Dosage Forms
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]
Pharmacology
Mechanism of Action
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.
Pharmacokinetics/Pharmacodynamics
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
Use: Labeled Indications
Factor IX deficiency: On-demand treatment and control of bleeding and perioperative management of bleeding 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 routine prophylaxis in patients with hemophilia B; not indicated for immune tolerance induction in patients with hemophilia B.
Contraindications
Hypersensitivity to factor IX (recombinant [glycopegylated]), hamster protein, or any component of the formulation.
Dosage and Administration
Dosing: Adult
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:
Minor/moderate bleeding (eg, uncomplicated joint bleeds, minor muscular bleeds, mucosal/subcutaneous bleeds): 40 units/kg. A single dose should be sufficient; however, additional doses of 40 units/kg may be administered.
Major bleeding (eg, intracranial, retroperitoneal, iliopsoas, and neck bleeds; muscle bleeds with compartment syndrome; bleeds associated with a significant decrease in hemoglobin): 80 units/kg; additional doses of 40 units/kg may be administered.
Perioperative management of bleeding: IV:
Minor surgical procedure (eg, implanting pumps in subcutaneous tissue, skin biopsies, invasive dental procedures): 40 units/kg preoperatively. A single dose should be sufficient; however, additional doses may be administered if needed.
Major surgical procedure (eg, body cavity is entered, mesenchymal barrier is crossed, fascial plane is opened, organ is removed, normal anatomy is altered): 80 units/kg preoperatively; may administer 40 units/kg perioperatively as needed (in 1 to 3 day intervals) within the first week after surgery. Note: Frequency of dosing post-surgery may be extended to once weekly after the first week until bleeding stops and healing is achieved.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
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.
Reconstitution
Refer to instructions provided by the manufacturer. Diluent and factor IX should come to room temperature (if refrigerated) before combining.
Administration
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]).
Storage
Store at 2°C to 8°C (36°F to 46°F) in the original packaging for ≤24 months from the date of manufacture until the expiration date stated on the label. Protect from light; do not freeze. May be stored at room temperature ≤30°C (86°F) for ≤6 months within the 24-month time period. Do not return to the refrigerator. Do not use after the end of the 6-month period at room temperature storage, or after the expiration date stated on the vial, whichever occurs earlier. Use within 4 hours after reconstitution when stored at room temperature; discard any unused product.
Drug Interactions
Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. 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. Monitor therapy
Adverse Reactions
1% to 10%:
Dermatologic: Pruritus (3%)
Hypersensitivity: Hypersensitivity reaction (1%)
Local: Injection site reaction (4%)
Frequency not defined:
Hypersensitivity: Anaphylaxis
Warnings/Precautions
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.
Monitoring Parameters
Heart rate and blood pressure (before and during IV administration); signs/symptoms of hypersensitivity reaction; signs of bleeding, hemoglobin, hematocrit; factor IX levels (by chromogenic assay or selected one-stage clotting assay if available); development of factor IX inhibitors
Pregnancy
Pregnancy Considerations
Pregnant hemophilia B carriers may have an increased bleeding risk following abortion, invasive procedures, miscarriage, 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 <0.5 IU/mL 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 2013]).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience itching or injection site redness, edema, or pain. Have patient report immediately to prescriber signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain) or signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
