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

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

The safety and efficacy of Refixia® in previously untreated patients has not been examined. Limited data are currently available.

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 above 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

Subjects who are treated for long-term prophylaxis and miss a dose will be instructed to administer their dose when they forget to do so and then continue with their usual dosing schedule of a weekly dose. A double dose should be avoided. The recommended dose for the prophylaxis of bleeding in adult previously treated patients with hemophilia B (congenital factor IX deficiency) is 40 IU/kg of Refixia®.

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.

In order to ensure the traceability of biotechnologically manufactured medicinal products, it is recommended that the trade name and batch number be documented in the case of each treatment.

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 (rDNA) 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.

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.

Immunological tolerance induction

The safety and efficacy of the use of Refixia® for immunological tolerance induction have not been studied.

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.

Previously treated patients:

A total of 115 previously treated male patients with moderate or severe hemophilia B received Refixia® for a total of 170 patient-years in the clinical trials conducted.

Table 3       Frequency of adverse reactions in clinical trials

*Number of patients with reaction divided by the sum of all patients exposed in all clinical trials (115).

**Pruritus includes the terms pruritus and ear itching

***Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and  injection site rash.

Previously untreated patients

In an ongoing trial in previously untreated patients, anaphylaxis has occurred in close temporal association with development of factor IX inhibitors after treatment with Refixia®. The likelihood of developing the inhibitor and an anaphylactic reaction is increased in the early phases of substitution treatment (see section 4.4).

Description of selected adverse effects

Not applicable

Peadiatric population

Previously treated patients: No differences in the safety profile of Refixia® were observed between previously treated children and adults.

Previously untreated patients: See undesirable effects under “Tabular presentation of undesirable effects” – “Undesirable effects in previously untreated patients”.

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) conjugated with a 40 kDa polyethylene glycol (PEG). The mean molecular mass of Refixia® is approximately 98 kDa and the molecular mass of the protein content alone is 56 kDa.

Factor IX is a single-chain glycoprotein. It is a vitamin K-dependent coagulation factor that is synthesized in the liver. Factor IX is activated by factor XIa and factor VII/tissue factor complex.

After the activation of Refixia®, the activation peptide, including the 40 kDa polyethylene glycol molecule, is cleaved, leaving the original factor IX molecule. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, creating a clot.

Hemophilia B is a sex-linked hereditary clotting disorder in which the decreased levels of factor IX result in severe bleeding into joints, muscles, or internal organs either spontaneously or as a result of an accident or surgical trauma. Factor IX plasma levels are increased by substitution treatment, with temporary correction of factor deficiency and bleeding diathesis.

Clinical efficacy

The clinical trial program conducted included a Phase 1 study and four multicenter, uncontrolled Phase 3 studies. The total number of previously treated male patients with hemophilia B (factor IX activity ≤2%) included in the clinical trial program was 115; 72 adult patients (aged 18 years and older), 18 adolescents (aged 13 to 17 years) and 25 children (aged 0 to 12 years). Ten patients participated in only the single-dose PK study. The overall exposure in the clinical trial program was 8,801 days of exposure with Refixia® and 40 (35%) of the 115 patients were treated for more than 2 years. Of these patients, 21 children continued treatment in the extension phase of the ongoing pediatric study with at least 2 years of treatment.

The pivotal study included 74 previously treated adolescents (13 to 17 years) and adults (18 to 65 years). The study included an open-label arm in which patients were treated as needed and were treated for approximately 28 weeks, and two prophylaxis arms with single-blind randomization at 10 IU/kg or 40 IU/kg once weekly for approximately 52 weeks. Only the prophylactic dose of 40 IU/kg resulted in a pre-defined reduction in the annualized bleeding rate compared to the clinically relevant annualized bleeding rate from the history. When comparing the 10 IU/kg and 40 IU/kg treatments, the annualized bleeding rate of patients in the 40 IU/kg arm was 49% lower than the bleeding rate of patients in the 10 IU/kg arm (p < 0.05).

The treatment period in the pediatric study included 52 weeks. Included in the studies were 25 previously treated pediatric patients (aged 0 to 12 years) who received a prophylactic dose of 40 IU/kg once a week.

In the studies, bleeding episodes were treated with Refixia® 40 IU/kg for mild or moderate bleeding or 80 IU/kg for severe bleeding.

An overall assessment of efficacy was made by the patient (treatment at home) or the investigator at the study site (treatment under the supervision of healthcare professionals) using a 4-point scale (excellent, good, moderate, or poor). The overall success rate (defined as excellent or good) for the treatment of bleeding was 93% (551 of 591) after pooling all studies. Of 597 bleeds treated, which occurred in 79 (75%) of the 105 patients, 521 (87%) were stopped with one injection and another 60 (10%) with 2 injections of Refixia®.

The success rate and dose required to treat bleeding episodes were independent of the location of the bleeding. The success rate of the treatment of bleeding episodes was also not dependent on whether the bleeding was traumatic or spontaneous in nature.

Prophylaxis

54 (47%) of patients were treated with a weekly prophylactic dose of 40 IU/kg. No bleeding episodes occurred in 23 (43%) of these patients. The median annualized bleeding rates for these patients are presented in Table 4.

Table 4       Annualized bleeding rates in patients (0-65 years) treated with a prophylactic dose of 40 IU/kg once weekly (median (IQR))

In the pivotal adolescent and adult study, all patients who experienced spontaneous bleeding during the period of once-weekly prophylaxis with nonacog beta pegol 40 IU/kg also had pre-existing joint disease in one or more joints at baseline as a result of their hemophilia B.

Out of 29 treated adults and adolescents, 13 patients with 20 target joints received a weekly prophylactic dose of 40 IU/kg for one year. 18 of these 20 joints (90%) were no longer considered target joints at the end of the study.

Acute treatment

The pivotal study included a non-randomized arm in which 15 patients received acute treatment with 40 IU/kg for mild and moderate bleeding and 80 IU/kg for major bleeding. The overall success rate (defined as excellent or good) for the treatment of bleeding was 95%, with 98% of bleeding treated with one injection or two injections.

Paediatric population

The European Medicines Agency has postponed the conduct of the study with Refixia® in previously untreated patients (see section “Posology/Administration” for information on use in children).

Surgery

Three studies, of which this was a dedicated surgical study, included a total of 15 more major and 26 more minor surgical procedures (patients aged 13 to 56 years). The hemostatic effect of Refixia® during surgery was confirmed with a success rate of 100% in the 15 more major surgical procedures in the studies. All more minor surgeries assessed were successfully performed.

In a dedicated surgery study, the efficacy analysis included 13 more major surgeries performed in 13 previously treated adults and adolescents. These were 9 orthopedic surgeries, 1 gastrointestinal surgery and 3 surgeries in the oral cavity. Patients received a preoperative injection of 80 IU/kg on the day of surgery and post-operative injections of 40 IU/kg.

A preoperative dose of 80 IU/kg of Refixia® was effective and no patient required additional doses on the day of surgery. In the postoperative period Days 1 to 6 and Days 7 to 13, the median number of additional 40 IU/kg doses was 2.0 and 1.5, respectively. The mean total consumption of Refixia® during and after surgery was 241 IU/kg (range: 81 to 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 5       Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescents and adults (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.

The pharmacokinetic parameters of a single dose of Refixia® in children, adolescents and adults are presented by age in Table 6.

Table 6       Pharmacokinetic parameters of a single dose of Refixia® (40 IU/kg) in children, adolescents and adults 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 estimated mean steady-state trough levels found during studies with weekly administration of 40 IU/kg are shown in Table 7.

Table 7       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.

Steady-state factor IX activity profiles were simulated using a onec-ompartment distribution model with first-order elimination kinetics with PK parameters for clearance (CL) and volume of distribution (Vss) at steady state.

Patients with hemophilia B (older than 13 years) treated with 40 IU/kg Refixia® once weekly have predicted factor IX activity above 0.40 IU/mL for 130 out of 168 hours, corresponding to 80% of the week.

Pharmacokinetics were assessed in 16 adults and adolescents, with 6 patients being of normal weight (BMI 18.5-24.9 kg/m2) and 10 being overweight (BMI 25-< 29.9 kg/m2). There were no apparent differences in the pharmacokinetic profiles of normal and overweight patients. Pharmacokinetic parameters were not affected by BMI.

The preclinical data based on the usual studies on safety, pharmacology and repeated-dose toxicity in animals do not indicate any concerns in the case of humans.

Long-term studies in animals that are intended to determine the carcinogenic potential of Refixia® and studies to determine the effects of Refixia® on genotoxicity, fertility, development or reproduction have not been conducted.

A review of the carcinogenic potential of Refixia® was conducted, with no carcinogenic risk identified.

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.