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IDELVION™
[Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP)]
Lyophilized Powder Reconstituted for Intravenous Injection
| Route of Administration | Dosage Form / Strength | Clinically Relevant Non-medicinal Ingredients |
| Intravenous Injection | Lyophilized powder in following nominal strengths: 250 IU1/vial, 500 IU/vial, 1000 IU/vial, 2000 IU/vial | Mannitol, Polysorbate 80, Sucrose, Trisodium citrate. For a complete listing see Dosage Forms, Composition and Packaging. |
The number of units of FIX administered is expressed in International Units (IU), which are related to the current WHO standard for FIX products. One IU of FIX activity in plasma is equivalent to that quantity of FIX in one mL of normal human plasma. FIX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for FIX in plasma).
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a long acting purified protein produced by recombinant DNA technology, generated by the genetic fusion of recombinant albumin to recombinant coagulation Factor IX (rFIX).
IDELVION is a preservative free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection (SWFI) for intravenous injection. It is available in single-use vials in the following presentations: 250 IU, 500 IU, 1000 IU, and 2000 IU of the active substance rIX-FP.
Proper name: Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP)
Chemical name: Albutrepenonacog Alfa
Molecular formula and molecular mass: Full length rIX-FP is expressed as a single chain glycopeptide of 1018 amino acids with a molecular weight of ~125 kDa.
Structural formula: The primary amino acid sequence is comparable to the most prevalent Thr148 allelic form of native FIX. rIX-FP was generated by the genetic fusion of recombinant human albumin to recombinant FIX. FIX complementary DNA (cDNA) was joined to human albumin cDNA by a FIX-derived cleavable linker sequence extended by an N-terminal proline residue.
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Physicochemical properties: The purified drug substance is a yellow to colorless solution that is visibly free of particulates. It is produced to have a minimum concentration of 8 mg/mL protein with a specific activity no less than 53 IU/mg.
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a long acting purified protein produced by recombinant DNA technology, generated by the genetic fusion of recombinant albumin to recombinant coagulation Factor IX (rFIX). The genetic fusion of the cDNA of human albumin to the cDNA of human coagulation Factor IX (FIX) enables the protein to be produced as a single recombinant protein and assures product homogeneity by avoiding chemical conjugation. The rFIX portion is identical to the Thr148 allelic form of plasma-derived FIX. The cleavable linker between the rFIX and albumin molecules is derived from the endogenous activation peptide in native FIX. rIX-FP remains intact in the circulation until FIX is activated, whereupon albumin is cleaved off, releasing activated FIX (FIXa) only when it is needed for coagulation.
No human or animal proteins are added during any stage of manufacturing or formulation of IDELVION. IDELVION is a glycoprotein consisting of 1018 amino acids secreted by a genetically engineered Chinese Hamster ovary (CHO) cell line. The CHO cell line secretes rIX-FP into a chemically defined, cell culture medium that does not contain hormones with the exception of recombinant human insulin, and the rIX-FP is purified by a chromatography purification process that does not require a monoclonal antibody step. The linker is derived from the actual activation peptide in native FIX. rIX-FP remains intact in the circulation until initiation of the coagulation cascade. The normal activation mechanism cleaves the albumin moiety simultaneously releasing albumin and activating FIX to facilitate coagulation. The manufacturing process includes two validated virus inactivation/removal steps, namely solvent/detergent treatment and nanofiltration.
The potency in International Units (IU) is determined using an in vitro activated partial thromboplastin time (aPTT)-based one-stage clotting assay calibrated against the World Health Organization (WHO) International Standard for FIX concentrate.
The manufacturing process has two dedicated, orthogonal virus reduction steps including nanofiltration.
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is an antihemophilic factor indicated in patients with hemophilia B (congenital FIX deficiency) or Christmas disease for:
Studies described in this monograph have been performed only in previously treated patients (PTPs).
See subsection Special Population, under Section WARNINGS AND PRECAUTIONS.
See subsection Special Population, under Section WARNINGS AND PRECAUTIONS.
Treatment with IDELVION should be initiated under the supervision of a healthcare professional experienced in the treatment of hemophilia B (factor IX deficiency).
The decision on the use of home treatment of bleeding and prophylaxis of bleeding in patients with haemophilia B should be made by the treating physician. The physician should ensure that appropriate training is provided and the use is reviewed at intervals.
For intravenous use after reconstitution only.
The recommended dose is 25 to 40 IU of IDELVION per kg body weight every 7 days, or 50 to 75 IU of IDELVION per kg every 14 days. Adjust the dosing regimen based upon the individual patient's clinical condition and response. The recommended dose regimen for pediatric patients is the same as for adults (See Section ACTION AND CLINICAL PHARMACOLOGY).
The calculation of the required dose of IDELVION is based on the empirical finding that one IU of IDELVION per kg body weight is expected to increase the circulating level of FIX by an average of 1.3 IU/dL (1.3% of normal) in patients ≥ 12 years of age and by 1.0 IU/dL (1.0% of normal) in patients < 12 years of age.
The required dose of IDELVION for treatment of bleeding episodes is determined using the following formula:
Required Units (IU) = body weight (kg) x desired FIX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL)
OR
Increase in FIX IU/dL (or % of normal) = Dose (IU) x Recovery (IU/dL per IU/kg)/body weight (kg)
Adjust the dose based on the individual patient's clinical condition and response.
For an incremental recovery of 1 IU/dL per 1 IU/kg, the dose is calculated as follows:
Dose (IU) = body weight (kg) x desired FIX increase (IU/dL) x 1 dL/kg
Example
For an incremental recovery of 1.3 IU/dL per 1 IU/kg, the dose is calculated as follows:
Dose (IU) = body weight (kg) x desired FIX increase (IU/dL) x 0.77 dL/kg
Example
3. A peak level of 50 % of normal is required in an 80 kg patient with severe haemophilia B. The appropriate dose would be 80 kg x 50 IU/dL x 0.77 dL/kg = 3080 IUs.
4. A dose of 2000 IUs of IDELVION, administered to a 80 kg patient, should be expected to result in a peak post-injection FIX increase of 2000 IUs x 1.3 (IU/dL per IU/kg) /80 kg = 32.5 IU/dL (32.5 % of normal).
A guide for dosing IDELVION in the control and prevention of bleeding episodes and perioperative management is provided in Table 2 and Table 3, respectively. Ensure that the FIX activity level is achieved and maintained in the corresponding period. The recommended circulating FIX level requirement for pediatric patients is the same as for adults (See Section ACTION AND CLINICAL PHARMACOLOGY).
Table 2: Dosing for Control and Prevention of Bleeding
Episodes
| Type of Bleeding Episode | Circulating FIX Level Required (%) (IU/dL) | Frequency of Dose (hours) / Duration of Therapy (Days) |
| Minor or Moderate Hemarthrosis, muscle bleeding (except iliopsoas) or oral bleeding | 30-60 | Single dose of 25-50 IU/kg should be sufficient for majority of bleeds. Maintenance dose after 48-72 hours, if there is further evidence of bleeding. |
| Major Life threatening hemorrhages, deep muscle bleeding, including iliopsoas | 60-100 | 50-80 IU/kg Repeat every 48-72 hours for the first week. Maintenance dose weekly until bleeding stops and healing is achieved. |
Table 3: Dosing for Perioperative Management
| Type of Surgery | Circulating FIX Required (% or IU/dL) | Dosing Interval (hours) Duration of Therapy (days) |
| Minor (including uncomplicated tooth extraction) | 50-80 (initial level) | Single dose of 40-60 IU/kg should be sufficient for a majority of minor surgeries. If needed, maintenance dose after 48-72 hours until bleeding stops and healing is achieved. |
| Major | 60-100 (initial level) | 50-80 IU/kg Repeat dose every 48-72 hours for the first week. Maintenance dose 1-2 times per week until bleeding stops and healing is achieved. |
The procedures provided in Table 4 are general guidelines for the preparation and reconstitution of IDELVION.
Table 4: IDELVION Reconstitution Instructions
Follow the steps below and use aseptic techniques to administer IDELVION.
A. PREPARATION
Prepare the vials/Mix2Vial® and infusion supplies.
Ensure that the diluent and IDELVION vials are at room temperature.
Prepare syringes, infusion sets and other supplies for the administration.
B. RECONSTITUTION: follow these steps to reconstitute IDELVION
1. Clean Stoppers:
Remove the flip caps from both vials (IDELVION and diluent). Wipe the rubber stoppers with an antiseptic and allow the rubber stopper to dry.
2. Open the Mix2Vial® package by peeling away the lid. To maintain sterility, leave the Mix2Vial® set in its clear outer package.
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3. Prepare Diluent Vial:
Place the diluent vial on an even flat surface and hold the vial tightly. Grip the Mix2Vial® keeping it in the package. Push the plastic spike at the blue end of the Mix2Vial® set firmly through the center of the diluent vial stopper.
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4.Remove the Mix2Vial® packaging:
While holding the diluent vial, carefully remove the outer package from the Mix2Vial® set. Make sure that you pull off only the package, not the Mix2Vial® set.
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5.Transfer Diluent into IDELVION Vial:
Place the product vial on an even flat surface and hold the vial tight. Invert the diluent vial with the Mix2Vial® set attached to it and push the plastic spike of the clear end of the Mix2Vial® end firmly through the stopper of the IDELVION vial. The diluent will transfer into the IDELVION vial automatically.
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6. Dissolve IDELVION:
With the diluent and IDELVION vial still attached to the Mix2Vial® set, gently swirl the IDELVION vial to ensure the product is fully dissolved. Do not shake the vial.
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7. Unscrew empty diluent (Blue) vial:
With one hand, grip the clear end of the Mix2Vial® set and with the other hand grip the blue end of the Mix2Vial® set and unscrew the set into two pieces.
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8. Load the syringe:
Draw air into an empty, sterile syringe. Use the syringe provided with the product. With the IDELVION vial upright, screw the syringe to the Mix2Vial® set. Inject air into the product vial. While keeping the syringe plunger pressed, invert the IDELVION vial and draw the solution into the syringe by pulling the plunger back slowly.
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9. Prepare the administration set equipped with microbore tubing:
Once the solution has been transferred into the syringe, firmly grip the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial® set. Attach the syringe to the provided infusion set or another suitable administration set.
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10. After reconstitution, administration should begin promptly or within 3 hours.
11.Use a separate, unused Mix2Vial® transfer set for each product vial.
C. Administer IDELVION using aseptic technique:
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a preservative free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection (SWFI) for intravenous injection. IDELVION is available in single-use vials containing actual FIX activity printed on the vial label and product carton, expressed in International Units (IU). Each vial contains nominally 250 IU, 500 IU, 1000 IU, or 2000 IU of IDELVION and must be reconstituted with the respective supplied volume of SWFI (diluent) listed in Table 7:
Table 7: Reconstitution Diluent Volume
| Lyophilized rIX-FP Format | Diluent Volume for Reconstitution | Concentration of product once reconstituted |
| 250 IU | 2.5 mL | 100 IU/mL |
| 500 IU | 2.5 mL | 200 IU/mL |
| 1000IU | 2.5 mL | 400 IU/mL |
| 2000IU | 5 mL | 400 IU/mL |
The IDELVION package consists of 2 boxes.
The “Product box” contains one single-use product vial containing lyophilized Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP) and one vial of Sterile Water for Injection (Diluent).
The “Device box” contains one Mix2Vial® filter transfer set, one syringe, one infusion set and a plaster (non-sterile).
After reconstitution of the lyophilized powder, all dosage strengths yield a clear, yellow to colorless solution. The concentrations of excipients based on the presentation are summarized in Table 8.
Table 8: Excipients within each
nominal composition of IDELVION following reconstitution with WFI
| Excipient | Nominal Composition after Reconstitution with WFI | |||
| 250 IU vial | 500 IU vial | 1000 IU vial | 2000 IU vial | |
| Tri-sodium citrate | 6.5 mg/mL | 6.5 mg/mL | 6.5 mg/mL | 6.5 mg/mL |
| Polysorbate 80 | 0.06 mg/mL | 0.12 mg/mL | 0.24 mg/mL | 0.24 mg/mL |
| Mannitol | 18 mg/mL | 29 mg/mL | 29 mg/mL | 29 mg/mL |
| Sucrose | 7 mg/mL | 12 mg/mL | 12 mg/mL | 12 mg/mL |
Product after reconstitution: the product administration should begin promptly or within 3 hours.
CSL Behring Canada, Inc. Revised: Jan 2016
The most common adverse reaction (incidence ≥ 1%) reported in clinical trials was headache.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
In 4 multicenter, prospective, open-label clinical trials with IDELVION, 107 previously treated patients (PTPs, exposed to a FIX-containing product for ≥ 100 exposure days) were evaluated. A total of 6,384 injections were administered over a median of 469 days (range: 25 to 986 days), with a median 3000 IU per injection (range: (138.9-10,570.0 IU). The median total amount of rIX-FP administered was 127,110.0 IU (range: 1900.0-999,051.4).
Two subjects withdrew from the study due to an adverse reaction (headache, infusion related reaction). No neutralizing antibodies (inhibitors) to FIX or antibodies to CHO host cell protein have been detected with the use of IDELVION. No events of anaphylaxis or thrombosis were reported.
Related Adverse Events were reported in 8 of 107 (7.5%) subjects. Out of these 8 cases, 5 cases were considered to be Adverse Reactions (ARs) and are listed in Table 1.
Table 1: Summary of Adverse Reactions
| MedDRA Standard System Organ Class | MedDRA Preferred Term (Adverse Reaction) | Number of subjects n (%), (N=107) |
Frequency Category |
| Nervous system disorders | Headache | 2 (1.9) | Uncommon |
| Dizziness | 1 (0.9) | Rare | |
| Skin and subcutaneous tissue disorders | Rash | 1 (0.9) | Uncommon |
| Immune system disorders | Infusion related reaction* | 1 (0.9) | Rare |
| * One patient reported a non-serious hypersensitivity reaction with atypical symptoms. This was later considered to be an infusion related reaction. | |||
One previously untreated patient from the ongoing clinical trial reported low-titer inhibitor against factor IX. There are insufficient data to provide information on inhibitor incidence in PUPs.
There are no known drug interactions reported with IDELVION. No drug interactions studies have been performed.
Included as part of the PRECAUTIONS section.
Hypersensitivity reactions, including anaphylaxis, have been reported with FIX-containing products. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis) occur, immediately discontinue administration and initiate appropriate treatment. Due to the risk of allergic reactions with FIX-containing products, use judgement to determine if initial administration of FIX should be administered under medical observation.
IDELVION contains trace amounts of Chinese hamster ovary (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Formation of inhibitors to FIX has been reported with the use of FIX replacement therapy in treating hemophilia B. Evaluate patients regularly for the development of neutralizing antibodies (inhibitors) by appropriate clinical observations or laboratory tests. Perform an assay that confirms the presence of an inhibitor and quantifies the titre if expected plasma FIX activity levels are not attained, or if the bleeding is not controlled with an appropriate dose. Contact a specialized hemophilia treatment center if bleeding is not controlled with the previously successful dose. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Closely observe patients for signs and symptoms of acute hypersensitivity reactions, particularly during early phases of exposure to the product.
Because of the potential risk of thrombotic complications with the use of FIX-containing products, 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 IDELVION should be weighed against the risk of these complications.
Nephrotic syndrome has been reported following attempted immune tolerance induction using FIX-containing products in hemophilia B patients with factor IX inhibitors. The safety and efficacy of using IDELVION for immune tolerance induction have not been established.
Animal reproduction and developmental toxicity studies have not been conducted with IDELVION. However, no adverse effects on reproductive organs were observed by macroscopic and microscopic pathological investigations in animal repeated dose toxicity studies. No investigations on impairment of fertility have been conducted.
Animal reproduction and developmental toxicity studies have not been conducted with IDELVION. It is also not known whether IDELVION can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Based on the rare occurrence of hemophilia B in women, experience regarding the use of FIX during pregnancy is not available. IDELVION should be given to a pregnant woman only if clearly needed.
IDELVION should only be administered to nursing mothers if clearly needed. Lactation studies have not been conducted with IDELVION. It is not known whether IDELVION is excreted into human milk. Caution should be exercised if IDELVION is administered to nursing mothers.
In clinical studies that included 34 subjects < 18 years old, the prophylactic administration with IDELVION every 7, 10, and 14 days was successful in prevention of spontaneous bleeding episodes requiring treatment (See Section Clinical Trials). The PK profile of IDELVION shows an average 5-fold increase in half-life when compared to a licensed regular acting FIX product. The data support a weekly to every 14 day dosing regimen for patients < 18 years. There were no apparent differences in the safety profile in subjects < 18 years as compared to adults (See Section ADVERSE REACTIONS). Compared to adults, incremental recovery appeared to be slightly lower and body weight-adjusted clearance appeared to be higher (See Section ACTION AND CLINICAL PHARMACOLOGY).
Clinical studies of IDELVION did not include subjects over 65 to determine whether or not they respond differently from younger subjects.
No symptoms of overdose with IDELVION have been reported.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is contraindicated in patients who have a known hypersensitivity to IDELVION, any of its components, excipients or hamster protein. For a complete listing, see Dosage Forms, Composition And Packaging.
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a recombinant fusion protein linking recombinant coagulation FIX with recombinant albumin that effectively replaces the missing coagulation FIX needed for hemostasis and provides for longer dose regimens. The prolongation of the half-life of IDELVION and the enhanced systemic exposure are achieved by fusion with recombinant albumin, which has a long intrinsic half-life. IDELVION remains intact in the circulation until FIX is activated, whereupon albumin is cleaved, releasing activated FIX (FIXa) when it is needed for coagulation. Albumin is a natural, inert carrier protein in plasma with a long half-life of approximately 20 days that is not involved in immune defense or immune response. Genetic fusion of recombinant coagulation FIX with albumin extends the half-life of FIX (See Sub-Section Pharmacokinetics).
Haemophilia B is a sex linked hereditary disorder of blood coagulation due to decreased levels of FIX 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 FIX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
FIX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic coagulation pathway. Activated FIX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. FIX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required.
The administration of IDELVION increases plasma levels of FIX, and can temporarily correct the coagulation defect in these patients.
The pharmacokinetics of IDELVION were evaluated following an intravenous injection of a single dose of 25, 50 and 75 IU/kg. The PK parameters were based on plasma FIX activity measured by the one-stage clotting assay. Blood samples for PK analysis were collected prior to dosing and up to 336 hours (14 days) after dosing. The PK data demonstrate that rIX-FP has an improved PK profile in comparison to plasma-derived FIX (pdFIX) and rFIX products.
Table 5 provides the pharmacokinetic parameters following a single injection of 50 IU/kg of IDELVION.
Table 5: Pharmacokinetic Parameters (Arithmetic Mean,
CV%) Following a Single Injection of 50 IU/kg of IDELVION
| PK Parameters | rIX-FP 50 IU/kg (N=47) |
| IR (IU/dL)/(IU/kg) | 1.30 (23.8) |
| Cmax (IU/dL) | 66.6 (26.7) |
| AUCo-inf (h*IU/dL) | 7482 (28.4) |
| t-½ (h) | 104.2 (25.4) |
| MRT (h) | 142.8 (22.7) |
| CL (mL/h/kg) | 0.731 (26.8) |
| Vss (dL/kg) | 1.020 (27.9) |
| Time to 1% FIX Activity (d)a | 21.0 |
| Time to 3% FIX Activity (d)a | 15.5 |
| Time to 5% FIX Activity (d)a | 12.0 |
| a = Estimated time to median FIX activity
maintained above the pre-specified % IR = incremental recovery recorded 30 minutes after injection; AUC = area under the FIX activity time curve; t½ = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state. |
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In the pivotal trial, after a single dose of 50 IU/kg IDELVION has a prolonged circulating half-life, enlarged area under the FIX activity time curve, lower clearance and an increased incremental recovery. The mean (CV%) incremental recovery of IDELVION was 1.30 (23.8%) which is higher than that of the previous FIX product [pdFIX or rFIX; 1.00 (25.7%)]. Therefore, one IU/kg IDELVION provides a mean increase of 1.30 IU/dL in the circulating level of FIX.
Repeat PK assessment for up to 30 weeks demonstrated a stable pharmacokinetic profile and that incremental recovery was consistent over time.
The PK after a single dose of 75 IU/kg IDELVION was derived from 8 evaluable subjects. The mean FIX activity at Day 14 was 6.65%. The estimated time to 1% FIX activity is approximately 27 days after a single dose of 75 IU/kg IDELVION, based on population PK modeling simulations.
The PK after a single dose of 25 IU/kg IDELVION was derived from 7 evaluable subjects. The mean FIX activity at Day 14 was 2.97%. The estimated time to 1% FIX activity is approximately 16.5 days after a single dose of 25 IU/kg IDELVION, based on population PK modeling simulations.
Pharmacokinetics parameters of rIX-FP were evaluated in 8 adolescents (12 to < 18 years of age) and 27 children (1 to < 12 years of age) in open-label, multi-center studies following a 50 IU/kg intravenous injection of IDELVION. The PK samples were collected prior to dosing and at multiple time points up to 336 hours (14 days) after dosing.
Table 6 summarizes the PK parameters calculated from the pediatric data of 35 subjects 1 to < 18 years of age. These parameters were estimated based on the plasma FIX activity over time profile. Compared to adults, incremental recovery appeared to be slightly lower and body weight-adjusted clearance appeared to be higher in children.
Table 6: Comparison of Pharmacokinetic Parameters by
Age Category (Arithmetic Mean, CV%) Following a Single Injection of 50 IU/kg of
IDELVION
| PK Parameters | 1 to < 12 years (N=27) |
12 to < 18 years (N=8) |
| IR (IU/dL)/(IU/kg) | 1.01 (22.5) | 1.11 (27.7) |
| Cmax (IU/dL) | 50.9 (21.8) | 55.3 (28.1) |
| AUC0-inf (h*IU/dL) | 4788 (31.3) | 5347 (48.2) |
| 1-½ (h) | 91.0 (17.7) | 87.3 (35.7) |
| MRT (h) | 125.8 (17.4) | 119 (31.2) |
| CL (mL/h/kg) | 1.13 (27.1) | 1.08 (39.3) |
| Vss (dL/kg) | 1.38 (21.0) | 1.16 (14.0) |
| IR = incremental recovery recorded 30 minutes after injection; AUC = area under the FIX activity time curve; t½ = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state. | ||
The efficacy, PK and safety of IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), has been evaluated in a prospective, open-label, multicenter clinical study that compared episodic (on-demand) treatment to weekly routine prophylaxis; compared weekly routine prophylaxis to every 10 or 14 day routine prophylaxis; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management of subjects undergoing surgical procedures. PK of IDELVION was evaluated in all subjects in the pivotal study, except those who completed a PK assessment in a prior study.
A total of 63 male PTPs with severe hemophilia B ( ≤ 2% endogenous FIX activity), between 12 and 61 years of age (median 30 years) received IDELVION for up to 27 months. Forty subjects in the prophylaxis arm received weekly routine prophylaxis at an initial dose of 35-50 IU/kg, with median dose of 40 IU/kg of IDELVION at the end of the weekly prophylaxis period. Twenty-six out of 40 subjects in the prophylaxis arm subsequently crossed-over to every 10 or 14 day routine prophylaxis and received 50-75 IU/kg of IDELVION after approximately 26 weeks of weekly prophylaxis. Twenty-three subjects in the on-demand arm received IDELVION as needed for the treatment of bleeding episodes, 19 subjects subsequently crossed-over to weekly prophylaxis after approximately 26 weeks of episodic treatment. If a subject required a surgical procedure during the study, the subject could be enrolled in the surgical substudy.
Based on a matched pairs design, the median percent reduction in the number of spontaneous bleeds per year (annualized spontaneous bleeding rate, (AsBR)) with IDELVION prophylaxis compared to on-demand was 100% (IQR 90.5%, 100%). A comparison of the AsBRs and Annualized Bleeding Rates (ABRs) in 19 subjects evaluable for efficacy is summarized in Table 9.
Table 9: Comparison of Annualized Bleeding Rates (ABR)
| Bleeding episode etiology | On-demand (n=19)* |
Weekly Prophylaxis (n=19)* |
Percent Reduction in ABR with prophylaxis (n=19)* |
| Spontaneous | |||
| Mean (SD) | 14.57 (8.421) | 0.73 (1.171) | 95.96 (5.539) |
| Median | 15.43 | 0 | 100 |
| IQR | 7.98, 17.96 | 0, 0.96 | 90.5, 100 |
| Range | 2.0, 39.5 | 0, 4.2 | 82.8, 100 |
| Total | |||
| Mean (SD) | 20.78 (9.194) | 2.87 (4.814) | 88.80 (17.762) |
| Median | 19.22 | 1.58 | 90.94 |
| IQR | 16.70, 25.84 | 0, 4.06 | 81.19, 100 |
| Range | 2.0, 46.1 | 0, 21.1 | 54.3, 100 |
| * Based on matched pairs design IQR = interquartile range, defined for 25th percentile and 75th percentile; SD = standard deviation; Subjects evaluable for efficacy are subjects who received at least one dose of on-demand treatment, and one dose of prophylaxis treatment. |
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Based on matched pairs design for spontaneous ABRs, both 7 day prophylaxis and 14 day prophylaxis regimens with IDELVION were demonstrated to be effective. The spontaneous ABRs in subjects on weekly and 14-day prophylaxis are summarized in Table 10.
Table 10: Comparison of Annualized Bleeding Rate by
Prophylaxis Regimen
| Bleeding Episode Etiology | Weekly Routine Prophylaxis (n=21)* |
14-day Prophylaxis (n=21)* |
| Spontaneous | ||
| Mean (SD) | 0.28 (1.010) | 1.07 (2.114) |
| Median | 0 | 0 |
| IQR | 0, 0 | 0, 1.00 |
| Range | 0, 4.5 | 0, 7.3 |
| * Based on a matched pairs design IQR = interquartile range; SD = Standard deviation |
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A total of 358 bleeding events were treated with IDELVION; 93.6% of bleeds were resolved with one injection and 98.6% with no more than two injections. Assessment of response to each injection was recorded in an eDiary by subjects at 24 hours after treatment. Overall treatment efficacy was assessment for each bleeding episode by the investigator based on a 4-point scale.
Efficacy in control of bleeding episodes is summarized in Table 11.
Table 11: Efficacy* in Control of Bleeding
| Number of Bleeding Episodes Requiring Treatment (n = 358) | |
| Number of injections to treat bleeding episodes | |
| 1 injection, n (%) | 335 (93.6) |
| 2 injections, n (%) | 18 (5.0) |
| 1 or 2 injections, n (%) | 353 (98.6) |
| > 2 injections, n (%) | 5 (1.4) |
| Assessment of Efficacy* | |
| Excellent or Good efficacy, n (%) | 337 (94.1) |
| Moderate efficacy, n (%) | 9 (2.5) |
| Poor/no response, n (%) | 1 (0.3) |
| * Excellent: Pain relief and/or unequivocal improvement in objective signs of bleeding and no additional infusion required in order to achieve hemostasis; Good: Definite pain relief and/or improvement in signs of bleeding at approximately 8 hours after the first infusion, but may require a second infusion; Moderate: Probable or slight beneficial effect, and requires more than two infusions to achieve hemostasis; Poor/no response: No improvement at all or condition worsens, additional hemostatic intervention is required. Responses evaluated at approximately 24 hours after treatment. | |
In three clinical studies, 7 subjects received IDELVION for perioperative management in 9 surgical procedures. Dose was individualized based on subject's PK and clinical response to treatment at the investigator's discretion. The efficacy analysis of IDELVION in perioperative management included 7 surgeries in 5 PTPs between 12 and 61 years of age undergoing major or minor surgical procedure, including dental surgeries. The nine surgical procedures included a double mastectomy, 2 knee replacements, a hemorrhoidectomy, a rhinoplasty and 3 complicated and 1 uncomplicated dental surgeries. Two of the 4 dental surgeries were performed in children < 12 years.
Perioperative FIX replacement with IDELVION was by intravenous bolus injection only. The safety of continuous infusion was not evaluated. Hemostasis was assessed by the investigator/surgeon at wound closure (intraoperative assessment), 72 hours after surgery or at hospital discharge and at the end of the surgical substudy using a 4 point-scale of excellent, good, fair and none. The nine surgeries included in the intraoperative assessment of hemostatic response was rated as excellent (n = 8). One patient was not rated post-dental extraction. At 72 hours or hospital discharge 7/9 had a rating of “excellent” and 2/9 had a rating of “good”. There was no clinical evidence of thrombotic complications in any of the subjects.
See Section ACTION AND CLINICAL PHARMACOLOGY.
Not applicable.
The toxicological program included studies after single or repeated bolus dosing in rodent and non-rodent species. Rats and monkeys were selected as they represent the standard animals for these types of toxicological investigations and rIX-FP was shown to be pharmacologically active in these species.
A single intravenous bolus injection of rIX-FP at doses up to 500 IU/kg was well tolerated in cynomolgus monkeys and rats with no toxicologically significant changes. The No Observed Adverse Effect Level (NOAEL) was considered to be 500 IU/kg for both species.
The repeat-dose studies (28 days) reflect the clinical practice of multiple treatments for hemophilia B patients. Due to the expected immune response against the heterologous human protein, an interim sacrifice was carried out at Day 6. Overall, administration of rIX-FP by intravenous injections on 28 consecutive days at doses up to 500 IU/kg/day was well tolerated in the rat with no findings indicative of adverse toxicity and a NOAEL of 500 IU/kg was considered under the conditions of this study.
The same was observed following repeated dosing in cynomolgus monkeys leading to a NOAEL of 500 IU/kg.
To evaluate the potential genotoxicity risk, two in vitro studies were performed with rIX-FP, i.e. the bacterial reverse mutation test (Ames test) and the chromosome aberration test in human lymphocytes. Both assays showed no evidence of mutagenic activity.
Local tolerance investigations were included in the single-dose and repeat-dose toxicity studies in rats and monkeys. Furthermore, a separate local tolerance study was performed in rabbits with no local or systemic signs of reaction to treatment leading to the overall conclusion that rIX-FP was locally well tolerated following repeated intravenous bolus injections in the rat and cynomolgus monkey and following a single intravenous, intra-arterial and perivenous administration to rabbits.
The thrombogenic potential of rIX-FP was evaluated using a modified Wessler stasis model in rabbits, a standard model to investigate thrombogenicity. There was no indication of thrombogenic activity at the three doses of rIX-FP tested, i.e. 75 IU/kg, 150 IU/kg and 500 IU/kg.
Nonclinical studies evaluating the carcinogenic potential of rIX-FP have not been conducted.
Animal reproductive and developmental toxicity studies were also not conducted with rIX-FP. However, no adverse effects on reproductive organs were observed by macroscopic and microscopic pathological investigations in repeated dose toxicity studies.
REFERENCES
1. Santagostino E, Negrier C, Klamroth R, Tiede A, Pabinger-Fasching I, Voigt C, Jacobs I, Morfini M. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012 Sep 20; 120(12):2405-11.
IDELVION™
Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP)
Read this carefully before you start taking IDELVION. This leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare professional about your medical condition and treatment and ask if there is any new information about IDELVION.
ABOUT THIS MEDICATION
What is IDELVION used for?
IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein is a medicine used to replace clotting factor (Factor IX) that is missing in people with hemophilia B (also called congenital Factor IX deficiency or Christmas disease). Hemophilia B is an inherited bleeding disorder that prevents blood from clotting normally.
IDELVION can reduce the number of bleeding episodes when used regularly (prophylaxis) and reduce the risk of joint damage due to bleeding. IDELVION is used to prevent and control bleeding in all patients with hemophilia B. Your healthcare provider may give you IDELVION when you have surgery.
How does IDELVION work?
IDELVION is injectable clotting (coagulation) Factor IX made using recombinant technology. Factor IX is involved in blood clotting. Lack of this factor means that blood does not clot as quickly as it should so there is an increased tendency to bleed. IDELVION works by replacing factor IX in haemophilia B patients to enable their blood to clot.
What are the ingredients in IDELVION?
Medicinal ingredients: Coagulation Factor IX (Recombinant), Albumin (recombinant) Fusion Protein.
Non-medicinal ingredients: Mannitol, Polysorbate 80, Sucrose, Tri-sodium citrate.
IDELVION comes in the following dosage forms:
IDELVION is a preservative free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection (SWFI) for intravenous injection. IDELVION comes in 4 different dosage strengths: 250 IU, 500 IU, 1000 IU, or 2000 IU and must be reconstituted with the respective supplied volume of SWFI (diluent) listed in the table below before it is administered:
| Lyophilized Product Format | Diluent Volume for Reconstitution | Concentration of product once reconstituted |
| 250 IU | 2.5 mL | 100 IU/mL |
| 500 IU | 2.5 mL | 200 IU/mL |
| 1000IU | 2.5 mL | 400 IU/mL |
| 2000IU | 5 mL | 400 IU/mL |
The IDELVION package consists of 2 boxes.
The “Product box” contains one single-use IDELVION vial and one vial of Sterile Water for Injection (Diluent).
The “Device box” contains one Mix2Vial® filter transfer set, one syringe, one infusion set and a plaster (non-sterile).
WARNINGS AND PRECAUTIONS
Do not use IDELVION if:
To help avoid side effects and ensure proper use, talk to your healthcare professional before you take IDELVION. Talk about any health conditions or problems you may have, including if:
Allergic reactions may occur with IDELVION. Call your healthcare provider right away and stop treatment if you get a rash or hives, itching, tightness of the chest or throat, difficulty breathing, light-headedness, dizziness, nausea, or a decrease in blood pressure.
Your body may form inhibitors to Factor IX. An inhibitor is a part of the body's defense system. If you form inhibitors, it may stop IDELVION from working properly. Your healthcare provider may need to test your blood for inhibitors from time to time.
INTERACTIONS WITH THIS MEDICATION
Tell your healthcare professional about all the medicines you take, including any drugs, vitamins, minerals, natural supplements or alternative medicines.
PROPER USE OF THIS MEDICATION
How to take IDELVION:
IDELVION is given directly into the bloodstream. IDELVION should be administered as directed by your healthcare provider. You should be trained on how to do intravenous injections by your healthcare provider. Many people with hemophilia B learn to inject their IDELVION by themselves or with the help of a family member.
For intravenous use after reconstitution only.
Home administration of IDELVION
Do not attempt to self-administer unless you have been taught how by your healthcare provider.
Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using IDELVION. If you are unsure of the instructions, call your healthcare provider before using IDELVION. Talk to your healthcare provider before traveling. Dispose of all unused solution, empty vial(s), and other used medical supplies in an appropriate medical waste container.
Administration
Reconstitution
The procedures provided in the table below are general guidelines for the preparation and reconstitution of IDELVION.
Follow the steps below and use aseptic techniques to administer IDELVION.
A. PREPARATION
Prepare the vials/Mix2Vial® and administration supplies.
Ensure that the diluent and IDELVION vials are at room temperature.
Prepare syringes, infusion sets and other supplies for the administration.
B. RECONSTITUTION: follow these steps to reconstitute IDELVION
1. Clean Stoppers:
Remove the flip caps from both vials (IDELVION and diluent). Wipe the rubber stoppers with an antiseptic and allow the rubber stopper to dry.
2. Open the Mix2Vial® package by peeling away the lid. To maintain sterility, leave the Mix2Vial® set in its clear outer package.
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3. Prepare Diluent Vial:
Place the diluent vial on an even flat surface and hold the vial tightly. Grip the Mix2Vial® keeping it in the package. Push the plastic spike at the blue end of the Mix2Vial® set firmly through the center of the diluent vial stopper.
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4. Remove the Mix2Vial® packaging:
While holding the diluent vial, carefully remove the outer package from the Mix2Vial® set. Make sure that you pull off only the package, not the Mix2Vial® set.
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5. Transfer Diluent into IDELVION Vial:
Place the product vial on an even flat surface and hold the vial tight. Invert the diluent vial with the Mix2Vial® set attached to it and push the plastic spike of the clear end of the Mix2Vial® end firmly through the stopper of the IDELVION vial. The diluent will transfer into the IDELVION vial automatically.
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6. Dissolve IDELVION:
With the diluent and IDELVION vial still attached to the Mix2Vial® set, gently swirl the IDELVION vial to ensure the product is fully dissolved. Do not shake the vial.
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7. Unscrew empty diluent (Blue) vial:
With one hand, grip the clear end of the Mix2Vial® set and with the other hand grip the blue end of the Mix2Vial® set and unscrew the set into two pieces.
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8. Load the syringe:
Draw air into an empty, sterile syringe. Use the syringe provided with the product. With the IDELVION vial upright, screw the syringe to the Mix2Vial® set. Inject air into the product vial. While keeping the syringe plunger pressed, invert the IDELVION vial and draw the solution into the syringe by pulling the plunger back slowly.
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9. Prepare the administration set equipped with microbore tubing:
Once the solution has been transferred into the syringe, firmly grip the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial® set. Attach the syringe to the provided infusion set or another suitable administration set.
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10. After reconstitution, administration should begin promptly or within 3 hours.
11. Use a separate, unused Mix2Vial® transfer set for each product vial.
C. Administer IDELVION using aseptic technique:
Usual dose
Your healthcare provider will tell you how much IDELVION to use based on your weight, the severity of your hemophilia B, and where you are bleeding. You may have to have blood tests done after getting IDELVION to be sure that your blood level of Factor IX is high enough to clot your blood. Call your healthcare provider right away if your bleeding does not stop after taking IDELVION.
Overdose
No symptoms of overdose with IDELVION have been reported.
If you think you have taken too much IDELVION, contact your healthcare professional, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.
Missed Dose
Talk to your healthcare provider if you miss a dose.
HOW TO STORE IT
Product after reconstitution: the product administration should begin promptly or within 3 hours.
Side Effects, How Often They Happen And What To Do About Them
What are possible side effects from using IDELVION?
A common side effect of IDELVION is headache. Other possible side effects include rash, dizziness, and infusion related reactions.
These are not all the possible side effects you may feel when taking IDELVION. If you experience any side effects not listed here, contact your healthcare professional. Please also see section WARNINGS AND PRECAUTIONS.
| Serious side effects and what to do about them | |||
| Symptom / effect | Talk to your healthcare professional | Stop taking drug and get immediate medical help | |
| Only if severe | In all cases | ||
| The following side effects could mean you are having an allergic reaction: | |||
| - Difficult breathing | XXXXX10003; | ||
| - Chest tightness | XXXXX10003; | ||
| - Swelling of the face, rash or hives | XXXXX10003; | ||
If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to interfere with your daily activities, talk to your healthcare professional.
Reporting Suspected Side Effects
You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways:
Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to the management of side effects, contact your health professional.
The Canada Vigilance Program does not provide medical advice.
*We recommend that CSL Behring Canada be copied when reporting suspected side effects, at the following address: [email protected], or be informed by pager. Pager Number: 1-613-783-1892
MORE INFORMATION
If you want more information about IDELVION:
