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Idelvion

Generic Name: Factor IX (Recombinant), albumin fusion protein
Class: Hemostatics
VA Class: BL500

Medically reviewed by Drugs.com. Last updated on Feb 4, 2019.

Introduction

Biosynthetic (recombinant DNA origin) preparation of blood coagulation factor IX (rIX-FP) genetically fused to recombinant albumin via a short, cleavable peptide derived from the activation peptide of native factor IX.1 4 6 7 11

Uses for Idelvion

Hemophilia B

On-demand control and prevention of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency; Christmas Disease).1 3 15

Maintenance of hemostasis in patients with hemophilia B undergoing surgery (i.e., perioperative management).1 15

Designated an orphan drug by FDA for treatment of patients with hemophilia B.20

Routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce frequency of hemorrhagic events.1 Such prophylactic therapy considered the current standard of care for patients with hemophilia B.17 171 176 Decreases frequency of spontaneous musculoskeletal hemorrhage, preserves joint function, and improves quality of life.171 185 186

Circulating half-life of factor IX (recombinant), albumin fusion protein longer than that of unmodified recombinant or plasma-derived factor IX preparations; may allow for less frequent dosing and improved patient compliance with prophylactic regimens.3 19

Several factor IX concentrates are currently available in the US, including a variety of recombinant and plasma-derived preparations;1 16 18 156 the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends preferential use of recombinant factor IX preparations because of their potentially superior safety profile with respect to pathogen transmission.155 156 176 Other experts (e.g., World Federation of Hemophilia) state that choice of preparation should be determined by local criteria.171 When selecting an appropriate factor IX product, consider characteristics of each clotting factor concentrate, individual patient variables, patient/provider preference, and emerging data.155 156 171 187

Manufacturer states that factor IX (recombinant), Fc fusion protein not indicated for induction of immune tolerance in patients with hemophilia B.1

Idelvion Dosage and Administration

General

  • Individualize dosage and duration of therapy based on severity of factor IX deficiency, location and extent of bleeding, and patient’s clinical condition, age, and recovery of factor IX.1 171

  • Monitor factor IX activity (with one-stage clotting assay) to individualize dosage and assess response to therapy.1 Ensure that adequate levels are attained and maintained.1 (See Laboratory Monitoring under Cautions.)

Administration

IV Administration

Administer by slow IV injection.1 (See Rate of Administration under Dosage and Administration.)

Reconstitution and Administration

Reconstitute with sterile water for injection (provided by manufacturer).1

Allow drug vial and diluent to warm to room temperature prior to reconstitution.1 After addition of diluent, gently swirl vial until powder is completely dissolved; do not shake.1 Resultant solution should be clear or yellow to colorless; do not use if cloudy, discolored or if particulate matter observed.1 2

If more than 1 vial is required to prepare dose, may pool reconstituted contents of multiple vials into a single syringe.1

Administer using sterile infusion set and syringe.1

Do not administer in the same tubing or container with other drugs.1

Administer immediately or within 4 hours after reconstitution.1

Consult manufacturer’s labeling for specific instructions on reconstitution and preparation of factor IX (recombinant), albumin fusion protein.1

Rate of Administration

Determine rate of administration by patient’s comfort level (not to exceed 10 mL/minute).1

Dosage

Dosage (potency) expressed in terms of international units (IU, units) of factor IX activity.1 Potency is determined by an aPTT-based one-stage clotting assay calibrated against a WHO standard.1 14 Administration of 1 unit/kg factor IX (recombinant), albumin fusion protein increases circulating levels of factor IX by 1.3 units/dL in patients ≥12 years of age and by 1 unit/dL in patients <12 years of age.1

Estimate dose required to achieve a particular percentage increase in plasma factor IX using the following formula:1

Dose (units) = body weight (in kg) x desired factor IX increase (in % of normal or units/dL) × reciprocal of recovery (in units/kg per units/dL) 1

Determine desired factor IX level by the clinical situation and severity of bleeding.1 For recommendations on target factor IX levels for a given clinical situation, see the specific dosage sections for various uses below. These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and individualization of dosage based on the hemostatic requirements of patients.1 Measure factor IX activity after a dose is given to verify calculated dose.1 171

If calculated dose is ineffective in achieving appropriate factor IX levels, consider possibility that neutralizing antibodies (inhibitors) may have developed.1 171 (See Development of Inhibitors to Factor IX under Cautions.)

Pediatric Patients

Hemophilia B

Higher doses or more frequent dosing may be required in pediatric patients because of increased clearance, shorter half-life, and lower recovery of factor IX.1

On-Demand Control and Prevention of Bleeding
IV

Minor or moderate bleeding (e.g., uncomplicated hemarthroses, muscle bleeding [except iliopsoas], oral bleeding): Administer appropriate dose to achieve factor IX levels of 30–60% of normal.1 Repeat every 48–72 hours until bleeding resolves and healing achieved; single injection usually sufficient.1

Major bleeding (e.g., limb- or life-threatening hemorrhage; deep muscle bleeding, including iliopsoas; intracranial; retropharyngeal): Administer appropriate dose to achieve factor IX levels of 60–100% of normal; repeat every 48–72 hours for 7–14 days until bleeding resolves and healing achieved.1 Administer maintenance dose weekly.1

Perioperative Hemostasis
IV

Minor surgery (e.g., uncomplicated dental extraction): Administer appropriate dose to achieve a factor IX level of 50–80% of normal.1 Repeat every 48–72 hours until healing achieved; single injection usually sufficient.1

Major surgery (e.g., intracranial, pharyngeal, retropharyngeal, retroperitoneal): Administer appropriate dose to achieve initial factor IX level of 60–100% of normal.1 Repeat every 48–72 hours for 7–14 days, or until bleeding resolves and healing achieved.1 Administer maintenance dose 1 or 2 times weekly.1

Routine Prophylaxis
IV

Pediatric patients <12 years of age: 40–55 units/kg every 7 days.1 Adjust dosage based on patient response.1

Pediatric patients ≥12 years of age: Initially, 25–40 units/kg every 7 days.1 Patients well controlled on this regimen may be switched to 50–75 units/kg every 14 days.1 Adjust dosage based on patient response.1

According to MASAC, institute prophylactic therapy at an early age (e.g., 1–2 years), prior to the onset of frequent bleeding; however, optimum duration of prophylaxis not known.176

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.1 171 176

Adults

Hemophilia B
On-Demand Control and Prevention of Bleeding
IV

Minor or moderate bleeding (e.g., uncomplicated hemarthroses, muscle bleeding [except iliopsoas], oral bleeding): Administer appropriate dose to achieve factor IX levels of 30–60% of normal.1 Repeat every 48–72 hours until bleeding resolves and healing achieved; single injection usually sufficient.1

Major bleeding (e.g., limb- or life-threatening hemorrhage; deep muscle bleeding, including iliopsoas; intracranial; retropharyngeal): Administer appropriate dose to achieve factor IX levels of 60–100% of normal; repeat every 48–72 hours for 7–14 days until bleeding resolves and healing achieved.1 Administer maintenance dose weekly.1

Perioperative Hemostasis
IV

Minor surgery (e.g., uncomplicated dental extraction): Administer appropriate dose to achieve a factor IX level of 50–80% of normal.1 Repeat dose every 48–72 hours until healing achieved; single injection usually sufficient.1

Major surgery (e.g., intracranial, pharyngeal, retropharyngeal, retroperitoneal): Administer appropriate dose to achieve initial factor IX level of 60–100% of normal.1 Repeat every 48–72 hours for 7–14 days, or until bleeding resolves and healing achieved.1 Administer maintenance dose 1 or 2 times weekly.1

Routine Prophylaxis
IV

Initially, 25–40 units/kg every 7 days.1 Patients well controlled on this regimen may be switched to 50–75 units/kg every 14 days.1 Adjust dosage based on patient response.1

Individualize prophylactic dosage regimens; evaluate patients periodically to determine continued need for prophylaxis.1 171 176 Optimum duration of prophylaxis not known.176

Cautions for Idelvion

Contraindications

  • Known history of life-threatening hypersensitivity to factor IX (recombinant), albumin fusion protein or any ingredient in the formulation (including hamster proteins).1

Warnings/Precautions

Development of Inhibitors to Factor IX

Risk for development of inhibitors to factor IX following treatment with any factor IX preparation.1 171 Reported in <5% of patients with hemophilia B receiving factor IX concentrates.171

Monitor patients regularly for development of inhibitors with appropriate clinical observation and laboratory tests.1 171 (See Laboratory Monitoring under Cautions.) Suspect presence of inhibitors if expected factor IX levels not achieved or bleeding not controlled with recommended dose, particularly in those who previously achieved a response.1 171

Because of an association between inhibitor development and allergic reactions, evaluate for presence of inhibitors in any patient experiencing hypersensitivity.1 (See Hypersensitivity under Cautions.) In patients with inhibitors, increased risk of anaphylaxis following re-exposure to factor IX (recombinant), albumin fusion protein.1

Consultation with a hemophilia treatment center is strongly recommended for patients with inhibitors.171

Thromboembolic Events

Risk of thromboembolic complications (e.g., pulmonary embolism, venous thromboembolism, arterial thrombosis).1

Monitor for early manifestations of thromboembolism and consumptive coagulopathy in patients with hepatic disease, signs of fibrinolysis, or other risk factors for thromboembolism or disseminated intravascular coagulation (DIC).1

Nephrotic Syndrome

Nephrotic syndrome reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors and history of allergic reactions.1 Safety and efficacy of factor IX (recombinant), albumin fusion protein for immune tolerance induction not established.1

Laboratory Monitoring

Monitor factor IX levels (using aPTT-based one-stage clotting assay) to guide dosing and assess therapeutic response.1 171 Results can vary based on type of aPTT reagent; a kaolin-based reagent is likely to result in an underestimation of factor IX activity.1 14

Monitor for development of inhibitors.1 Perform appropriate laboratory test (i.e., Bethesda assay) to confirm presence of an inhibitor.1 171 (See Development of Inhibitors to Factor IX under Cautions.)

Sensitivity Reactions

Hypersensitivity

Risk of hypersensitivity reactions, including anaphylaxis.1

Closely observe patient for signs and symptoms of hypersensitivity (e.g., angioedema, chest tightness, hypotension, generalized urticaria, wheezing, dyspnea).1 If a hypersensitivity reaction occurs, immediately discontinue drug and initiate appropriate therapy.1

Specific Populations

Pregnancy

No adequate and well-controlled studies of factor IX (recombinant), albumin fusion protein in pregnant women.1 Animal reproductive and development studies lacking.1 Use during pregnancy only when clearly needed.1

Lactation

Not known whether distributed into human milk; use with caution.1 7

Pediatric Use

Safety, efficacy, and pharmacokinetics of factor IX (recombinant), albumin fusion protein evaluated in 32 pediatric patients.1 Prophylactic administration of factor IX (recombinant), albumin fusion protein successful in preventing spontaneous bleeding episodes; no differences in safety profile in pediatric patients compared with adults.1

Compared with adults, pediatric patients may have higher body weight-adjusted clearance, shorter half-life, and lower factor IX recovery; higher doses or more frequent dosing may be required.1 7 (See Dosage under Dosage and Administration.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Headache.1

Idelvion Pharmacokinetics

Absorption

Plasma Concentrations

Exhibits dose-proportional pharmacokinetics.4 5

Mean recovery of factor IX approximately 1.3 units/dL in patients ≥12 years of age and 1 unit/dL in patients <12 years of age for each unit/kg of factor IX (recombinant), albumin fusion protein administered.1

Compared with adults, pediatric patients appear to have lower incremental recovery of factor IX.1 In clinical studies, incremental recovery was approximately 0.95, 1.06, or 1.11 units/dL per each unit/kg administered in patients 0–5 years, 6–11 years, or 12–17 years of age, respectively.1

Distribution

Extent

Not known whether factor IX (recombinant), albumin fusion protein is distributed into milk.1

Elimination

Half-life

Following administration of a single 50-unit/kg dose in adults with hemophilia B, half-life is approximately 104 hours; average time to decline to 1% factor IX activity is 23 days.1

Compared with adults, pediatric patients appear to have higher body weight-adjusted clearance and shorter half-life of factor IX.1 In clinical studies, half-life was approximately 90, 93, or 87 hours in patients 0–5 years, 6–11 years, or 12–17 years of age, respectively.1

In clinical trials, factor IX (recombinant), albumin fusion protein has demonstrated approximately a threefold to fivefold prolongation of the half-life of factor IX activity in circulation when compared with the half-lives of unmodified factor IX preparations.12 13

Stability

Storage

Parenteral

Powder for Injection

2–25°C; do not freeze.1 Store in original carton and protect from light.1

May store reconstituted solution at room temperature prior to administration.1 Use solution as soon as possible but within 4 hours of reconstitution.1

Actions

  • Biosynthetic (recombinant DNA-origin) preparation of blood coagulation factor IX genetically fused to recombinant albumin via a short, cleavable peptide derived from the activation peptide of native factor IX.1 4 6 7 11 Albumin prolongs half life of factor IX through interaction with the Fc neonatal receptor (also present on many adult cells).1 3 10 11 Factor IX portion is similar in structure and function to endogenous factor IX.7

  • Patients with hemophilia B have decreased levels of endogenous factor IX, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, joints, and internal organs.3 171 Clinical severity and frequency of bleeding generally correlate with degree of deficiency of factor IX activity.171 Patients with mild hemophilia B generally have >5% of normal factor IX activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.10 171

  • Administration of factor IX (recombinant), albumin fusion protein to patients with hemophilia B increases plasma levels of factor IX and temporarily corrects coagulation defect.1

  • Produced by recombinant DNA technology in a Chinese hamster ovary (CHO) cell line; undergoes several purification processes (e.g., solvent/detergent treatment, filtration) and is manufactured without hormones or human and animal components.1 7

Advice to Patients

Importance of advising patients to read the manufacturer-provided patient information and instructions for use.1

Importance of patients reporting any adverse reactions or other issues following administration of factor IX (recombinant), albumin fusion protein to their clinician.1

Importance of discontinuing therapy and informing a clinician if any manifestations of hypersensitivity or allergic reactions (e.g., urticaria, generalized urticaria, chest tightness, wheezing, hypotension) occur.1

Possible development of inhibitors; advise patients to inform clinician if they experience a lack of response to factor IX (recombinant), albumin fusion protein therapy.1

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Factor IX (Recombinant), Albumin Fusion Protein

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

number of units indicated on label (nominally 250, 500, 1000, or 2000 units)

Idelvion (with sterile water for injection diluent and filter transfer set)

CSL Behring

AHFS DI Essentials™. © Copyright 2019, Selected Revisions February 4, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. CSL Behring. Idelvion coagulation factor IX (recombinant), albumin fusion protein prescribing information. Kankakee, IL; 2016 Mar.

2. CSL Behring. Idelvion coagulation factor IX (recombinant), albumin fusion protein patient labeling. Kankakee, IL; 2016 Mar.

3. Santagostino E, Martinowitz U, Lissitchkov T et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016; 127:1761-9. http://www.ncbi.nlm.nih.gov/pubmed/26755710?dopt=AbstractPlus

4. Santagostino E, Negrier C, Klamroth R et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012; 120:2405-11. http://www.ncbi.nlm.nih.gov/pubmed/22859609?dopt=AbstractPlus

5. Santagostino E. PROLONG-9FP clinical development program--phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP). Thromb Res. 2013; 131 Suppl 2:S7-10. http://www.ncbi.nlm.nih.gov/pubmed/23537724?dopt=AbstractPlus

6. Martinowitz U, Lissitchkov T, Lubetsky A et al. Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients. Haemophilia. 2015; 21:784-90. http://www.ncbi.nlm.nih.gov/pubmed/25990590?dopt=AbstractPlus

7. Food and Drug Administration. Summary basis for regulatory action: BLA#STN125582/0. From FDA website. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM491636.pdf

8. Food and Drug Administration. Clinical review: STN BLA#125582/0. From FDA website. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM491972.pdf

9. Food and Drug Administration. Statistical review: STN BLA#125582/0. From FDA website. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM492492.pdf

10. Nazeef M, Sheehan JP. New developments in the management of moderate-to-severe hemophilia B. J Blood Med. 2016; 7:27-38. http://www.ncbi.nlm.nih.gov/pubmed/27099538?dopt=AbstractPlus

11. Metzner HJ, Pipe SW, Weimer T et al. Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin. Thromb Haemost. 2013; 110:931-9. http://www.ncbi.nlm.nih.gov/pubmed/24178510?dopt=AbstractPlus

12. Food and Drug Administration. Final CMC review: STN BLA#125582/0. From FDA website. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM492248.pdf

13. Laffan M. New products for the treatment of haemophilia. Br J Haematol. 2016; 172:23-31. http://www.ncbi.nlm.nih.gov/pubmed/26456702?dopt=AbstractPlus

14. Wilmot HV, Hogwood J, Gray E. Recombinant factor IX: discrepancies between one-stage clotting and chromogenic assays. Haemophilia. 2014; 20:891-7. http://www.ncbi.nlm.nih.gov/pubmed/24800651?dopt=AbstractPlus

15. Food and Drug Administration. FDA news release: FDA approves first coagulation factor-albumin fusion protein to treat patients with hemophilia B. From FDA website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm489266.htm

16. Wyeth. BeneFIX coagulation factor IX (recombinant) prescribing information. Philadelphia, PA; 2015 Aug.

17. Carcao M. Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia. 2014; 20 Suppl 4:99-105. http://www.ncbi.nlm.nih.gov/pubmed/24762284?dopt=AbstractPlus

18. Biogen Idec. Alprolix coagulation factor IX (recombinant), Fc fusion protein prescribing information. Cambridge, MA; 2014 Mar.

19. Schulte S. Half-life extension through albumin fusion technologies. Thromb Res. 2009; 124 Suppl 2:S6-8. http://www.ncbi.nlm.nih.gov/pubmed/20109653?dopt=AbstractPlus

20. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed [2016 5 11] http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

155. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendation regarding the use of recombinant clotting factor products with respect to pathogen transmission (May 6, 2014). MASAC recommendation #226. From National Hemophilia Foundation website. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/All-MASAC-Recommendations

156. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (revised October 2016). MASAC recommendation #246. From National Hemophilia Foundation website. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations

171. World Federation of Hemophilia. Guidelines for the management of hemophilia 2nd edition. 2012. From the World Federation of Hemophilia website. http://www1.wfh.org/publications/files/pdf-1472.pdf

176. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendation concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding) (February 28, 2016). MASAC recommendation #241. From National Hemophilia Foundation website. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations

185. Carcao MD, Aledort L. Prophylactic factor replacement in hemophilia. Blood Rev. 2004; 18:101-13. http://www.ncbi.nlm.nih.gov/pubmed/15010149?dopt=AbstractPlus

186. Nilsson IM, Berntorp E, Löfqvist T et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992; 232:25-32. http://www.ncbi.nlm.nih.gov/pubmed/1640190?dopt=AbstractPlus

187. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding factor concentrate prescriptions and formulary development and restrictions (March 12, 2005). MASAC recommendation #159. From National Hemophilia Foundation website. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations

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