Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

Refixia can be used for all age groups.

Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.

Treatment monitoring

Routine monitoring of factor IX activity levels with the goal of dose adjustment is generally not required. No dose adjustment was made in the clinical trial program. Mean trough levels of factor IX steady state ≥15% were observed in all age groups, see section 5.2 for details.

For modified long-acting factor preparations, the results of the one-step coagulation test are known to be highly dependent on the aPTT reagents used and the reference standard. For Refixia®, polyethylene glycol (PEG) may cause interference in the one-step coagulation test, but not in the chromogenic test. Certain aPTT reagents such as Cephascreen® and SynthaFax® have been proven in laboratory studies to be worthwhile for reliable monitoring after the infusion of Refixia®. However, it is recommended that silicon based reagents not be used as they may result in overestimates. The chromogenic test is not affected by PEG and the FIX kits ROX FACTOR IX and BIOPHEN Factor IX have in laboratory studies proven their worth for use with nonacog beta pegol. They can be used for reliable monitoring after the administration of Refixia®.

Posology

One International Unit (IU) of factor IX activity is equivalent to the amount of factor IX in a milliliter of normal human 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 

Surgery

The dose level and dosing intervals for surgery depend on the procedure and local practice. Refer to Table 2 for general recommendations.

Table 2       Treatment in surgery with Refixia® 

    Paediatric population

    In children, the same dose is recommended as in adults: 40 IU/kg of body weight.

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 how to reconstitute the medicinal product prior to administration, see section 6.6.

Appropriate training is recommended prior to administration of the product.

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

As with all protein products for intravenous use, hypersensitivity reactions typical of allergy are also possible with Refixia®. The preparation contains trace amounts of hamster proteins. Patients should be advised to discontinue the use of the medicinal product immediately in the event of signs of hypersensitivity and to contact the treating physician. You must be informed of the first signs of hypersensitivity reactions, including hives, generalized urticaria, chest tightness, wheezing, low blood pressure and anaphylaxis.

In case of anaphylactic shock, current medical standards of shock treatment should be followed.

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.

Due to the risk of allergic reactions that may occur with factor IX preparations, the first administration of factor IX should be performed under medical supervision according to the treating physician’s judgment so that appropriate medical care can be provided in case of allergic reactions.

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

Due to the potential risk of thrombotic complications, clinical monitoring for early signs of thrombotic and consumption coagulopathy should be initiated by appropriate biological testing when administered to patients with liver disease, postoperative patients, neonates, or patients at risk of thrombotic phenomena or DIC. In these situations, the benefits of treatment with Refixia® must be balanced against the risk of these complications.

Cardiovascular event

In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.

Nephrotic syndrome

Nephrotic syndrome has been reported following attempted treatment for immunological tolerance induction with factor IX in patients with hemophilia B and often a history of allergic reaction.

Catheter-related complications

If a central venous access device (CVAD) is required, the risk of CVAD-associated complications, including local infection, bacteremia, and thrombosis at the catheter insertion site, should be considered.

Paediatric population

The listed warnings and precautions apply to both adults and children.

No interactions of human coagulation factor IX (rDNA) preparations with other medicinal products have been reported.

Animal reproductive studies have not been conducted with factor IX. Due to the rare occurrence of hemophilia B in women, there is no clinical experience with the use of factor IX during pregnancy and breastfeeding. Therefore, factor IX should only be used during pregnancy and lactation if clearly indicated.

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

Summary of the safety profile

Hypersensitivity or allergic reactions (including 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 developed to severe anaphylaxis, and have  occurred in close temporal association with development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported following attempted immunological tolerance induction with factor IX inhibitors in patients with hemophilia B and a history of allergic reaction.

Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.

Patients with hemophilia B may develop neutralizing antibodies (inhibitors) to factor IX. The occurrence of such inhibitors manifests as an inadequate clinical response. In such cases, contact with a specialized hemophilia center is recommended.

There is a potential risk of thromboembolic episodes following the administration of factor IX preparations, with a higher risk for low purity preparations. The use of low purity factor IX preparations has been associated with cases of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX such as Refixia® is rarely associated with such adverse effects.

Tabulated list of adverse reactions

The table below is based on MedDRA Organ Classes (SOC and Preferred Term Level).

Frequencies are defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency class, adverse reactions are listed in order of decreasing severity.

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

* 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 effects

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.

Peadiatric population

Frequency, type and severity of adverse reactions in children are expected to be similar as in adults.

Reporting of suspected adverse reactions

 Overdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated with overdoses have been reported.

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 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

*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

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).

Refixia® has an extended half-life compared to unmodified factor IX. All pharmacokinetic studies of Refixia® were conducted in previously treated patients with hemophilia B (factor IX ≤2%). Plasma samples were analyzed using the one-stage coagulation test.

Steady-state pharmacokinetic parameters for adolescents and adults are shown in Table 5.

Table 6       Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescents and adults PTPs (geometric mean (CV%)) 

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.

In all patients evaluated in the steady-state PK study, activity levels were above 0.24 IU/mL with weekly administration of 40 IU/kg of factor IX 168 hours post dose.

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%)) 

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 necessary for paediatric or adolescent patients.

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       Refixia® factor IX trough levels* (40 IU/kg) by age at steady state 

* Factor IX trough level = factor IX activity measured at all visits prior to the following weekly dose (5 to 10 days post dose).

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.

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 (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 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.

Powder

Sodium chloride

Histidine

Sucrose

Polysorbate 80

Mannitol

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Solvent

Histidine

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

In the absence of compatibility studies, Refixia® must not be mixed or reconstituted with solvents other than the accompanying histidine solution.

Do not administer reconstituted Refixia® through the same tubing and containers as other medicinal products.

Store in a refrigerator (2°C – 8°C). Do not freeze.

Store in the original package in order to protect from light.

Keep out of the sight and reach of children.

For storage at room temperature and storage conditions after reconstitution of the medicinal product, see section 6.3.

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.

Refixia® should be administered intravenously after reconstitution of the powder with the solvent provided in the injection syringe. After reconstitution, the solution appears to be a clear and colorless solution that is free of visible particles. The reconstituted medicinal product should be visually inspected for particulate matter and discoloration prior to administration. Do not use solutions that are cloudy or have deposits.

The rate of administration should depend on the patient’s condition, with a maximum injection rate of 4 mL/min.

You will also need an infusion set (tubing and butterfly needle), sterile alcohol wipes, gauze pads, and patches. These materials are not included with Refixia®.

Always use an aseptic technique.

Disposal

Dispose of the syringe containing the infusion set and vial with the adapter for the vial safely after injection. Dispose of any unused product and other waste materials according to local requirements.