Hemophilia B, without inhibitors:
Note: Contains only factor IX. Therefore, NOT INDICATED for replacement therapy of other clotting factors besides factor IX, hemophilia A patients with inhibitors to factor VIII, reversal of anticoagulation due to vitamin K antagonists or other anticoagulants, or bleeding due to low levels of liver-dependent clotting factors.
Treatment and control of bleeding episodes or perioperative management:
Intermittent IV bolus dosing: IV: Utilize steps 1 to 4 to determine intermittent bolus dosing strategy. Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment.
Step 1: Identify product-specific in vivo recovery (IVR) for dosing calculations (Note: IVR indicates the expected increase in factor IX level, which occurs with 1 unit/kg of factor IX product administration):
Rebinyn IVR: 1.9.
Step 2: Determine desired factor IX peak level and anticipated duration of therapy based on the World Federation of Hemophilia (WFH) treatment recommendations; see table. Selection of the lower dose practice pattern requires closer observation with the potential for requiring escalation to higher doses based on clinical response.
|
Type of hemorrhage or surgery |
Lower dose practice pattern |
Higher dose practice pattern | ||
|---|---|---|---|---|
|
Desired peak factor IX level (units/dL) |
Treatment duration (days) |
Desired peak factor IX level (units/dL) |
Treatment duration (days) | |
|
a WFH = World Federation of Hemophilia; (WFH [Srivastava 2020]). b May be longer if response is inadequate. c Sometimes longer as secondary prophylaxis during physical therapy. d A single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response. | ||||
|
Joint |
10 to 20 |
1 to 2b,d |
40 to 60 |
1 to 2b,d |
|
Superficial muscle/no neurovascular compromise (except iliopsoas) |
10 to 20 |
2 to 3b |
40 to 60 |
2 to 3b |
|
Iliopsoas or deep muscle with neurovascular injury or substantial blood loss | ||||
|
Initial |
15 to 30 |
1 to 2 |
60 to 80 |
1 to 2 |
|
Maintenance |
10 to 20 |
3 to 5c |
30 to 60 |
3 to 5c |
|
Intracranial | ||||
|
Initial |
50 to 80 |
1 to 3 |
60 to 80 |
1 to 7 |
|
Maintenance |
20 to 40 |
8 to 14 |
30 |
8 to 21 |
|
30 to 50 |
4 to 7 |
- |
- | |
|
Throat and neck | ||||
|
Initial |
30 to 50 |
1 to 3 |
60 to 80 |
1 to 7 |
|
Maintenance |
10 to 20 |
4 to 7 |
30 |
8 to 14 |
|
GI | ||||
|
Initial |
30 to 50 |
1 to 3 |
60 to 80 |
7 to 14 |
|
Maintenance |
10 to 20 |
4 to 7 |
30 |
- |
|
Renal |
15 to 30 |
3 to 5 |
40 |
3 to 5 |
|
Deep laceration |
15 to 30 |
5 to 7 |
40 |
5 to 7 |
|
Surgery (major) | ||||
|
Pre-op |
50 to 70 |
- |
60 to 80 |
- |
|
Post-op |
30 to 40 |
1 to 3 |
40 to 60 |
1 to 3 |
|
20 to 30 |
4 to 6 |
30 to 50 |
4 to 6 | |
|
10 to 20 |
7 to 14 |
20 to 40 |
7 to 14 | |
|
Surgery (minor) | ||||
|
Pre-op |
40 to 80 |
- |
50 to 80 |
- |
|
Post-op |
20 to 50 |
1 to 5 |
30 to 80 |
1 to 5 |
Step 3: Calculate dose using IVR from step 1, desired peak factor IX level from step 2, and the following equation:
Factor IX units required = ([desired peak factor IX level − patient's baseline factor IX level] × body weight [kg])/IVR
(Note: Factor IX units are in units/dL.)
Example (Rebinyn) for 50 kg patient with desired peak factor IX level of 35 units/dL, baseline factor IX level of 5 units/dL, IVR = 1.9:
Factor IX units required = ([35 units/dL − 5 units/dL] × 50 kg) ⁄ 1.9 = 789 units factor IX
Step 4: Determine need for repeat dosing based on manufacturer’s recommended frequency of repeat dosing. Note: Frequency of administration must also take into consideration subsequent factor IX activity measurements and clinical response.
|
Product |
Bleeding event |
Surgery | |||
|---|---|---|---|---|---|
|
Minor severity |
Moderate severity |
Major severity |
Minor bleeding risk |
Major bleeding risk | |
|
Rebinyn |
Single dose is typically adequate. Additional doses can be given if needed. Due to prolonged half-life of ~115 hours, base timing of redosing on serial factor IX level measurements. |
Single dose is typically adequate. Additional doses can be considered. Due to prolonged half-life of ~115 hours, base timing of redosing on serial factor IX level measurements. |
Single dose is typically adequate. Additional doses can be considered. Due to prolonged half-life of ~115 hours, base timing of redosing on serial factor IX level measurements. |
Single preoperative dose is typically adequate. Additional doses can be given if needed. Due to prolonged half-life of ~115 hours, base timing of redosing on serial factor IX level measurements. |
Every 1 to 3 days based on response and factor IX levels. After the first week, dosing frequency may be extended to once weekly. |
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with moderate/severe hemophilia B without inhibitors :
IV: 40 units/kg once weekly; may titrate dose or frequency based on patient's clinical response. Dosing should be tailored to ensure trough factor IX levels of ≥1% and preferably ≥3% to 5% are achieved, but prophylaxis targets should be tailored to individual level of activity, lifestyle, and pharmacokinetics. Dose escalation should be considered for patients adherent to prescribed prophylaxis but still experiencing breakthrough bleeding events (WFH [Srivastava 2020]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; monitor factor IX levels.
There are no dosage adjustments provided in the manufacturer's labeling; monitor factor IX levels. Use with caution due to the risk of thromboembolic complications.
Factor IX deficiency: Note: Contains only factor IX. Therefore, NOT INDICATED for the treatment of other factor deficiencies (eg, factors II, VII, VIII, and X), hemophilia A with inhibitors to factor VIII, reversal of coumarin-induced anticoagulation, and bleeding due to low levels of liver-dependent clotting factors. Dose and duration of treatment depends on the severity of factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age, and recovery of factor IX. Adjust dosing regimen based on individual response.
On-demand control and prevention of bleeding episodes: IV: Refer to adult dosing.
Perioperative management of bleeding: IV: Refer to adult dosing.
There are no dosage adjustments provided in the manufacturer's labeling; monitor factor IX levels.
There are no dosage adjustments provided in the manufacturer's labeling; monitor factor IX levels. Use with caution due to the risk of thromboembolic complications.
Refer to adult dosing.
There are insufficient data to recommend the best dosing weight to use in patients with obesity. Dose adjustments should ultimately be made based on individual patient response to therapy. Due to the paucity of data, refer to institutional protocols. Refer to adult dosing for indication-specific dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Rebinyn: 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea) [pyrogen free; contains polysorbate 80]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Rebinyn: 500 units (1 ea); 1000 units (1 ea); 2000 units (1 ea) [contains polysorbate 80]
IV: For IV infusion only. Solution should be infused at room temperature. Infuse slowly over 1 to 4 minutes based on patient response and comfort.
IV: For IV infusion only. Solution should be infused at room temperature. Infuse slowly over 1 to 4 minutes based on patient response and comfort. With patients who have had allergic reactions during factor IX infusion, administration of hydrocortisone prior to infusion may be necessary (WFH [Srivastava 2013]).
Hemophilia B: On-demand treatment and control of bleeding, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes in patients with factor IX deficiency (hemophilia B).
Limitations of use: Not indicated for the treatment of other factor deficiencies (eg, factor II, VII, VIII, X), for the treatment of hemophilia A patients with inhibitors to factor VIII, the reversal of coumarin-induced anticoagulation, or for the treatment of bleeding because of low levels of liver-dependent coagulation factors. Not indicated for immune tolerance induction in patients with hemophilia B.
Factor IX may be confused with Factor IX Complex
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in pediatric patients and adults unless otherwise indicated.
>10%: Dermatologic: Skin rash (infants and children: 18%)
1% to 10%:
Dermatologic: Pruritus (3% to 4%)
Hematologic & oncologic: Factor IX inhibitor in hemophilia B (infants and children: 8%)
Hypersensitivity: Anaphylaxis (infants and children: 2%), hypersensitivity reaction (1% to 6%)
Local: Injection-site reaction (2% to 4%)
Hypersensitivity to factor IX (recombinant [glycopegylated]), hamster protein, or any component of the formulation.
Concerns related to adverse effects:
• Antibody formation: The development of factor IX antibodies (or inhibitors) has been reported with factor IX therapy (usually occurs within the first 10 to 20 exposure days); the risk of severe hypersensitivity reactions occurring may be greater in these patients. When clinical response is suboptimal, the patient has reached a specified number of exposure days, or patient is to undergo surgical procedure, screen for inhibitors. Patients with severe hemophilia compared to those with mild or moderate hemophilia are more likely to develop inhibitors (WFH [Srivastava 2013]).
• Hypersensitivity reactions: Allergic-type hypersensitivity reactions, including anaphylaxis, may occur. Observe patients for signs/symptoms of acute hypersensitivity reactions, particularly during the initial exposure. Due to potential for allergic reactions, the initial ~10 to 20 administrations should be performed under appropriate medical supervision. Hypersensitivity reactions may be associated with factor IX inhibitor development; patients experiencing allergic reactions should be evaluated for factor IX inhibitors. If hypersensitivity reactions occur, discontinue immediately; in the case of severe allergic reactions, consider the use of alternative hemostatic measures (WFH [Srivastava 2013]).
• Nephrotic syndrome: Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors and a history of allergic reactions. Safety and efficacy in this situation have not been established.
• Thrombotic events: Observe closely for signs or symptoms of intravascular coagulation or thrombosis; risk is generally associated with the use of factor IX complex concentrates (containing therapeutic amounts of additional factors); however, potential risk exists with use of factor IX products (containing only factor IX). Use with caution when administering to patients with liver disease, postoperatively, neonates, or patients at risk of thromboembolic phenomena, disseminated intravascular coagulation or patients with signs of fibrinolysis due to the potential risk of thromboembolic complications.
Disease-related concerns:
• Hepatic impairment: Use with extreme caution in patients with hepatic impairment due to the increased risk of thromboembolic complications.
Dosage form specific issues:
• Hamster protein: May contain trace amounts of Chinese hamster proteins; hypersensitivity to these proteins may develop.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Clinical response: Response to factor IX administration may vary. If bleeding is not controlled with the recommended dose, determine plasma level of factor IX and follow with a sufficient dose to achieve satisfactory clinical response. If plasma levels of factor IX fail to increase as expected or bleeding continues, suspect the presence of an inhibitor; test as appropriate.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Risk C: Monitor therapy
Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Risk C: Monitor therapy
Pregnant carriers of hemophilia B may have an increased bleeding risk following invasive procedures, spontaneous miscarriage, termination of pregnancy, and delivery; close surveillance is recommended. Factor IX levels should be monitored at the first antenatal visit, once or twice during the third trimester, prior to surgical or invasive procedures, and at delivery. Although factor IX levels remain stable during pregnancy, factor IX replacement is recommended if concentrations are <50 units/dL and any of the following occur: need for invasive procedures (including delivery), spontaneous miscarriage, insertion and removal of epidural catheters, or active bleeding. Hemostatic factor IX concentrations should be maintained for at least 3 to 5 days following invasive procedures or postpartum. If replacement with a factor IX concentrate is indicated to increase factor IX during pregnancy, a recombinant product is preferred (NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2020]).
It is not known if factor IX (recombinant [glycopegylated]) is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Monitoring assay selection: For Rebinyn, the World Federation of Hemophilia recommends use of a chromogenic FIX assay or an aPTT-based one-stage factor IX activity assay with validated reagents, calibrated with a plasma standard traceable to a WHO international standard. Note: Most one-stage FIX assays significantly overestimate or underestimate Rebinyn FIX activity and should not be used. One-stage assays using the ellagic acid activator reagent SynthAFax or the polyphenol activator reagent Cephascreen are suitable for monitoring Rebinyn therapy (WFH [Srivastava 2020]).
Monitoring frequency: During treatment of an acute bleeding event or in the perioperative setting using intermittent bolus administration, factor IX levels should be measured at baseline, and as peaks 15 to 30 minutes after infusion to assess target level achievement. The frequency of peak factor IX activity monitoring during active treatment depends on the indication, clinical response, and treatment day. Measurement of FIX trough levels may aid in calculation of subsequent doses (WFH [Srivastava 2020]).
For long-term bleeding prophylaxis, trough factor IX measurements should be obtained to tailor prophylaxis regimens, with the goal of achieving factor IX troughs >3 to 5 units/dL; prophylaxis targets should be tailored to individual level of activity, lifestyle, and pharmacokinetics.
Additional monitoring considerations: Heart rate and BP before and during IV administration, signs of hypersensitivity reactions (which may be an early sign of inhibitor development), hemoglobin/hematocrit, and signs and symptoms of intravascular hemolysis.
Lower than expected factor IX recovery or reduced half-life are early signs of inhibitor formation.
Classification of hemophilia; normal is defined as 100% factor IX (WFH [Srivastava 2020]).
Severe: Factor level <1% of normal.
Moderate: Factor level 1% to 5% of normal.
Mild: Factor level 5% to <40% of normal.
Replaces deficient clotting factor IX. Hemophilia B, or Christmas disease, is an X-linked inherited disorder of blood coagulation characterized by insufficient or abnormal synthesis of the clotting protein factor IX. Factor IX is a vitamin K-dependent coagulation factor which is synthesized in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway. Activated factor IX (IXa) in combination with factor VII:C activates factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous factor IX to replace the deficiency present in hemophilia B temporarily restores hemostasis. Factor IX is conjugated to a 40-kDa polyethylene glycol molecule, which slows down its removal from the circulation.
Distribution:
Single dose: Vd: Children ≤6 years of age: 72.3 mL/kg; Children 7 to 12 years: 68.3 mL/kg; Adolescents 13 to 17 years: 58.6 mL/kg; Adults: 47 mL/kg.
After multiple once-weekly prophylactic doses (steady state): Vdss: Adolescents 13 to 17 years: 60.5 mL/kg; Adults: 65.8 mL/kg
Half-life elimination:
Single dose: Children ≤6 years of age: 69.6 hours; Children 7 to 12 years: 76.3 hours; Adolescents 13 to 17 years: 89.4 hours; Adults: 83 hours.
After multiple once-weekly prophylactic doses (steady state): Adolescents 13 to 17 years: 103.1 hours; Adults: 114.9 hours
Solution (reconstituted) (Rebinyn Intravenous)
500 unit (Price provided is per AHF Unit): $5.41
1000 unit (Price provided is per AHF Unit): $5.41
2000 unit (Price provided is per AHF Unit): $5.41
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