Rebinyn (factor IX (human) recombinant, pegylated)

Dose (potency) of coagulation factor IX (recombinant), glycoPEGylated is expressed in terms of international units (IU) of factor IX activity. Potency is determined by a one-stage clotting assay based on the activated partial thromboplastin time (aPTT) calibrated againsta standard established by the World Health Organization (WHO). Results of such potency tests can vary depending on the type of aPTT reagent and reference standard used. Each vial states the actual factor IX potency in IU on the label.

The dosage and duration of therapy of coagulation factor IX (recombinant), glycoPEGylated required to establish hemostasis in patients with hemophilia B will vary with each patient based on the location and extent of bleeding and clinical condition. Therefore, dosage should be carefully individualized and factor IX levels monitored frequently during therapy.

No dosing information is available for this tab.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Factor Ix; Anti-Inhibitor Coagulant Conc/Antifibrinolytics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the coagulation pathways.(1-3)

CLINICAL EFFECTS: Concurrent use may result in thrombosis.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of aminocaproic acid states that aminocaproic acid should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates.(1) The US manufacturer of tranexamic acid states that concomitant use with Factor IX Complex concentrates or with Anti-inhibitor Coagulant concentrates should be avoided.(2,3) The Japanese manufacturer of tranexamic acid recommends caution when coadministered with drugs such as coagulation factor agents as coagulation may be further activated at sites with enhanced local fibrinolysis.(4) Concurrent use may be warranted in select patients with hemophilia A or hemophilia B or in select major trauma scenarios. Monitor patients closely for signs of thrombosis, disseminated intravascular coagulation, and hypercoagulability if concurrent use is deemed necessary.(5-13)

DISCUSSION: There is very limited data on the risk of thrombosis with combination therapy. In a study, eight hemophilia B patients undergoing dental extraction procedures received combination therapy with aminocaproic acid or tranexamic acid and monoclonal antibody purified factor IX for bleeding prophylaxis. All patients achieved hemostasis without clinical evidence of thrombosis as well as no changes were seen in hemoglobin, hematocrit, or in markers of hemostatic system activation.(5) In a study, seven hemophilia A patients with inhibitors and one with acquired hemophilia patient received activated prothrombin complex concentrate (APCC) and tranexamic acid for management of bleeding episodes and prevention of hemorrhage during surgery. Hemostatic outcomes were rated excellent or good in 10 out of 11 (91%) treatment episodes. No episodes of thrombosis or disseminated intravascular coagulation occurred during treatment.(6) A study in six hemophilia A patients and five healthy volunteers evaluated the use of tranexamic acid as an adjunct to APCC to control bleeding. Patients who received tranexamic acid had a significant increase in maximum clot firmness compared to healthy controls. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed.(7) In a retrospective cohort of 76 patients who received PCC for bleeding not caused by anticoagulation, some patients received additional hemostatic agents (protamine (59%), desmopressin (43%), and tranexamic acid (42%). Eight patients (11%) suffered thromboembolic complications but this was not stratified by the hemostatic agent.(8) In a prospective case crossover study, five healthy volunteers and six hemophilia patients with inhibitors received tranexamic acid with single-dose activated PCC or with recombinant activated factor VII. There were no thromboembolic events during the study.(9) In a double-blind, randomized, placebo-controlled superiority trial to investigate the efficacy and safety of 4-factor prothrombin complex concentrate (4F-PCC) administration in trauma patients at risk of massive transfusion, a significantly higher risk of thromboembolic events occurred in the 4F-PCC group compared to the placebo group (35% vs 24%; relative risk 1.48 [95% CI, 1.04-2.10]). This was observed despite more frequent use of tranexamic acid in the placebo group (86% vs 76%).(10) Case reports reviewed the use of recombinant factor VIIa and FEIBA in 4 patients with severe hemophilia with inhibitors who underwent major surgery. The patients were also treated with tranexamic acid. Non-surgical bleeding was encountered in 4 of 8 surgical procedures. The overall outcome was good for all procedures.(11) In a retrospective cohort of 112 ambulatory tooth extractions in 23 hemophilia patients using a coagulation factor replacement therapy in combination with tranexamic acid, only one episode of mild postoperative bleeding occurred after seven days in a patient who did not have good treatment compliance.(12) In a prospective study evaluating the use of initial hemoglobin levels as a guideline for the initial treatment of clotting disorders in multiple trauma patients, 25 patients received a combination of hemostatic agents (fibrinogen (100%), PCC (96%), desmopressin (56%), tranexamic acid (52%), and factor VIIa (44%). Of the 25 patients treated, 16 (64%) survived. Two patients (8%) suffered thromboembolic complications but this was not stratified by the hemostatic agent. One patient survived after developing a grade II pulmonary embolism caused by deep leg vein trombosis and one patient died from multi-organ failure after developing multiple small vessel thrombosis.(13)

There are no moderate interactions for this drug.

*Patients who have known sensitivity to the drug or its components (including hamster proteins).

There are no contraindication contraindications for this drug.

• Disseminated intravascular coagulation
• Thromboembolic disorder

There are no moderate contraindications for this drug.

Adverse effects observed in >=1% of previously treated patients receiving coagulationfactor IX (recombinant), glycoPEGylated in clinical trials include itching and injection site reactions.

Adverse effects observed in >=1% of previously untreated patients receiving coagulationfactor IX (recombinant), glycoPEGylated in clinical trials include itching, injection site reactions, rash, factor IX inhibition,hypersensitivity, and anaphylactic reaction.

More Frequent

• Acute myocardial infarction
• Disseminated intravascular coagulation
• Pulmonary thromboembolism
• Thromboembolic disorder
• Thrombotic disorder

Less Frequent

• Anaphylaxis
• Urinary tract obstructive uropathy

Rare or Very Rare

• Hypersensitivity drug reaction
• Hypotension
• Renal colic

Less Frequent

• Chills
• Injection site sequelae
• Nausea
• Oral paresthesia

Rare or Very Rare

• Anorexia
• Dizziness
• Dysgeusia
• Fatigue
• Fever
• Halitosis
• Headache disorder
• Hematuria
• Lethargy
• Palpitations
• Paresthesia
• Urticaria

No enhanced messaging available.

Safety and efficacy of coagulationfactor IX (recombinant), glycoPEGylated were evaluated in 4 clinical trials that included 43 previously treated pediatric patients and in one clinical trial that included 50 previously untreated pediatric patients. Body weight-adjusted clearance was observed to be higher for pediatric patients than for adults. However, in clinical trials, no dose adjustment was needed in pediatricpatients who received a fixed dose of 40 IU/kg every week for routine prophylaxis.

A juvenile animal neurotoxicity study was conducted to evaluate the potential neurotoxicity of coagulationfactor IX (recombinant), glycoPEGylated whenadministered IV at a dosage of 120-1200 IU/kg/twice weekly in immature male rats from 3 to 13 weeks of age, followed by a 13-week treatment-free period. Accumulation of PEG was observed in the choroid plexus, pituitary, circumventricular organs, and the cranial motor neurons, increased with dose and dose duration (10 weeks), and remained detectable after the 13-week treatment-free period. This accumulation of PEG was not associated with neurobehavioral changes, fertility, or functional effects in these animals.

There are no data with coagulation factor IX (recombinant), glycoPEGylated use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with the drug. It is not known whether coagulationfactor IX (recombinant), glycoPEGylated can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

There is no information regarding the presence of coagulationfactor IX (recombinant), glycoPEGylated in human milk, the effect onthe breastfed infant, or the effects on milk production.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical studies of coagulationfactor IX (recombinant), glycoPEGylated did not include sufficient numbers of patients 65 years of age and over to determine whether or not they respond differently than younger subjects. No adverse neurologic effects of PEG have been reported in adults exposed to coagulationfactor IX (recombinant), glycoPEGylated during clinical trials, however, use of the drug in older adults with baseline cognitive dysfunction has not been fully evaluated.