRT) (hours) | 95 (15) | 105 (24) | 124 (24) | 116 (22) |
| Volume of distribution (Vss) (ml/kg) | 72 (15) | 68 (22) | 59 (8) | 47 (16) |
| Factor IX activity 168 h post dosing (IU/ml) | 0.08 (16) | 0.11 (19) | 0.15 (60) | 0.17 (31) |
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = 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 higher compared to adults. No dose adjustment was required for paediatric or adolescent patients in clinical trials.
The mean trough levels at steady state are presented in Table 8; based on all pre-dose measurements taken 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 state\*\*
| | | | | |
| --- | --- | --- | --- | --- |
| | \*\*0–6 years N=12\*\* | \*\*7–12 years N=13\*\* | \*\*13–17 years N=9\*\* | \*\*18–65 years N=20\*\* |
| Estimated mean factor IX trough levels IU/ml (95% CI) | 0.15 (0.13;0.18) | 0.19 (0.16;0.22) | 0.24 (0.20;0.28) | 0.29 (0.26;0.33) |
\\* 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 apparent differences in the pharmacokinetic profiles between normal weight and overweight patients.
In the paediatric PTP trial, the Factor IX mean trough levels at steady state were within the range of mild haemophilia (i.e. 0.05–0.4 IU/ml), independent of age.
In the paediatric PUP trial, the estimated mean trough level at steady state was 0.15 IU/ml in patients < 6 years old, i.e., within the range of mild haemophilia.5.3 Preclinical safety data
A juvenile animal neurotoxicity study was conducted to evaluate the potential neurotoxicity of Refixia when intravenously administered 120-1 200 IU/kg/twice weekly in immature male rats from 3 to 13 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 was detected 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 or pathological 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 post dosing 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). No mechanism 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 and repeated dose toxicity studies in rats and monkeys.
In repeat dose toxicity studies in rats and monkeys, 40 kDa polyethylene-glycol (PEG) was detected by immunohistochemical staining in epithelial cells of choroid plexus in the brain. This finding was not 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 in urine (44–56%) 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 reach steady 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 adverse effect level (NOAEL) versus predicted clinical PEG-exposure, ranged from 5-fold in the juvenile rat neurotoxicity 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 determine the effects of Refixia on genotoxicity, fertility, development, or reproduction have not been performed.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*\*Powder\*\*
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)
\*\*Solvent\*\*
Histidine
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 medicinal products or reconstituted with infusion solutions other than the provided histidine solvent.6.3 Shelf life
\*\*Unopened\*\*
30 months. During the shelf life Refixia may be stored up to 30 °C for a single period not exceeding 1 year. Once the product has been taken out of the refrigerator the product must not be returned to the refrigerator. Please record the beginning of storage at room temperature on the product carton.
\*\*After reconstitution\*\*
Chemical 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).
From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the users and 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 and validated aseptic conditions.6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C). Do not freeze.
Store in the original package 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 supplied in the syringe. After reconstitution the solution appears as a clear and colourless liquid, free of visible particles. Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. Do not use solutions that are cloudy or have deposits.
For instructions on reconstitution of the medicinal product before administration, see the package leaflet.
The rate of administration should be determined by the patient's comfort level up to a maximum injection rate of 4 ml/min.
An infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters will also be needed. These devices are not included in the Refixia package.
Always use an aseptic technique.
\*\*Disposal\*\*
After 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 local requirements.
- Instruction Content
- ## 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.
## Clinical Particulars
4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
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 monitoring\*\*
Routine monitoring of factor IX activity levels for the purpose of dose adjustment is not necessary. In the clinical trial programme, dose adjustment was not performed. Mean steady state factor IX trough levels ≥ 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 aPTT reagents, it is recommended to use a chromogenic assay (e.g. Rox Factor IX or Biophen) when monitoring is needed. If a chromogenic assay is not available, it is recommended to use a one-stage clotting assay with an aPTT reagent (e.g. Cephascreen) qualified for use with Refixia. For modified long-acting factor products, it is known that the one-stage clotting assay results are highly dependent on the aPTT reagent and reference standard used. For Refixia some reagents will cause underestimation (30–50%), while most silica containing reagents will cause severe overestimation of the factor IX activity (more than 400%). Therefore, silica based reagents should be avoided. Use of a reference laboratory is recommended when a chromogenic assay or a qualified one-stage clotting assay is not available locally.
\*\*Posology\*\*
The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma).
\*\*\*Prophylaxis\*\*\*
40 IU/kg body weight once weekly.
Adjustments of doses and administration intervals may be considered based on achieved FIX levels and individual bleeding tendency. The trough levels achieved with the weekly 40 IU/kg dosing regimen are summarised in section 5.2.
Patients on prophylaxis who forget a dose are advised to take their dose upon discovery and thereafter continue 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 haemorrhage\*\* | \*\*Recommended dose IU/kg of Refixia\*\* | \*\*Dosing recommendations\*\* |
| Early haemarthrosis, muscle bleeding or oral bleeding. More extensive haemarthrosis, muscle bleeding or haematoma. | 40 | A single dose is recommended. |
| Severe or life threatening haemorrhages. | 80 | Additional doses of 40 IU/kg can be given. |
\*\*\*Surgery\*\*\*
The dose level and dosing intervals for surgery depend on the procedure and local practice. General recommendations are provided in Table 2.
\*\*Table 2 Treatment in surgery with Refixia\*\*
| | | |
| --- | --- | --- |
| \*\*Type of surgical procedure\*\* | \*\*Recommended dose IU/kg body weight\*\* | \*\*Dosing recommendations\*\* |
| Minor surgery including tooth extraction. | 40 | Additional doses can be given if needed. |
| Major surgery. | 80 | Pre-operative dose. |
| 40 | Consider two repeated doses of 40 IU/kg (in 1–3 day intervals) within the first week after surgery. Due to the long half-life of Refixia, the frequency of dosing in the post-surgical period may be extended to once weekly after the first week until bleeding stops and healing is achieved. |
\*\*\*Paediatric population\*\*\*
The dose recommendations in children are the same as for adults: (for more details on paediatrics see sections 5.1 and 5.2).
\*\*Method of administration\*\*
Intravenous use.
Refixia is administered by intravenous bolus injection over several minutes after reconstitution of the powder for injection with the histidine solvent. The rate of administration should be determined by the patient'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
\*\*Traceability\*\*
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
\*\*Hypersensitivity\*\*
Allergic type hypersensitivity reactions are possible with Refixia. The product contains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early 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.
\*\*Inhibitors\*\*
After repeated treatment with human coagulation factor IX products, patients should be monitored for the 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 IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased 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 IX should, according to the treating physician's judgement, be performed under medical observation where 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 Nijmegen modified Bethesda assay for inhibitor testing. Therefore a pre-heating step or a wash-out is recommended in order to ensure detection of low-titre inhibitors.
\*\*Thromboembolism\*\*
Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of 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 the cardiovascular risk.
\*\*Catheter-related complications\*\*
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
\*\*Paediatric population\*\*
The listed warnings and precautions apply both to children and adults.
\*\*Sodium content\*\*
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium-free”.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 have been reported.4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only if 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
\*\*Summary of the safety profile\*\*
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely with 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 have occurred 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 in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre is contacted.
There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia is rarely associated with such adverse reactions.
\*\*Tabulated list of adverse reactions\*\*
The 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); very rare (< 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 50 previously untreated patients (PUPs) with moderate or severe haemophilia B have been exposed to Refixia for a total of 434 patient years in the completed and on-going clinical trials.
\*\*Table 3 Frequency of adverse reactions in clinical trials\*\*
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Adverse reaction\*\* | \*\*Frequency\*\* |
| Blood and lymphatic system disorders | Factor IX inhibition | Common\\* |
| Immune system disorders | Hypersensitivity Anaphylactic reaction | Common Common\\* |
| Cardiac disorders | Palpitations | Uncommon |
| Gastrointestinal disorders | Nausea | Common |
| Skin and subcutaneous tissue disorders | Pruritus\\*\\* Rash | Common Common |
| General disorders and administration site conditions | Fatigue Hot flush Injection site reactions\\*\\*\\* | Common Uncommon Common |
\\* Frequency based on occurrence in PUP trial (N=50)
\\*\\*Pruritus includes the terms pruritus and ear pruritus
\\*\\*\\*Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and injection site rash.
\*\*Description of selected adverse reactions\*\*
Factor IX inhibition and anaphylactic reactions have not been observed in PTPs, and frequencies are therefore based on an ongoing PUP trial with 50 patients. In this trial, Factor IX inhibition occurred in 4/50 (8%) and anaphylactic reaction occurred in 1/50 (2%) categorising these events as common. The case with anaphylactic reaction occurred in a patient that also developed Factor IX inhibition.
\*\*Paediatric population\*\*
Frequency, type and severity of adverse reactions in children are expected to be similar as in adults.
\*\*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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Overdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated with overdoses have been reported.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04.
\*\*Mechanism of action\*\*
Refixia 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 the molecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated factor IX molecule.
Factor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it is synthesised 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 X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
\*\*Clinical efficacy\*\*
The clinical trial programme included one phase 1 trial and five phase 3 multicentre, non-controlled trials. 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 and between different clinical trials.
\*\*\*Prophylaxis\*\*\*
One hundred and 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 had no bleeding episodes (see details below).
\*\*\*Pivotal trial\*\*\*
The pivotal trial included 74 adolescent (13–17 years) and adult (18–65 years) previously treated patients (PTPs). The trial included one open-label on-demand arm with treatment for approximately 28 weeks and two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or 40 IU/kg once-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kg treatments, the annualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lower than 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/kg once weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00 (0.00; 2.05), joint ABR was 0.97 (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 for 16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment of breakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70 bleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds.
In 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one year with a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longer considered 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-demand regimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overall success rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleeds treated with one or two injections.
\*\*Paediatric population\*\*
Previously 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 patients initially enrolled at 0 to 12 years of age received routine prophylactic administration of Refixia 40 IU/kg once weekly for 52 weeks. The patients were stratified into two age groups; 12 patients were 0 to 6 years and 13 patients 7 to 12 years at the time of signing informed consent. Twenty-two patients continued on to the extension phase and out of those, 12 patients had up to 8 years of routine prophylactic treatment. Due to the long trial duration several patients crossed age-groups and 10 patients that were initially enrolled as ≤ 6 years also contributed to the age category of 7-12 years. Main efficacy results in patients ≤ 12 years separated by main and extension phase are summarised in table 4.
\*\*Table 4: Annualised Bleeding Rate (ABR) in the Paediatric PTP Trial - Main & Extension Phase – actual age groups\*\*
| | | | | |
| --- | --- | --- | --- | --- |
| | \*\*Main Phase\*\* | | \*\*Extension Phase\*\* | |
| \*\*Age of patient\\*\*\* | \*\*≤ 6 years\*\* \*\*N=12\*\* | \*\*7-12 years\*\* \*\*N=14\*\* | \*\*≤ 6 years\*\* \*\*N=10\*\* | \*\*7-12 years\*\* \*\*N=20\*\* |
| \*\*Mean treatment period (years)\*\* | 0.86 | 0.92 | 2.39 | 3.09 |
| \*\*Total ABR\*\* | | | | |
| Poisson-estimated mean (95% CI) | 0.97 (0.50; 1.89) | 2.10 (1.34; 3.30) | 1.05 (0.65; 1.69 | 0.58 (0.21; 1.64) |
| Median (IQR) | 0.00 (0.00; 1.99) | 2.00 (0.00; 3.02) | 0.00 (0.00; 1.65) | 0.15 (0.00; 1.29) |
\\*Some patients contributed to both age groups.
For the main and extension phase of the trial together, the overall median/poisson-estimated ABR was 0.55/1.02 (95% CI: 0.68; 1.54) in patients ≤ 6 years and 0.52/0.84 (95% CI: 0.41; 1.75) in patients 7-12 years. The median/poisson-estimated ABR was 0/0.2 (95% CI: 0.09; 0.47) and 0/0.23 (95% CI: 0.05; 0.96) for spontaneous bleeds as well as 0.53/0.82 (95% CI: 0.55; 1.23) and 0.33/0.56 (95% CI: 0.25; 1.27) for traumatic bleeds in patients ≤ 6 years and patients 7-12 years, respectively. Treatment success (defined as excellent or good response) was concluded for 88.6% and 93.7% of bleeding episodes that occurred during prophylaxis in patients ≤ 6 years and patients 7-12 years, respectively. Five out of 25 patients (20%) did not have any bleeds throughout the trial.The mean annual consumption for prophylaxis was 2 208.6 (SD: 78.8) IU/kg and 2 324.8 (SD: 83.3) 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. In the main phase of the paediatric PUP trial, 47 out of 50 patients < 6 years old received 40 IU/kg once weekly and 38 patients continued on to the extension phase. 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\*\* \*\*N=47\*\* | \*\*Extension Phase\*\* \*\*N=38\*\* |
| \*\*Mean treatment period (years)\*\* | 0.75 | 2.23 |
| \*\*Total ABR\*\* | | |
| Poisson-estimated mean (95% CI) | 0.82 (0.34 ; 1.98) | 0.58 (0.35 ; 0.96) |
| Median (IQR) | 0.00 (0.00 ; 1.02) | 0.00 (0.00 ; 0.88) |
The overall median ABR was 0 for spontaneous, traumatic, and joint bleeding episodes. For the trials main and extension phase the median/poisson-estimated ABR was 0.25/0.65 (95% CI: 0.34; 1.25) for PUPs on prophylaxis. The poisson-estimated ABRs for spontaneous and traumatic bleeds were 0.14 (95% CI: 0.05; 0.43) and 0.2 (95% CI: 0.05; 0.81) throughout the trial period, respectively (the median ABRs was 0 for both).46.8% of PUPs did not experience any bleeding events. None of the paediatric patients developed target joints in the trial. The overall success rate (defined as excellent or good) for treatment of bleeds in previously untreated patients was 96% (135 out of 140). Of the 140 treated bleeds observed in 34 (68%) out of 50 patients, 124 (89%) of the bleeds were resolved with 1 injection and 13 (9%) of the bleeds were resolved with 2 injections of Refixia.
\*\*Overall haemostatic efficacy\*\*
Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg for severe bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacy was performed by the patient or caretaker (for home treatment) or study site investigator (for treatment under 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 treated patients was 92% (626 out of 683). Of the 677 treated bleeds observed in 84 (80%) of the 105 patients, 590 (86%) of the bleeds were resolved with 1 injection and 70 (10%) of the bleeds were resolved with 2 injections of Refixia
The success rate and dose needed for treatment of the bleeding episodes were independent of the localisation of the bleed. The success rate for treatment of bleeding episodes was also independent of whether the bleed was traumatic or spontaneous of nature.
\*\*Surgery\*\*
Three trials, of which one trial was a dedicated surgery trial, included in total 15 major and 26 minor surgery procedures (patients aged 13 to 56 years). Haemostatic effect of Refixia during surgery was confirmed with a success rate of 100% in the 15 major surgeries in the trials. All evaluated minor surgeries were performed successfully.
In a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in 13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1 gastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of 80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of 80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In the post-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg doses administered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and after surgery 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%). The analysis of plasma samples was conducted using the one-stage clotting assay.
Steady state pharmacokinetic parameters for adolescents and adults are shown in Table 4
\*\*Table 6 Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescent and adult PTPs (geometric mean (CV%))\*\*
| | | |
| --- | --- | --- |
| \*\*PK Parameter\*\* | \*\*13–17 years N=3\*\* | \*\*≥18 years N=6\*\* |
| Half-life (t1/2) (hours) | 103 (14) | 115 (10) |
| Incremental Recovery (IR) (IU/ml per IU/kg) | 0.018 (28) | 0.019 (20) |
| Area under the curve (AUC)0-168h (IU\\*hours/ml) | 91 (22) | 93 (15) |
| 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 (IU/ml) | 0.29 (19) | 0.32 (17) |
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = 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 above 0.24 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\*\* \*\*N=12\*\* | \*\*7–12 years\*\* \*\*N=13\*\* | \*\*13–17 years\*\* \*\*N=3\*\* | \*\*≥18 years\*\* \*\*N=6\*\* |
| Half-life (t1/2) (hours) | 70 (16) | 76 (26) | 89 (24) | 83 (23) |
| Incremental Recovery (IR) (IU/ml per IU/kg) | 0.015 (7) | 0.016 (16) | 0.020 (15) | 0.023 (11) |
| Area under the curve (AUC)inf (IU\\*hours/ml) | 46 (14) | 56 (19) | 80 (35) | 91 (16) |
| Clearance CL (ml/hour/kg) | 0.8 (13) | 0.6 (22) | 0.5 (30) | 0.4 (15) |
| Mean residence time (MRT) (hours) | 95 (15) | 105 (24) | 124 (24) | 116 (22) |
| Volume of distribution (Vss) (ml/kg) | 72 (15) | 68 (22) | 59 (8) | 47 (16) |
| Factor IX activity 168 h post dosing (IU/ml) | 0.08 (16) | 0.11 (19) | 0.15 (60) | 0.17 (31) |
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = 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 higher compared to adults. No dose adjustment was required for paediatric or adolescent patients in clinical trials.
The mean trough levels at steady state are presented in Table 8; based on all pre-dose measurements taken 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 state\*\*
| | | | | |
| --- | --- | --- | --- | --- |
| | \*\*0–6 years N=12\*\* | \*\*7–12 years N=13\*\* | \*\*13–17 years N=9\*\* | \*\*18–65 years N=20\*\* |
| Estimated mean factor IX trough levels IU/ml (95% CI) | 0.15 (0.13;0.18) | 0.19 (0.16;0.22) | 0.24 (0.20;0.28) | 0.29 (0.26;0.33) |
\\* 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 apparent differences in the pharmacokinetic profiles between normal weight and overweight patients.
In the paediatric PTP trial, the Factor IX mean trough levels at steady state were within the range of mild haemophilia (i.e. 0.05–0.4 IU/ml), independent of age.
In the paediatric PUP trial, the estimated mean trough level at steady state was 0.15 IU/ml in patients < 6 years old, i.e., within the range of mild haemophilia.5.3 Preclinical safety data
A juvenile animal neurotoxicity study was conducted to evaluate the potential neurotoxicity of Refixia when intravenously administered 120-1 200 IU/kg/twice weekly in immature male rats from 3 to 13 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 was detected 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 or pathological 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 post dosing 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). No mechanism 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 and repeated dose toxicity studies in rats and monkeys.
In repeat dose toxicity studies in rats and monkeys, 40 kDa polyethylene-glycol (PEG) was detected by immunohistochemical staining in epithelial cells of choroid plexus in the brain. This finding was not 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 in urine (44–56%) 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 reach steady 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 adverse effect level (NOAEL) versus predicted clinical PEG-exposure, ranged from 5-fold in the juvenile rat neurotoxicity 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 determine the effects of Refixia on genotoxicity, fertility, development, or reproduction have not been performed.
## Pharmaceutical Particulars
6.1 List of excipients
\*\*Powder\*\*
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)
\*\*Solvent\*\*
Histidine
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 medicinal products or reconstituted with infusion solutions other than the provided histidine solvent.6.3 Shelf life
\*\*Unopened\*\*
30 months. During the shelf life Refixia may be stored up to 30 °C for a single period not exceeding 1 year. Once the product has been taken out of the refrigerator the product must not be returned to the refrigerator. Please record the beginning of storage at room temperature on the product carton.
\*\*After reconstitution\*\*
Chemical 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).
From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the users and 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 and validated aseptic conditions.6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C). Do not freeze.
Store in the original package 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 supplied in the syringe. After reconstitution the solution appears as a clear and colourless liquid, free of visible particles. Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. Do not use solutions that are cloudy or have deposits.
For instructions on reconstitution of the medicinal product before administration, see the package leaflet.
The rate of administration should be determined by the patient's comfort level up to a maximum injection rate of 4 ml/min.
An infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters will also be needed. These devices are not included in the Refixia package.
Always use an aseptic technique.
\*\*Disposal\*\*
After 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 local requirements.
