- Approval Id
- 61e0828a96ed096d
- Drug Approval Emc Name
- IDELVION 2000 IU powder and solvent for solution for injection
- Drug Name
- IDELVION 2000 IU powder and solvent for solution for injection
- Company Name
- CSL Behring UK Limited
- Company Address
- 4 Milton Road, Haywards Heath, West Sussex, RH16 1AH, UK
- Company Website
- http://www.cslbehring.co.uk
- Company Telephone
- +44 (0)1444 447 400
- Company Medical Info Direct Line
- +44 (0)1444 447 405
- Company Medical Info Email
- medinfo@cslbehring.com
- Company Customer Care Direct Line
- +44 (0)1444 447 402
- Atc Code
- B02BD04
- Legal Category
- Prescription only medicine
- Authorisation Holder
- CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
- Authorisation Number
- \*\*250 IU:\*\*
PLGB 15036/0143
\*\*500 IU:\*\*
PLGB 15036/0144
\*\*1000 IU:\*\*
PLGB 15036/0141
\*\*2000 IU:\*\*
PLGB 15036/0142
\*\*3500 IU:\*\*
PLGB 15036/0155
- Authorisation Date
- \*\*250 IU, 500 IU, 1000 IU & 2000 IU:\*\*
01 January 2021 / 04 February 2021
\*\*3500 IU:\*\*
01 January 2021 / 04 February 2021
- Instruction Authorisation Holder
- CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
- Instruction Authorisation Number
- \*\*250 IU:\*\*
PLGB 15036/0143
\*\*500 IU:\*\*
PLGB 15036/0144
\*\*1000 IU:\*\*
PLGB 15036/0141
\*\*2000 IU:\*\*
PLGB 15036/0142
\*\*3500 IU:\*\*
PLGB 15036/0155
- Instruction Authorisation Date
- \*\*250 IU, 500 IU, 1000 IU & 2000 IU:\*\*
01 January 2021 / 04 February 2021
\*\*3500 IU:\*\*
01 January 2021 / 04 February 2021
- Instruction Dosage Form
- Powder and solvent for solution for injection.
Pale yellow to white powder and clear, colourless solvent for solution for injection.
pH: 6.6 - 7.2
Osmolality:
\*\*IDELVION 250 IU powder and solvent for solution for injection\*\*
175 – 215 mOsm/kg.
\*\*IDELVION 500 IU powder and solvent for solution for injection\*\*
260 – 300 mOsm/kg.
\*\*IDELVION 1000 IU powder and solvent for solution for injection\*\*
260 – 300 mOsm/kg.
\*\*IDELVION 2000 IU powder and solvent for solution for injection\*\*
260 – 300 mOsm/kg.
IDELVION 3500 IU powder and solvent for solution for injection
260 – 300 mOsm/kg.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
IDELVION can be used for all age groups.4.2 Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia B.
\*\*Treatment monitoring\*\*
During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their responses to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.
When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor IX activity in patients' blood samples, plasma factor IX activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Measurement with a one-stage clotting assay using a kaolin-based aPTT reagent or Actin FS aPTT reagent will likely result in an underestimation of activity level. This is of importance particularly when changing the laboratory and/or reagents used in the assay.
\*\*Posology\*\*
Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient's clinical condition.
The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma).
One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.
\*\*\*On demand treatment\*\*\*
The calculation of the required dose of factor IX is based on the empirical finding that 1 IU factor IX per kg body weight raises the plasma factor IX activity by an average of 1.3 IU/dl (1.3 % of normal activity) in patients ≥ 12 years of age and by 1.0 IU/dl (1.0 % of normal activity) in patients < 12 years of age. The required dose is determined using the following formulae:
Required dose (IU) = body weight (kg) x desired factor IX rise (% of normal or IU/dl) x {reciprocal of observed recovery (IU/kg per IU/dl)}
Expected factor IX rise (IU/dl or % of normal) = Dose (IU) x Recovery (IU/dl per IU/kg)/body weight (kg)
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
\*\*Patients <12 years of age\*\*
For an incremental recovery of 1 IU/dl per 1 IU/kg, the dose is calculated as follows:
Required dose (IU) = body weight (kg) x desired factor IX rise (IU/dl) x 1 dl/kg
Example:
1. A peak level of 50 % of normal is required in a 20 kg patient with severe haemophilia B. The appropriate dose would be 20 kg x 50 IU/dl x 1 dl/kg = 1000 IUs.
2. A dose of 1000 IUs of IDELVION, administered to a 25 kg patient, should be expected to result in a peak post-injection factor IX increase of 1000 IUs/25 kg x 1.0 (IU/dl per IU/kg) = 40 IU/dl (40 % of normal).
\*\*Patients ≥12 years of age\*\*
For an incremental recovery of 1.3 IU/dl per 1 IU/kg, the dose is calculated as follows:
Required dose (IU) = body weight (kg) x desired factor IX rise (IU/dl) x 0.77 dl/kg
Example:
3. A peak level of 50 % of normal is required in a 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 factor IX increase of 2000 IUs x 1.3 (IU/dl per IU/kg) /80 kg = 32.5 IU/dl (32.5 % of normal).
In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
| | | |
| --- | --- | --- |
| \*\*Degree of haemorrhage / Type of surgical procedure\*\* | \*\*Factor IX level required (%) (IU/dl)\*\* | \*\*Frequency of doses (hours) / Duration of therapy (days)\*\* |
| \*\*Haemorrhage\*\* Minor or moderate haemarthrosis, muscle bleeding (except iliopsoas) or oral bleeding | 30 – 60 | Single dose should be sufficient for majority of bleeds. Maintenance dose after 24 – 72 hours if there is further evidence of bleeding. |
| \*\*Major haemorrhage\*\* Life threatening haemorrhages, deep muscle bleeding including iliopsoas | 60 – 100 | Repeat every 24 – 72 hours for the first week, and then maintenance dose weekly until bleeding stops and healing is achieved. |
| \*\*Minor surgery\*\* Including uncomplicated tooth extraction | 50 – 80 (pre- and post-operative) | Single dose may be sufficient for a majority of minor surgeries. If needed, maintenance dose can be provided after 24 – 72 hours until bleeding stops and healing is achieved. |
| \*\*Major surgery\*\* | 60 - 100 (pre- and post-operative) | Repeat every 24 – 72 hours for the first week, and then maintenance dose 1 – 2 times per week until bleeding stops and healing is achieved. |
\*\*\*Prophylaxis\*\*\*
For long-term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 35 to 50 IU/kg once weekly.
Some patients who are well-controlled on a once-weekly regimen might be treated with up to 75 IU/kg on an interval of 10 or 14 days. For patients >18 years, further extension of the treatment interval may be considered (see section 5.1).
In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.
After a bleeding episode during prophylaxis, patients should maintain their prophylaxis regimen as closely as possible, with 2 doses of IDELVION being administered at least 24 hours apart but longer if deemed suitable for the patient.
\*\*\*Paediatric population\*\*\*
For long term prophylaxis the recommended dose regimen is 35 to 50 IU/kg once weekly (see sections 5.1 and 5.2). For adolescents of 12 years of age and above, the dose recommendations are the same as for adults (see above).
\*\*Method of administration\*\*
Intravenous use.
The reconstituted preparation should be injected slowly intravenously at a rate comfortable for the patient up to a maximum of 5 ml/min.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known allergic reaction to hamster protein.4.4 Special warnings and precautions for use
\*\*Traceability\*\*
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
\*\*Hypersensitivity\*\*
Allergic type hypersensitivity reactions are possible with IDELVION. The product contains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
\*\*Inhibitors\*\*
After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing. Formation of inhibitor to factor IX has been reported during factor replacement therapy with IDELVION in the treatment of haemophilia B.
There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor IX products, the initial administration of factor IX should, according to the treating physician's judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.
\*\*Thromboembolism\*\*
Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to newborn 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.
\*\*Cardiovascular events\*\*
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
\*\*Catheter-related complications\*\*
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
\*\*Elderly\*\*
Clinical studies of IDELVION did not include subjects aged 65 and over. It is not known whether they respond differently from younger subjects.
\*\*Immune tolerance induction\*\*
The safety and efficacy of using IDELVION for immune tolerance induction has not been established.
\*\*Sodium content\*\*
This medicinal product contains up to 8.6 mg vial, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
\*\*Paediatric population\*\*
The listed warnings and precautions apply both to adults and children.4.5 Interaction with other medicinal products and other forms of interaction
No interactions of human coagulation factor IX (rDNA) products with other medicinal products have been reported.4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available.
Therefore, factor IX should be used during pregnancy and lactation only if clearly indicated.
There is no information on the effects of factor IX on fertility.4.7 Effects on ability to drive and use machines
IDELVION has no influence on the ability to drive and use machines.4.8 Undesirable effects
\*\*Summary of the safety profile\*\*
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. One case with high-titre inhibitor was reported in the clinical study which evaluated previously untreated patients. Inhibitor development has been observed in previously treated patients in the post-marketing experience with IDELVION.
There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such adverse reactions.
\*\*Tabulated list of adverse reactions\*\*
The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). The table lists adverse reactions that were reported in clinical trials and/or were identified in post-marketing use.
Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| | | |
| --- | --- | --- |
| \*\*MedDRA Standard System Organ Class\*\* | \*\*Adverse reactions\*\* | \*\*Frequency per patient\*\* |
| Blood and lymphatic disorders | FIX inhibition/Inhibitor development\\* | Not known |
| Immune system disorders | Hypersensitivity | Common |
| Nervous system disorders | Headache | Common |
| Dizziness | Common |
| Skin and subcutaneous tissue disorders | Rash | Common |
| Eczema | Uncommon |
| General disorders and administration site conditions | Injection site reactions | Common |
\*\*Description of selected adverse reactions\*\*
One case with high-titre inhibitor was reported in the clinical study with previously untreated patients (refer to section 5.1). Due to the narrow data-base no inhibitor-incidence is provided.
\*\*Paediatric population\*\*
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store.4.9 Overdose
No symptoms of overdose with IDELVION have been reported.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics - blood coagulation factor IX,
ATC code: B02BD04.
\*\*Mechanism of action\*\*
Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin-K dependent coagulation factor and it is synthesised in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. 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 is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Of note, ABR (annualized bleeding rate) is not comparable between different factor concentrates and between different clinical studies.
Albutrepenonacog alfa) is a recombinant coagulation factor IX. Prolongation of the half-life of albutrepenonacog alfa and the enhanced systemic exposure (see section 5.2) are achieved by fusion with recombinant albumin. Albumin is a natural, inert carrier protein in plasma with a half-life of approximately 20 days.
Albutrepenonacog alfaremains intact in the circulation until factor IX is activated, whereupon albumin is cleaved, releasing activated factor IX (FIXa) when it is needed for coagulation.
\*\*General information on clinical efficacy and safety\*\*
A phase 1/2 study evaluated the treatment efficacy and prevention of bleeding episodes of rIX-FP in 17 subjects (ages 13-46 years), 13 subjects in the prophylaxis arm received weekly prophylaxis with IDELVION for approximately 11 months, and 4 subjects in the on-demand arm received IDELVION upon occurrence of bleeding events. All 85 bleeding episodes were successfully treated with 1 or 2 doses of IDELVION.
The efficacy of IDELVION has been evaluated in the open-label, uncontrolled part of a phase 2/3 study, in which a total of 63 male, previously treated patients (PTPs) between 12 and 61 years of age received IDELVION either for prophylaxis once every 7-, 10- and/or 14-day intervals and/or for the treatment of bleeding episodes on an on-demand basis. All subjects had severe (FIX level <1%) or moderately severe (FIX level ≤ 2%) haemophilia B. Forty PTPs received IDELVION for prophylaxis.
Subjects who received prophylactic treatment started with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10 or 14 days) with a recommended dose of 75 IU/kg and individual adjustments. 21 PTPs remained on the extended 14-day prophylaxis interval for additional treatment duration of 98 to 575 (median 386) days. From those subjects, 8 (38%) experienced at least one bleeding during the 14 day-prophylaxis, while they had no bleeding events during once-weekly prophylaxis. Median Annualised Bleeding Rate (ABR) on 7 day prophylaxis with IDELVION for all bleeds was 0.0 (range 0-6) and on 14 day-prophylaxis it was 1.08 (range 0-9.1).
The long-term efficacy and safety of routine prophylaxis treatment was confirmed in an open-label extension study for up to 5 years. In this study, a total of 59 PTPs ≥12 years (54 adults and 5 adolescents) received IDELVION either for prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis.
Patients who received prophylactic treatment continued or started with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10, 14 or 21 days) with a recommended dose of 75 IU/kg (10 or 14 days) or 100 IU/kg (21 days). At the end of the study 14 PTPs (24%) were on the 7 day prophylaxis interval, and a total of 11 (19%), 25 (42%) and 9 (15%) PTPs remained on the extended prophylaxis interval of 10, 14 and 21 days, respectively. During the study, 2 PTPs (18%) in the 21-day regimen switched back to a more frequent dosing due to increased bleeding complications. The estimated median Annualised Bleeding Rates (ABRs) on 7-, 14-, and 21-day prophylaxis with IDELVION for all bleeds were 1.3 (range 0-8), 0.9 (range 0-13), and 0.3 (range 0-5), respectively.
Currently available information supports extension of treatment intervals for some patients, although potentially associated with an increased risk for bleeding compared to a once-weekly regimen.
\*\*Prophylaxis and control of bleeding in PTPs below 12 years\*\*
The efficacy of IDELVION has been evaluated in a phase 3 study, in which a total of 27 male PTPs between 1 and 10 years (median age 6.0 years) with 12 patients < 6 years, received IDELVION for prophylaxis and control of bleeding episodes. All 27 subjects received weekly prophylaxis treatment with IDELVION for a mean time on study of 13.1 months (9, 18 months).
Of the 106 bleeding episodes, the majority (94; 88.7%) was treated with single injection, 103; 97.2% were treated with 1-2 injections. Haemostatic efficacy at resolution of a bleed was rated excellent or good in 96% of all treated bleeding episodes.
The long-term efficacy and safety of routine prophylaxis treatment was confirmed in an open-label extension study for up to 5 years. In the study, a total of 24 PTPs < 12 years received IDELVION either for prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis.
Patients who received prophylactic treatment continued with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10 or 14 days) with a recommended dose of 75 IU/kg. At the end of the study 17 PTPs (71%) were on the 7 day prophylaxis interval, and a total of 3 (12%), and 4 (17%) PTPs remained on the extended prophylaxis interval of 10 and 14 days, respectively. During the study, 4 PTPs (50%) in the 14-day regimen switched back to a more frequent dosing due to increased bleeding complications. The estimated median Annualised Bleeding Rates (ABRs) for 7-, and 14-day prophylaxis with IDELVION for all bleeds were 2.0 (range 0-14), and 5.6 (range 0-8), respectively.
\*\*Perioperative management\*\*
The safety and efficacy in the perioperative setting was evaluated in two pivotal Phase 3 studies and a long-term extension study. The per protocol efficacy analysis includes 30 surgeries performed in 21 patients between 5 and 58 years undergoing major or minor surgical, dental or other surgical invasive procedures. Dosing was individualized based on the subject's PK and clinical response to treatment. A single preoperative bolus ranging from 14 to 163 IU/kg was used in 96.7% (n=29) of surgeries. Haemostatic efficacy was rated as excellent or good in all of the assessed procedures. During the 14-day postoperative period, patients received between 0 and 11 infusions and total doses ranging from 0 to 444 IU/kg.
\*\*Previously untreated patients (PUP)\*\*
Safety and efficacy of IDELVION were evaluated in a multicenter open-label clinical study with 12 previously untreated paediatric patients (PUPs) with hemophilia B (≤2% endogenous FIX activity), of whom 11 were in the age-range of 0 to 1 years. The median number of exposure days (EDs) was 50 (range 22 to 146 EDs), and 8 PUPs achieved ≥50 EDs during on-demand, prophylaxis, surgical and PK periods.
All 12 PUPs received routine prophylaxis with 11 receiving the 7-day regimen. The overall median time on prophylaxis was 11.5 months (range: 3.1 to 32.3 months). In the 9 PUPs on the 7-day prophylaxis regimen who reached > 6 months of treatment, median annualized bleeding rate (ABR) was 1.16 (range 0 to 3.1). Five of the 9 PUPs had an ABR of 0. The median monthly dose was 195.9 IU/kg (range 171.8 to 215.6 IU/kg) IU/kg for the 7-day prophylaxis regimen (N = 9).
Five subjects received on-demand treatment over varying periods prior to prophylaxis, with the number of EDs ranging from 1 to 4.
Of the 37 bleeding events observed in 10 PUPs across all study periods, 94% were successfully controlled with 1 or 2 infusions.5.2 Pharmacokinetic properties
\*\*Adult population\*\*
The pharmacokinetics (PK) of IDELVION were evaluated following an intravenous injections of a single dose of 25, 50, and 75 IU/kg. The PK parameters following a single injection of 50 IU/kg IDELVION (see table below) were based on plasma factor IX activity measured by the one-stage clotting assay. The mean factor IX activity at day 7, and day14 was 13.76% and 6.10%, respectively, after a single dose of 50 IU/kg IDELVION. Repeat PK assessment for up to 30 weeks demonstrated a stable pharmacokinetic profile and incremental recovery was consistent over time.
Trough levels of 5-10% have been targeted in clinical studies for achieving bleeding control while on prophylaxis. PK simulations suggest the time to reach 5% plasma FIX activity following a single injection of 50 IU/kg IDELVION to be 12.5 days for adults.
\*\*Pharmacokinetic parameters for subjects with severe haemophilia (Median (min, max)) following a single injection of IDELVION in adults\*\*
| | |
| --- | --- |
| \*\*PK parameters\*\* | \*\*50 IU/kg\*\* \*\*(N=22)\*\* |
| IRa (IU/dl)/(IU/kg) | 1.18 (0.86, 1.86) |
| Cmaxa (IU/dl) | 62.7 (40.5, 87.0) |
| AUC0-inf (h\\*IU/dl) | 6638 (2810, 9921) |
| Elimination t1/2 (h) | 95.3 (51.5, 135.7) |
| CL (ml/h/kg) | 0.875 (0.748, 1.294) |
a = corrected for baseline levels
IR = incremental recovery; AUC = area under the factor IX activity time curve; CL = body weight adjusted clearance; Elimination t1/2 = Elimination half-life
\*\*Paediatric population\*\*
Pharmacokinetic parameters of IDELVION were evaluated in adolescents (12 to <18 years of age) and infants and children (1 to <12 years of age) following an intravenous injection of a single dose of 50 IU/kg. PK parameters (presented below) were estimated based on the plasma factor IX activity over time profile measured by the one-stage clotting assay.
\*\*Comparison of pharmacokinetic parameters of IDELVION in children (Median (min, max)) following a single injection of 50 IU/kg IDELVION\*\*
| | | | |
| --- | --- | --- | --- |
| \*\*PK parameters\*\* | \*\*1 to <6 years\*\* \*\*(N=12)\*\* | \*\*6 to <12 years\*\* \*\*(N=15)\*\* | \*\*12 to <18 years\*\* \*\*(N=5)\*\* |
| IRa (IU/dl)/(IU/kg) | 0.968 (0.660, 1.280) | 1.07 (0.70, 1.47) | 1.11 (0.84, 1.61) |
| Cmaxa (IU/dl) | 48.2 (33.0, 64.0) | 50.5 (34.9, 73.6) | 55.3 (40.5, 80.3) |
| AUC0-inf (h\\*IU/dl) | 4301 (2900, 8263) | 4718 (3212, 7720) | 4804 (2810, 9595) |
| Elimination t1/2 (h) | 86.2 (72.6, 105.8) | 89.3 (62.1, 123.0) | 88.8 (51.5, 130.0) |
| CL (ml/h/kg) | 1.16 (0.61, 1.72) | 1.06 (0.65, 1.56) | 1.04 (0.52, 1.67) |
a = corrected for baseline levels
IR = incremental recovery; AUC = area under the factor IX activity time curve; CL = body weight adjusted clearance; Elimination t1/2 = Elimination half-life
Trough levels of 5-10% have been targeted in clinical studies for achieving bleeding control while on prophylaxis. PK simulations suggest the time to reach 5% plasma FIX activity following a single injection of 50 IU/kg IDELVION to be 7 days for 1-<6years, 9 days for 6-<12 years and 11 days for 12-<18 years of age).5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeat dose toxicity, genotoxicity, thrombogenicity and local tolerability.
No investigations on carcinogenicity and reproductive toxicology have been conducted.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*\*Powder:\*\*
Sodium citrate,
Polysorbate 80,
Mannitol, Sucrose,
Hydrochloric acid (for pH adjustment).
\*\*Solvent:\*\*
Water for injections6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Only the provided injection sets should be used because treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some injection equipment.6.3 Shelf life
3 years
After reconstitution the chemical and physical in-use stability has been demonstrated for 8 hours at 2-25 °C). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are in the responsibility of the user.6.4 Special precautions for storage
Do not store above 25 °C.
Do not freeze. Keep vials in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.6.5 Nature and contents of container
\*\*IDELVION 250 IU powder and solvent for solution for injection\*\*
Powder (250 IU) in a 6 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
2.5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 500 IU powder and solvent for solution for injection\*\*
Powder (500 IU) in a 6 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
2.5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 1000 IU powder and solvent for solution for injection\*\*
Powder (1000 IU) in a 6 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
2.5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 2000 IU powder and solvent for solution for injection\*\*
Powder (2000 IU) in a 10 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 3500 IU powder and solvent for solution for injection\*\*
Powder (3500 IU) in a 10 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*Presentations\*\*
Each pack contains:
\*\*IDELVION 250 IU powder and solvent for solution for injection:\*\*
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
\*\*IDELVION 500 IU powder and solvent for solution for injection\*\*
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
\*\*IDELVION 1000 IU powder and solvent for solution for injection\*\*
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
\*\*IDELVION 2000 IU powder and solvent for solution for injection\*\*
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
IDELVION 3500 IU powder and solvent for solution for injection
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
\*\*General instructions\*\*
- The reconstituted solution should be clear or slightly opalescent, yellow to colourless. After filtering/withdrawal (see below) the reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.
- Do not use solutions that are cloudy or have deposits.
- Reconstitution and withdrawal must be carried out under aseptic conditions.
\*\*Reconstitution\*\*
Bring the solvent to room temperature (below 25 °C). Ensure IDELVION and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
| | |
| --- | --- |
| SMPC\_31844\_219264a\_13.png | 1. Open the Mix2Vial by peeling off the lid. Do \*\*\*\*not\*\*\*\* remove the Mix2Vial from the blister package! |
| SMPC\_31844\_219264b\_13.png | 2. Place the \*\*solvent vial\*\* on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the \*\*blue\*\* adapter end \*\*straight down\*\* through the solvent vial stopper. |
| SMPC\_31844\_219264c\_13.png | 3. Carefully remove the blister package from the Mix2Vial set by holding at the rim and pulling \*\*vertically\*\* upwards. Make sure that you only pull away the blister package and not the Mix2Vial set. |
| SMPC\_31844\_219264d\_13.png | 4. Place the \*\*IDELVION vial\*\* on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the \*\*transparent\*\* adapter end \*\*straight down\*\* through the IDELVION vial stopper. The solvent will automatically flow into the IDELVION vial. |
| SMPC\_31844\_219264e\_13.png | 5. With one hand grasp the IDELVION side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully counter-clockwise into two pieces. Discard the solvent vial with the blue Mix2Vial adapter attached. |
| SMPC\_31844\_219264f\_13.png | 6. Gently swirl the IDELVION vial with the transparent adapter attached until the substance is fully dissolved. Do not shake. |
| SMPC\_31844\_219264g\_13.png | 7. Draw air into an empty, sterile syringe. While the IDELVION vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the IDELVION vial. |
\*\*Withdrawal and application\*\*
| | |
| --- | --- |
| SMPC\_31844\_219264h\_13.png | 8. While keeping the syringe plunger pressed, turn the system upside down and draw the solution into the syringe by pulling the plunger back slowly. |
| SMPC\_31844\_219264i\_13.png | 9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counter-clockwise. |
Care should be taken that no blood enters the syringe filled with product, as there is a risk that the blood could coagulate in the syringe and fibrin clots could therefore be administered to the patient.
The reconstituted IDELVION solution must not be diluted.
The reconstituted solution should be administered by slow intravenous injection The rate of administration should be determined by the patient's comfort level, up to a maximum of 5 ml/min.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Pharmaceutical Form
Powder and solvent for solution for injection.
Pale yellow to white powder and clear, colourless solvent for solution for injection.
pH: 6.6 - 7.2
Osmolality:
\*\*IDELVION 250 IU powder and solvent for solution for injection\*\*
175 – 215 mOsm/kg.
\*\*IDELVION 500 IU powder and solvent for solution for injection\*\*
260 – 300 mOsm/kg.
\*\*IDELVION 1000 IU powder and solvent for solution for injection\*\*
260 – 300 mOsm/kg.
\*\*IDELVION 2000 IU powder and solvent for solution for injection\*\*
260 – 300 mOsm/kg.
IDELVION 3500 IU powder and solvent for solution for injection
260 – 300 mOsm/kg.
## Clinical Particulars
4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
IDELVION can be used for all age groups.4.2 Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia B.
\*\*Treatment monitoring\*\*
During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their responses to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.
When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor IX activity in patients' blood samples, plasma factor IX activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Measurement with a one-stage clotting assay using a kaolin-based aPTT reagent or Actin FS aPTT reagent will likely result in an underestimation of activity level. This is of importance particularly when changing the laboratory and/or reagents used in the assay.
\*\*Posology\*\*
Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient's clinical condition.
The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma).
One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.
\*\*\*On demand treatment\*\*\*
The calculation of the required dose of factor IX is based on the empirical finding that 1 IU factor IX per kg body weight raises the plasma factor IX activity by an average of 1.3 IU/dl (1.3 % of normal activity) in patients ≥ 12 years of age and by 1.0 IU/dl (1.0 % of normal activity) in patients < 12 years of age. The required dose is determined using the following formulae:
Required dose (IU) = body weight (kg) x desired factor IX rise (% of normal or IU/dl) x {reciprocal of observed recovery (IU/kg per IU/dl)}
Expected factor IX rise (IU/dl or % of normal) = Dose (IU) x Recovery (IU/dl per IU/kg)/body weight (kg)
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
\*\*Patients <12 years of age\*\*
For an incremental recovery of 1 IU/dl per 1 IU/kg, the dose is calculated as follows:
Required dose (IU) = body weight (kg) x desired factor IX rise (IU/dl) x 1 dl/kg
Example:
1. A peak level of 50 % of normal is required in a 20 kg patient with severe haemophilia B. The appropriate dose would be 20 kg x 50 IU/dl x 1 dl/kg = 1000 IUs.
2. A dose of 1000 IUs of IDELVION, administered to a 25 kg patient, should be expected to result in a peak post-injection factor IX increase of 1000 IUs/25 kg x 1.0 (IU/dl per IU/kg) = 40 IU/dl (40 % of normal).
\*\*Patients ≥12 years of age\*\*
For an incremental recovery of 1.3 IU/dl per 1 IU/kg, the dose is calculated as follows:
Required dose (IU) = body weight (kg) x desired factor IX rise (IU/dl) x 0.77 dl/kg
Example:
3. A peak level of 50 % of normal is required in a 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 factor IX increase of 2000 IUs x 1.3 (IU/dl per IU/kg) /80 kg = 32.5 IU/dl (32.5 % of normal).
In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
| | | |
| --- | --- | --- |
| \*\*Degree of haemorrhage / Type of surgical procedure\*\* | \*\*Factor IX level required (%) (IU/dl)\*\* | \*\*Frequency of doses (hours) / Duration of therapy (days)\*\* |
| \*\*Haemorrhage\*\* Minor or moderate haemarthrosis, muscle bleeding (except iliopsoas) or oral bleeding | 30 – 60 | Single dose should be sufficient for majority of bleeds. Maintenance dose after 24 – 72 hours if there is further evidence of bleeding. |
| \*\*Major haemorrhage\*\* Life threatening haemorrhages, deep muscle bleeding including iliopsoas | 60 – 100 | Repeat every 24 – 72 hours for the first week, and then maintenance dose weekly until bleeding stops and healing is achieved. |
| \*\*Minor surgery\*\* Including uncomplicated tooth extraction | 50 – 80 (pre- and post-operative) | Single dose may be sufficient for a majority of minor surgeries. If needed, maintenance dose can be provided after 24 – 72 hours until bleeding stops and healing is achieved. |
| \*\*Major surgery\*\* | 60 - 100 (pre- and post-operative) | Repeat every 24 – 72 hours for the first week, and then maintenance dose 1 – 2 times per week until bleeding stops and healing is achieved. |
\*\*\*Prophylaxis\*\*\*
For long-term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 35 to 50 IU/kg once weekly.
Some patients who are well-controlled on a once-weekly regimen might be treated with up to 75 IU/kg on an interval of 10 or 14 days. For patients >18 years, further extension of the treatment interval may be considered (see section 5.1).
In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.
After a bleeding episode during prophylaxis, patients should maintain their prophylaxis regimen as closely as possible, with 2 doses of IDELVION being administered at least 24 hours apart but longer if deemed suitable for the patient.
\*\*\*Paediatric population\*\*\*
For long term prophylaxis the recommended dose regimen is 35 to 50 IU/kg once weekly (see sections 5.1 and 5.2). For adolescents of 12 years of age and above, the dose recommendations are the same as for adults (see above).
\*\*Method of administration\*\*
Intravenous use.
The reconstituted preparation should be injected slowly intravenously at a rate comfortable for the patient up to a maximum of 5 ml/min.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known allergic reaction to hamster protein.4.4 Special warnings and precautions for use
\*\*Traceability\*\*
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
\*\*Hypersensitivity\*\*
Allergic type hypersensitivity reactions are possible with IDELVION. The product contains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
\*\*Inhibitors\*\*
After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing. Formation of inhibitor to factor IX has been reported during factor replacement therapy with IDELVION in the treatment of haemophilia B.
There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor IX products, the initial administration of factor IX should, according to the treating physician's judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.
\*\*Thromboembolism\*\*
Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to newborn 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.
\*\*Cardiovascular events\*\*
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
\*\*Catheter-related complications\*\*
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
\*\*Elderly\*\*
Clinical studies of IDELVION did not include subjects aged 65 and over. It is not known whether they respond differently from younger subjects.
\*\*Immune tolerance induction\*\*
The safety and efficacy of using IDELVION for immune tolerance induction has not been established.
\*\*Sodium content\*\*
This medicinal product contains up to 8.6 mg vial, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
\*\*Paediatric population\*\*
The listed warnings and precautions apply both to adults and children.4.5 Interaction with other medicinal products and other forms of interaction
No interactions of human coagulation factor IX (rDNA) products with other medicinal products have been reported.4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available.
Therefore, factor IX should be used during pregnancy and lactation only if clearly indicated.
There is no information on the effects of factor IX on fertility.4.7 Effects on ability to drive and use machines
IDELVION has no influence on the ability to drive and use machines.4.8 Undesirable effects
\*\*Summary of the safety profile\*\*
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4). Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. One case with high-titre inhibitor was reported in the clinical study which evaluated previously untreated patients. Inhibitor development has been observed in previously treated patients in the post-marketing experience with IDELVION.
There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such adverse reactions.
\*\*Tabulated list of adverse reactions\*\*
The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). The table lists adverse reactions that were reported in clinical trials and/or were identified in post-marketing use.
Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| | | |
| --- | --- | --- |
| \*\*MedDRA Standard System Organ Class\*\* | \*\*Adverse reactions\*\* | \*\*Frequency per patient\*\* |
| Blood and lymphatic disorders | FIX inhibition/Inhibitor development\\* | Not known |
| Immune system disorders | Hypersensitivity | Common |
| Nervous system disorders | Headache | Common |
| Dizziness | Common |
| Skin and subcutaneous tissue disorders | Rash | Common |
| Eczema | Uncommon |
| General disorders and administration site conditions | Injection site reactions | Common |
\*\*Description of selected adverse reactions\*\*
One case with high-titre inhibitor was reported in the clinical study with previously untreated patients (refer to section 5.1). Due to the narrow data-base no inhibitor-incidence is provided.
\*\*Paediatric population\*\*
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store.4.9 Overdose
No symptoms of overdose with IDELVION have been reported.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics - blood coagulation factor IX,
ATC code: B02BD04.
\*\*Mechanism of action\*\*
Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin-K dependent coagulation factor and it is synthesised in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. 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 is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Of note, ABR (annualized bleeding rate) is not comparable between different factor concentrates and between different clinical studies.
Albutrepenonacog alfa) is a recombinant coagulation factor IX. Prolongation of the half-life of albutrepenonacog alfa and the enhanced systemic exposure (see section 5.2) are achieved by fusion with recombinant albumin. Albumin is a natural, inert carrier protein in plasma with a half-life of approximately 20 days.
Albutrepenonacog alfaremains intact in the circulation until factor IX is activated, whereupon albumin is cleaved, releasing activated factor IX (FIXa) when it is needed for coagulation.
\*\*General information on clinical efficacy and safety\*\*
A phase 1/2 study evaluated the treatment efficacy and prevention of bleeding episodes of rIX-FP in 17 subjects (ages 13-46 years), 13 subjects in the prophylaxis arm received weekly prophylaxis with IDELVION for approximately 11 months, and 4 subjects in the on-demand arm received IDELVION upon occurrence of bleeding events. All 85 bleeding episodes were successfully treated with 1 or 2 doses of IDELVION.
The efficacy of IDELVION has been evaluated in the open-label, uncontrolled part of a phase 2/3 study, in which a total of 63 male, previously treated patients (PTPs) between 12 and 61 years of age received IDELVION either for prophylaxis once every 7-, 10- and/or 14-day intervals and/or for the treatment of bleeding episodes on an on-demand basis. All subjects had severe (FIX level <1%) or moderately severe (FIX level ≤ 2%) haemophilia B. Forty PTPs received IDELVION for prophylaxis.
Subjects who received prophylactic treatment started with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10 or 14 days) with a recommended dose of 75 IU/kg and individual adjustments. 21 PTPs remained on the extended 14-day prophylaxis interval for additional treatment duration of 98 to 575 (median 386) days. From those subjects, 8 (38%) experienced at least one bleeding during the 14 day-prophylaxis, while they had no bleeding events during once-weekly prophylaxis. Median Annualised Bleeding Rate (ABR) on 7 day prophylaxis with IDELVION for all bleeds was 0.0 (range 0-6) and on 14 day-prophylaxis it was 1.08 (range 0-9.1).
The long-term efficacy and safety of routine prophylaxis treatment was confirmed in an open-label extension study for up to 5 years. In this study, a total of 59 PTPs ≥12 years (54 adults and 5 adolescents) received IDELVION either for prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis.
Patients who received prophylactic treatment continued or started with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10, 14 or 21 days) with a recommended dose of 75 IU/kg (10 or 14 days) or 100 IU/kg (21 days). At the end of the study 14 PTPs (24%) were on the 7 day prophylaxis interval, and a total of 11 (19%), 25 (42%) and 9 (15%) PTPs remained on the extended prophylaxis interval of 10, 14 and 21 days, respectively. During the study, 2 PTPs (18%) in the 21-day regimen switched back to a more frequent dosing due to increased bleeding complications. The estimated median Annualised Bleeding Rates (ABRs) on 7-, 14-, and 21-day prophylaxis with IDELVION for all bleeds were 1.3 (range 0-8), 0.9 (range 0-13), and 0.3 (range 0-5), respectively.
Currently available information supports extension of treatment intervals for some patients, although potentially associated with an increased risk for bleeding compared to a once-weekly regimen.
\*\*Prophylaxis and control of bleeding in PTPs below 12 years\*\*
The efficacy of IDELVION has been evaluated in a phase 3 study, in which a total of 27 male PTPs between 1 and 10 years (median age 6.0 years) with 12 patients < 6 years, received IDELVION for prophylaxis and control of bleeding episodes. All 27 subjects received weekly prophylaxis treatment with IDELVION for a mean time on study of 13.1 months (9, 18 months).
Of the 106 bleeding episodes, the majority (94; 88.7%) was treated with single injection, 103; 97.2% were treated with 1-2 injections. Haemostatic efficacy at resolution of a bleed was rated excellent or good in 96% of all treated bleeding episodes.
The long-term efficacy and safety of routine prophylaxis treatment was confirmed in an open-label extension study for up to 5 years. In the study, a total of 24 PTPs < 12 years received IDELVION either for prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis.
Patients who received prophylactic treatment continued with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10 or 14 days) with a recommended dose of 75 IU/kg. At the end of the study 17 PTPs (71%) were on the 7 day prophylaxis interval, and a total of 3 (12%), and 4 (17%) PTPs remained on the extended prophylaxis interval of 10 and 14 days, respectively. During the study, 4 PTPs (50%) in the 14-day regimen switched back to a more frequent dosing due to increased bleeding complications. The estimated median Annualised Bleeding Rates (ABRs) for 7-, and 14-day prophylaxis with IDELVION for all bleeds were 2.0 (range 0-14), and 5.6 (range 0-8), respectively.
\*\*Perioperative management\*\*
The safety and efficacy in the perioperative setting was evaluated in two pivotal Phase 3 studies and a long-term extension study. The per protocol efficacy analysis includes 30 surgeries performed in 21 patients between 5 and 58 years undergoing major or minor surgical, dental or other surgical invasive procedures. Dosing was individualized based on the subject's PK and clinical response to treatment. A single preoperative bolus ranging from 14 to 163 IU/kg was used in 96.7% (n=29) of surgeries. Haemostatic efficacy was rated as excellent or good in all of the assessed procedures. During the 14-day postoperative period, patients received between 0 and 11 infusions and total doses ranging from 0 to 444 IU/kg.
\*\*Previously untreated patients (PUP)\*\*
Safety and efficacy of IDELVION were evaluated in a multicenter open-label clinical study with 12 previously untreated paediatric patients (PUPs) with hemophilia B (≤2% endogenous FIX activity), of whom 11 were in the age-range of 0 to 1 years. The median number of exposure days (EDs) was 50 (range 22 to 146 EDs), and 8 PUPs achieved ≥50 EDs during on-demand, prophylaxis, surgical and PK periods.
All 12 PUPs received routine prophylaxis with 11 receiving the 7-day regimen. The overall median time on prophylaxis was 11.5 months (range: 3.1 to 32.3 months). In the 9 PUPs on the 7-day prophylaxis regimen who reached > 6 months of treatment, median annualized bleeding rate (ABR) was 1.16 (range 0 to 3.1). Five of the 9 PUPs had an ABR of 0. The median monthly dose was 195.9 IU/kg (range 171.8 to 215.6 IU/kg) IU/kg for the 7-day prophylaxis regimen (N = 9).
Five subjects received on-demand treatment over varying periods prior to prophylaxis, with the number of EDs ranging from 1 to 4.
Of the 37 bleeding events observed in 10 PUPs across all study periods, 94% were successfully controlled with 1 or 2 infusions.5.2 Pharmacokinetic properties
\*\*Adult population\*\*
The pharmacokinetics (PK) of IDELVION were evaluated following an intravenous injections of a single dose of 25, 50, and 75 IU/kg. The PK parameters following a single injection of 50 IU/kg IDELVION (see table below) were based on plasma factor IX activity measured by the one-stage clotting assay. The mean factor IX activity at day 7, and day14 was 13.76% and 6.10%, respectively, after a single dose of 50 IU/kg IDELVION. Repeat PK assessment for up to 30 weeks demonstrated a stable pharmacokinetic profile and incremental recovery was consistent over time.
Trough levels of 5-10% have been targeted in clinical studies for achieving bleeding control while on prophylaxis. PK simulations suggest the time to reach 5% plasma FIX activity following a single injection of 50 IU/kg IDELVION to be 12.5 days for adults.
\*\*Pharmacokinetic parameters for subjects with severe haemophilia (Median (min, max)) following a single injection of IDELVION in adults\*\*
| | |
| --- | --- |
| \*\*PK parameters\*\* | \*\*50 IU/kg\*\* \*\*(N=22)\*\* |
| IRa (IU/dl)/(IU/kg) | 1.18 (0.86, 1.86) |
| Cmaxa (IU/dl) | 62.7 (40.5, 87.0) |
| AUC0-inf (h\\*IU/dl) | 6638 (2810, 9921) |
| Elimination t1/2 (h) | 95.3 (51.5, 135.7) |
| CL (ml/h/kg) | 0.875 (0.748, 1.294) |
a = corrected for baseline levels
IR = incremental recovery; AUC = area under the factor IX activity time curve; CL = body weight adjusted clearance; Elimination t1/2 = Elimination half-life
\*\*Paediatric population\*\*
Pharmacokinetic parameters of IDELVION were evaluated in adolescents (12 to <18 years of age) and infants and children (1 to <12 years of age) following an intravenous injection of a single dose of 50 IU/kg. PK parameters (presented below) were estimated based on the plasma factor IX activity over time profile measured by the one-stage clotting assay.
\*\*Comparison of pharmacokinetic parameters of IDELVION in children (Median (min, max)) following a single injection of 50 IU/kg IDELVION\*\*
| | | | |
| --- | --- | --- | --- |
| \*\*PK parameters\*\* | \*\*1 to <6 years\*\* \*\*(N=12)\*\* | \*\*6 to <12 years\*\* \*\*(N=15)\*\* | \*\*12 to <18 years\*\* \*\*(N=5)\*\* |
| IRa (IU/dl)/(IU/kg) | 0.968 (0.660, 1.280) | 1.07 (0.70, 1.47) | 1.11 (0.84, 1.61) |
| Cmaxa (IU/dl) | 48.2 (33.0, 64.0) | 50.5 (34.9, 73.6) | 55.3 (40.5, 80.3) |
| AUC0-inf (h\\*IU/dl) | 4301 (2900, 8263) | 4718 (3212, 7720) | 4804 (2810, 9595) |
| Elimination t1/2 (h) | 86.2 (72.6, 105.8) | 89.3 (62.1, 123.0) | 88.8 (51.5, 130.0) |
| CL (ml/h/kg) | 1.16 (0.61, 1.72) | 1.06 (0.65, 1.56) | 1.04 (0.52, 1.67) |
a = corrected for baseline levels
IR = incremental recovery; AUC = area under the factor IX activity time curve; CL = body weight adjusted clearance; Elimination t1/2 = Elimination half-life
Trough levels of 5-10% have been targeted in clinical studies for achieving bleeding control while on prophylaxis. PK simulations suggest the time to reach 5% plasma FIX activity following a single injection of 50 IU/kg IDELVION to be 7 days for 1-<6years, 9 days for 6-<12 years and 11 days for 12-<18 years of age).5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeat dose toxicity, genotoxicity, thrombogenicity and local tolerability.
No investigations on carcinogenicity and reproductive toxicology have been conducted.
## Pharmaceutical Particulars
6.1 List of excipients
\*\*Powder:\*\*
Sodium citrate,
Polysorbate 80,
Mannitol, Sucrose,
Hydrochloric acid (for pH adjustment).
\*\*Solvent:\*\*
Water for injections6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Only the provided injection sets should be used because treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some injection equipment.6.3 Shelf life
3 years
After reconstitution the chemical and physical in-use stability has been demonstrated for 8 hours at 2-25 °C). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are in the responsibility of the user.6.4 Special precautions for storage
Do not store above 25 °C.
Do not freeze. Keep vials in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.6.5 Nature and contents of container
\*\*IDELVION 250 IU powder and solvent for solution for injection\*\*
Powder (250 IU) in a 6 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
2.5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 500 IU powder and solvent for solution for injection\*\*
Powder (500 IU) in a 6 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
2.5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 1000 IU powder and solvent for solution for injection\*\*
Powder (1000 IU) in a 6 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
2.5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 2000 IU powder and solvent for solution for injection\*\*
Powder (2000 IU) in a 10 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*IDELVION 3500 IU powder and solvent for solution for injection\*\*
Powder (3500 IU) in a 10 ml vial (type I glass), with a stopper (bromobutyl rubber) a disc (plastic) and a cap (aluminium).
5 ml of solvent in a vial (type I glass), with a stopper (bromo- or chlorobutyl rubber) a disc (plastic) and a cap (aluminium).
\*\*Presentations\*\*
Each pack contains:
\*\*IDELVION 250 IU powder and solvent for solution for injection:\*\*
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
\*\*IDELVION 500 IU powder and solvent for solution for injection\*\*
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
\*\*IDELVION 1000 IU powder and solvent for solution for injection\*\*
1 vial with powder
1 vial with 2.5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 5 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
\*\*IDELVION 2000 IU powder and solvent for solution for injection\*\*
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
IDELVION 3500 IU powder and solvent for solution for injection
1 vial with powder
1 vial with 5 ml water for injections
1 filter transfer device 20/20
One inner box containing:
1 disposable 10 ml syringe
1 venipuncture set
2 alcohol swabs
1 non-sterile plaster
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
\*\*General instructions\*\*
- The reconstituted solution should be clear or slightly opalescent, yellow to colourless. After filtering/withdrawal (see below) the reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.
- Do not use solutions that are cloudy or have deposits.
- Reconstitution and withdrawal must be carried out under aseptic conditions.
\*\*Reconstitution\*\*
Bring the solvent to room temperature (below 25 °C). Ensure IDELVION and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
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| --- | --- |
| SMPC\_31844\_219264a\_13.png | 1. Open the Mix2Vial by peeling off the lid. Do \*\*\*\*not\*\*\*\* remove the Mix2Vial from the blister package! |
| SMPC\_31844\_219264b\_13.png | 2. Place the \*\*solvent vial\*\* on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the \*\*blue\*\* adapter end \*\*straight down\*\* through the solvent vial stopper. |
| SMPC\_31844\_219264c\_13.png | 3. Carefully remove the blister package from the Mix2Vial set by holding at the rim and pulling \*\*vertically\*\* upwards. Make sure that you only pull away the blister package and not the Mix2Vial set. |
| SMPC\_31844\_219264d\_13.png | 4. Place the \*\*IDELVION vial\*\* on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the \*\*transparent\*\* adapter end \*\*straight down\*\* through the IDELVION vial stopper. The solvent will automatically flow into the IDELVION vial. |
| SMPC\_31844\_219264e\_13.png | 5. With one hand grasp the IDELVION side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully counter-clockwise into two pieces. Discard the solvent vial with the blue Mix2Vial adapter attached. |
| SMPC\_31844\_219264f\_13.png | 6. Gently swirl the IDELVION vial with the transparent adapter attached until the substance is fully dissolved. Do not shake. |
| SMPC\_31844\_219264g\_13.png | 7. Draw air into an empty, sterile syringe. While the IDELVION vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the IDELVION vial. |
\*\*Withdrawal and application\*\*
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| --- | --- |
| SMPC\_31844\_219264h\_13.png | 8. While keeping the syringe plunger pressed, turn the system upside down and draw the solution into the syringe by pulling the plunger back slowly. |
| SMPC\_31844\_219264i\_13.png | 9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counter-clockwise. |
Care should be taken that no blood enters the syringe filled with product, as there is a risk that the blood could coagulate in the syringe and fibrin clots could therefore be administered to the patient.
The reconstituted IDELVION solution must not be diluted.
The reconstituted solution should be administered by slow intravenous injection The rate of administration should be determined by the patient's comfort level, up to a maximum of 5 ml/min.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
