Benefix

— THERAPEUTIC CATEGORIES —
  • Bleeding disorders
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Benefix Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Coagulation Factor IX (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

    Pharmacological Class

    Clotting factor.

    How Supplied

    Kit—1 (vial + diluent, supplies)

    How Supplied

    BeneFIX, Coagulation Factor IX (Recombinant), is supplied in kits that include 

    • single-use vials which contain nominally 250, 500, 1000, 2000, or 3000 IU per vial 

    • with sterile pre-filled diluent syringe, 

    • vial adapter reconstitution device, 

    • sterile infusion set, 

    • two alcohol swabs, one bandage, and one gauze pad.

    Storage

    Store BeneFIX at room temperature or under refrigeration, at a temperature of 2-30° C (36-86° F).  

    Do not freeze to prevent damage to the diluent syringe.  

    Do not use BeneFIX after the expiration date on the label.

    Manufacturer

    Pfizer Inc.

    Generic Availability

    NO

    Benefix Indications

    Indications

    On-demand treatment and control of bleeding in hemophilia B. Perioperative management in patients with hemophilia B. Routine prophylaxis to reduce the frequency of bleeding episodes in patients aged ≥16yrs with hemophilia B.

    Limitations of Use

    Not for induction of immune tolerance in patients with hemophilia B.

    Benefix Dosage and Administration

    Adults and Children

    See full labeling. Initial Dose Required (IU) = Body Weight (kg) x Desired FIX increase x Reciprocal of observed recovery (IU/kg per IU/dL). Average recovery (≥12yrs): Dose Required (IU) = Body Weight (kg) x Desired FIX increase x 1.3 (IU/kg per IU/dL); (<12yrs): Dose Required (IU) = Body Weight (kg) x Desired FIX increase x 1.4 (IU/kg per IU/dL). Give by IV infusion over several minutes. If inhibitor present or low factor IX recovery, may need higher doses. Hemorrhage (Minor): 20–30% increase every 12–24hrs for 1–2 days; (Moderate): 25–50% increase every 12–24hrs for 2–7 days until resolved; (Major): 50–100% increase every 12–24hrs for 7–10 days. Routine prophylaxis (≥16yrs): 100 IU/kg once weekly; adjust dose or frequency based on clinical response.

    Adults and Children

    Calculating Initial Dose

    Number of factor IX IU required (IU) = Body weight (kg) x Desired factor IX increase (% of normal or IU/dL) x Reciprocal of observed recovery (IU/kg per IU/dL). 

    Average Recovery 

    Adolescents/Adults (≥12yrs)

    In adults, on average, one International Unit (IU) of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.8 ± 0.2 IU/dL (range 0.4 to 1.2 IU/dL). Use the following formula to estimate the dose with 0.8 IU/dL average increase of factor IX per IU/kg body weight administered:

    • Number of factor IX IU required (IU) = Body weight (kg) x Desired factor IX increase (% of normal or IU/dL) x 1.3 (IU/kg per IU/dL)

    Children (<12yrs): 

    In children, on average, one international unit of BeneFIX per kilogram of body weight increased the circulating activity of factor IX by 0.7 ± 0.3 IU/dL (range 0.2 to 2.1 IU/dL; median of 0.6 IU/dL per IU/kg). Use the following formula to estimate the dose with 0.7 IU/dL average increase of factor IX per IU/kg body weight administered:

    • Number of factor IX IU required (IU) = Body weight (kg) x Desired factor IX increase (% of normal or IU/dL) x 1.4 (IU/kg per IU/dL). 

    Doses administered should be titrated to the patient’s clinical response. Patients may vary in their pharmacokinetic (eg, half-life, recovery) and clinical responses to BeneFIX. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests, including serial factor IX activity assays, be performed.

    Dosing for On-demand Treatment and Control of Bleeding Episodes and Perioperative Management 

    Hemorrhage 

    • Minor (uncomplicated hemarthroses, superficial muscle, or soft tissue): 

      • Circulating Factor IX Activity Required [% of normal or (IU/dL)]: 20–30%

      • Dosing interval: every 12–24hrs 

      • Duration of therapy: 1–2 days 

    • Moderate (intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria): 

      • Circulating Factor IX Activity Required [% of normal or (IU/dL)]: 25–50% 

      • Dosing interval: every 12–24hrs 

      • Duration of therapy:  2–7 days, until bleeding stops and healing begins 

    • Major (pharynx, retropharynx, retroperitoneum, CNS, surgery): 

      • Circulating Factor IX Activity Required [% of normal or (IU/dL)]: 50–100% 

      • Dosing interval: every 12–24hrs 

      • Duration of therapy: 7–10 days 

    Routine prophylaxis (≥16yrs)

    • For long term prophylaxis against bleeding, the recommended regimen is 100 IU/kg once weekly. 

    • Adjust the dosing regimen (dose or frequency) based on the patient’s clinical response.

    Benefix Contraindications

    Contraindications

    Hamster protein hypersensitivity.

    Benefix Boxed Warnings

    Not Applicable

    Benefix Warnings/Precautions

    Warnings/Precautions

    Safety and efficacy as continuous infusion: not established. Perform initial (approx. 10–20) administrations under medical supervision. Monitor closely for acute hypersensitivity reactions (esp. during the early phases); discontinue immediately if occurs and treat appropriately. Monitor for development of factor IX inhibitors; increased risk of anaphylaxis. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Hypersensitivity Reactions 

    Hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. 

    Closely monitor patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to the product. Because of the potential for allergic reactions with factor IX concentrates, perform the initial (approximately 10-20) administrations of factor IX under medical supervision where proper medical care for allergic reactions could be provided. Immediately discontinue the administration and initiate appropriate treatment if symptoms occur. 

    BeneFIX contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. 

    Thromboembolic Complications 

    There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion BeneFIX through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates. The safety and efficacy of BeneFIX administration by continuous infusion have not been established.

    Nephrotic Syndrome 

    Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using BeneFIX for immune tolerance induction have not been established. 

    Neutralizing Antibodies (Inhibitors) 

    Neutralizing antibodies (inhibitors) have been reported following administration of BeneFIX. Evaluate patients using BeneFIX for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor IX inhibitor concentration. 

    Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis upon subsequent challenge with factor IX. Evaluate patients experiencing allergic reactions for the presence of an inhibitor and closely monitor patients with inhibitors for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to the product.

    Pregnancy Considerations

    There is no data with BeneFIX use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with BeneFIX. It is not known whether BeneFIX can affect reproductive capacity or cause fetal harm when given to pregnant women.

    Nursing Mother Considerations

    There is no information regarding the presence of BeneFIX in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BeneFIX and any potential adverse effects on the breastfed child from BeneFIX or from the underlying maternal condition.

    Pediatric Considerations

    Safety, efficacy, and pharmacokinetics of BeneFIX have been evaluated in previously treated (PTP) and previously untreated pediatric patients (PUP). On average, lower recovery, shorter half-life and higher clearance (based on kg body weight) have been observed in children <12 years old. Dose adjustment may be needed.

    Geriatric Considerations

    Clinical trials of BeneFIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized.

    Benefix Pharmacokinetics

    See Literature

    Benefix Interactions

    Not Applicable

    Benefix Adverse Reactions

    Adverse Reactions

    Fever, cough, nausea, inj site reaction/pain, headache, dizziness, rash; hypersensitivity reactions, inhibitor development, thromboembolic complications, nephrotic syndrome.

    Adverse Reactions

    The most common adverse reactions (incidence >5%) from clinical trials were fever, cough, nausea, injection site reaction, injection site pain, headache, dizziness and rash.

    The most serious adverse reactions are systemic hypersensitivity reactions, including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to factor IX replacement therapy.

    Benefix Clinical Trials

    Clinical Trials

    Efficacy of BeneFIX has been evaluated in clinical trials in which a total of 153 patients received BeneFIX either for the on-demand treatment and control of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia B.

    On-demand Treatment and Control of Bleeding Episodes 

    Fifty-six previously treated patients (PTPs) and sixty-three previously untreated patients (PUPs) were treated for bleeding episodes on an on-demand treatment and control of bleeds. The PTPs were followed over a median interval of 24 months (mean 23.4 ± 5.3 months) and for a median of 83.5. The PUPs were followed over a median interval of 37 months (mean 38.1 ± 16.4 months) and for a median of 89 exposure days. 

    Fifty-five PTPs and fifty-four PUPs received BeneFIX for the treatment of bleeding episodes. Bleeding episodes that were managed successfully included hemarthrosis and bleeding in soft tissue and muscle. In the PTPs, 88% of total infusions administered for on-demand treatment were rated as an “excellent” or “good” response. 

    A total of 20 PTPs were treated with BeneFIX for secondary prophylaxis (the regular administration of FIX replacement therapy to prevent bleeding in patients who may have already demonstrated clinical evidence of hemophilic arthropathy or joint disease) at some regular interval during the trial with a mean of 2 infusions per week. Thirty-two PUPs were administered BeneFIX for routine (primary and secondary) prophylaxis. Seven PTPs experienced a total of 26 spontaneous bleeding episodes within 48 hours after an infusion. Six spontaneous bleeds within 48 hours after an infusion were reported in 5 PUPs. Prophylaxis therapy was rated as “excellent” or “effective” in 93% of PTPs receiving prophylaxis one to two times per week.

    Perioperative Management

    Management of hemostasis was evaluated in the surgical setting in both PTPs and PUPs. Thirty-six surgical procedures have been performed in 28 PTPs with 23 major surgical procedures performed (including 6 complicated dental extractions). Thirty surgical procedures have been performed in 23 PUPs. Twenty-eight of these procedures were considered minor. Hemostasis was maintained throughout the surgical period; however, one PTP subject required evacuation of a surgical wound-site hematoma, and another PTP subject who received BeneFIX after a tooth extraction required further surgical intervention due to oozing at the extraction site. There was no clinical evidence of thrombotic complications in any of the subjects. See full labeling for results.

    Routine Prophylaxis

    In an open-label trial of 25 patients (age range 12-54 years) comparing on-demand treatment versus prophylaxis when administered at a dose of 100 IU/kg once weekly, the annualized bleed rate (ABR) for the prophylaxis period was significantly lower (P <0.0001) than the ABR for the on-demand period (mean ± standard deviation (SD): 3.6 ± 4.6, median: 2.0, min-max: 0-13.8 vs mean: 32.9 ± 17.4, median: 33.6, min-max: 6.1-69.0, respectively).

    In an open-label crossover trial in patients aged 6-64 years, of 100 IU/kg once weekly (44 patients) and 50 IU/kg twice weekly (43 patients) with 4-month treatment periods, the ABR for the 100 IU/kg once-weekly prophylaxis period was mean 4.4 ± 10.0 episodes per year (median: 0.0, min-max: 0–50.5) and mean 2.8 ± 5.7 (median: 0.0, min-max: 0–24.1) for the 50 IU/kg twice-weekly period.

    Benefix Note

    Not Applicable

    Benefix Patient Counseling

    Patient Counseling

    Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use)  

    Allergic-type hypersensitivity reactions are possible. Inform patients of the early signs of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product and contact their physicians if these symptoms occur.  

    Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor IX replacement therapy, as in some cases this may be a manifestation of an inhibitor.

    Cost Savings Program

    The BeneFIX savings program is available here.

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