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REBINYN®
(Coagulation Factor IX (Recombinant) for Reconstitution
REBINYN is a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution with the provided histidine diluent for intravenous infusion. After reconstitution, the solution appears as a clear and colorless liquid, free from visible particles and contains the following excipients per mL: sodium chloride, 2.34 mg; histidine, 3.10 mg; sucrose, 10 mg; mannitol, 25 mg; polysorbate 80, 0.05 mg. REBINYN is available in single-use vials containing the labeled amount of Factor IX activity, expressed in IU. Each vial contains nominally 500 IU, 1000 IU or 2000 IU. REBINYN potency is assigned using an in vitro, activated partial thromboplastin time (aPTT)-based, one-stage clotting assay calibrated against the World Health Organization (WHO) international standard for Factor IX concentrates. REBINYN contains no preservatives.
REBINYN is a purified recombinant human Factor IX (rFIX) with a 40 kilodalton (kDa) polyethylene-glycol (PEG) conjugated to the protein. The 40 kDa PEG group is selectively attached to specific -N-linked glycans in the rFIX activation peptide, with mono-PEGylated rFIX as the predominant form of REBINYN. The rFIX protein in REBINYN consists of a gamma-carboxylated (Gla) domain, two EGF-like (epidermal growth factor) domains, an activation peptide (which is cleaved off upon activation), and a protease domain. Once activated, the resulting rFIX has structural and functional properties similar to those of endogenous activated Factor IX. The primary amino acid sequence in REBINYN is identical to the Thr148 allelic form of human plasma-derived Factor IX and consists of 415 amino acids. The average molecular weight of REBINYN is approximately 98 kDa and the molecular weight of the protein moiety alone is 56 kDa. The nominal specific activity of REBINYN is 152 IU/mg protein.
REBINYN is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells. No additives of human or animal origin are used in the cell culture, purification, conjugation, or formulation of REBINYN. The rFIX protein is purified by a series of chromatographic steps, including an affinity chromatography step using a monoclonal antibody (produced in CHO cells), to selectively isolate rFIX from the cell culture medium. The production process includes two dedicated viral clearance steps, namely a detergent treatment step for inactivation and a 20 nm filtration step for removal of viruses. The conjugation of the PEG-group is done by an enzymatic reaction during the purification process, followed by final purification of REBINYN.
REBINYN, Coagulation Factor IX (Recombinant), GlycoPEGylated, is a recombinant DNA-derived coagulation Factor IX concentrate indicated for use in adults and children with hemophilia B for:
For intravenous infusion after reconstitution only.
REBINYN dosing for on-demand treatment and control of bleeding episodes is provided in Table 1.
Table 1: Dosing for On-demand Treatment and Control of
Bleeding Episodes
| Type of bleeding | Recommended dose IU/kg body weight | Additional information |
| Minor and moderate For example: Uncomplicated joint bleeds, minor muscular bleeds, mucosal or subcutaneous bleeds | 40 | A single dose should be sufficient for minor and moderate bleeds. Additional doses of 40 IU/kg can be given. |
| Major For example: Intracranial, retroperitoneal, iliopsoas and neck bleeds, muscle bleeds with compartment syndrome and bleeds associated with a significant decrease in the hemoglobin level | 80 | Additional doses of 40 IU/kg can be given. |
REBINYN dosing for perioperative management is provided in Table 2.
Table 2: Dosing for Perioperative Management
| Type of surgical procedure | Recommended dose IU/kg body weight | Additional Information |
| Minor For example: Implanting pumps in subcutaneous tissue, skin biopsies or simple dental procedures | 40 | A single pre-operative dose should be sufficient. Additional doses can be given if needed. |
| Major For example: Body cavity is entered, mesenchymal barrier is crossed, fascial plane is opened, organ is removed, normal anatomy is operatively altered | 80 | Pre-operative dose |
| 40 | As clinically needed for the perioperative management of bleeding, repeated doses of 40 IU/kg | |
| *See Pharmacokinetics, Table 8 | ||
 |
The instructions below serve as a general guideline for reconstitution of REBINYN. For full instructions, refer to the FDA-approved patient information and Instructions for Use.
Reconstitution
1. Bring the REBINYN vial and the pre-filled diluent syringe to room temperature.
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2. Remove the plastic cap from the REBINYN vial.
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3. Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to dry prior to use.
4. Remove the protective paper from the vial adapter. Do not remove the vial adapter from the protective cap.
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5. Place the vial on a flat and solid surface. While holding the protective cap, place the vial adapter over the REBINYN vial and press down firmly on the protective cap until the vial adapter spike penetrates the rubber stopper.
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6. Remove the protective cap from the vial adapter.
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7. Grasp the plunger rod as shown in the diagram. Attach the plunger rod to the syringe by holding the plunger rod by the wide top end. Turn the plunger rod clockwise into the rubber plunger inside the pre-filled diluent syringe until resistance is felt.
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8. Break off the syringe cap from the pre-filled diluent syringe by snapping the perforation of the cap.
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9. Connect the pre-filled diluent syringe to the vial adapter by turning it clockwise until it is secured.
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10. Push the plunger rod to slowly inject all the diluent into the vial.
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11. Without removing the syringe, gently swirl the REBINYN vial until all of the powder is dissolved.
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12. Administer the REBINYN solution immediately [see Administration]. If not used immediately after reconstitution, store the solution in the vial with the vial adapter and the syringe attached, at room temperature ≤ 86°F (30°C). Do not store for longer than 4 hours.
For intravenous infusion only.
1. Invert the REBINYN vial and slowly draw the solution into the syringe.
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2. Detach the syringe from the vial adapter by turning the syringe counterclockwise.
3. Attach the syringe to the luer end of an infusion needle set.
4. Infuse the reconstituted REBINYN intravenously slowly over 1 to 4 minutes.
5. After infusion, safely dispose of the syringe with the infusion set, the vial with the vial adapter, any unused REBINYN, and other waste materials.
Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector.
Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as ClaveREBINYN through incompatible needleless connectors, withdraw the reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe. ® /MicroClave®, InVision-Plus®, InVision-Plus CS®, Invision-Plus Junior®, Bionector®), and their use can damage the connector and affect administration. To administer
If you encounter any problems with attaching the pre-filled histidine-diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (844) 303-4448.
REBINYN is available as a white to off-white lyophilized powder in single-use vials containing nominally 500, 1000, or 2000 IU per vial. Each carton and vial label for REBINYN states the actual Factor IX potency in IU.
After reconstitution with 4 mL of histidine diluent, the reconstituted solution contains approximately 125, 250 or 500 IU per mL of REBINYN respectively.
Table 10: REBINYN Presentations
| Presentation (Nominal Product Strength; IU) | Cap Color Indicator | Carton NDC Number | Components |
| 500 | Red | NDC 0169 7905 01 |
|
| 1000 | Green | NDC 0169 7901 01 |
|
| 2000 | Yellow | NDC 0169 7902 01 |
|
Novo Nordisk Inc. 800 Scudders Mill Road, Plainsboro, NJ 08536, USA. 1-844-REB-INYN. Manufactured by: Novo Nordisk A/S , Novo Allé, DK-2880 Bagsvaerd. Revised: May 2017
Common adverse reactions (incidence ≥ 1%) reported in clinical trials for REBINYN were itching and injection site reactions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
During the clinical development program, 115 previously treated male patients received at least one dose of REBINYN [see Clinical Studies]. A previously treated patient was defined as a subject with a history of at least 150 exposure days to other Factor IX products (adolescent/adult subjects) or 50 exposure days to other Factor IX products (pediatric subjects), and no history of inhibitors. There were a total of 8801 exposure days, equivalent to 170 patient-years. A total of 40 patients (35%) were treated for more than 2 years.
Adverse reactions are shown in Table 3.
Table 3: Summary of Adverse Reactions in Previously
Treated Patients
| System Organ Class | Adverse Reaction | Number of subjects (%) |
| General disorders and administration site conditions | Injection site reactions | 4 (4) |
| Immune system disorders | Hypersensitivity | 1 (1) |
| Skin and subcutaneous tissue disorders | Itching | 3 (3) |
Subjects were monitored for inhibitory antibodies to factor IX prior to dosing, on a monthly basis for the first three months, every two months up to one year, every three months for an additional year, and then every 6 months until end of trial.
No inhibitors were reported in the clinical trials in previously treated patients.
In an ongoing trial in previously untreated patients, anaphylaxis has occurred with development of a factor IX inhibitor following treatment with REBINYN. Inhibitor development and anaphylactic reactions are more likely to occur during the early phases of factor IX replacement therapy [see WARNINGS AND PRECAUTIONS].
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus [see Animal Toxicology and/or Pharmacology]. The potential clinical implications of these animal findings are unknown. The physician should consider whether the patient may be vulnerable, such as infants and children who have developing brains and patients who are cognitively impaired. Physician's discretion is advised with regard to neurocognitive assessments, taking into consideration factors such as duration of use, cumulative dose, age of the patient and related comorbidities that are likely to increase the risks to patients. Adverse neurologic reactions should be reported.
No information provided.
Included as part of the PRECAUTIONS section.
Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with REBINYN. The product may contain traces of hamster proteins which in some patients may cause allergic reactions. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, difficulty breathing, wheezing, urticaria, and itching. Observe patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of exposure to the product. Discontinue use of REBINYN if allergic- or anaphylactic - type reactions occur, and initiate appropriate treatment.
The formation of inhibitors (neutralizing antibodies) to Factor IX may occur during Factor replacement therapy in the treatment of hemophilia B. Monitor all patients using clinical observations and laboratory tests for the development of inhibitors [see Monitoring Laboratory Tests].
An association between the development of Factor IX inhibitors and allergic reactions has been reported. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Patients with Factor IX inhibitors may be at an increased risk of severe allergic reactions with subsequent exposure to Factor IX.
The use of Factor IX-containing products has been associated with thrombotic complications. Due to the potential risk of thrombotic complications, monitor patients for early signs of thrombotic and consumptive coagulopathy when administering this product to patients with liver disease, post-operatively, to newborn infants, or to patients at risk of thrombosis or disseminated intravascular coagulation (DIC). In each of these situations, the benefit of treatment with REBINYN should be weighed against the risk of these complications.
Nephrotic syndrome has been reported following immune tolerance induction therapy with Factor IX products in hemophilia B patients with Factor IX inhibitors, often with a history of allergic reactions to Factor IX. The safety and efficacy of using REBINYN for immune tolerance induction have not been established.
If monitoring of Factor IX activity is performed, use a chromogenic assay or selected one-stage clotting assay validated for use with REBINYN [see DOSAGE AND ADMINISTRATION].
The one-stage clotting assay results can be significantly affected by the type of activated partial thromboplastin time (aPTT) reagent used, which can result in over- or under-estimation of Factor IX activity. Avoid the use of silica-based reagents, as some may overestimate the activity of REBINYN. If a validated one-stage clotting or chromogenic assay is not available locally, then use of a reference laboratory is recommended.
If bleeding is not controlled with the recommended dose of REBINYN, or if the expected Factor IX activity levels in plasma are not attained, then perform a Bethesda assay to determine if Factor IX inhibitors are present.
Studies in animals to evaluate the carcinogenic or genotoxic potential of REBINYN, or studies to determine the effects of REBINYN on fertility, have not been performed.
There are no data with REBINYN use in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with REBINYN. It is unknown whether REBINYN can cause fetal harm when administered to a pregnant woman or can affect fertility. REBINYN should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
There is no information regarding the presence of REBINYN 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 REBINYN and any potential adverse effects on the breastfed infant from REBINYN or from the underlying maternal condition.
Safety and efficacy of REBINYN were evaluated in 43 previously treated pediatric patients [see Clinical Studies]. Twelve of these subjects (28%) were 1 to 6 years of age; 13 subjects (30%) were 7 to 12 years of age; and 18 subjects (42%) were 13 to 17 years of age. Pharmacokinetic parameters were evaluated for 28 of these subjects who were treated with REBINYN 40 IU/kg [see CLINICAL PHARMACOLOGY].
No difference in the safety profile of REBINYN was observed between previously treated pediatric subjects and adult subjects. Body weight-adjusted clearance was higher for pediatric subjects than for adult subjects. Fixed doses were studied in the clinical trials and no dose adjustment was required for pediatric subjects.
Twenty-eight of the forty-three previously treated pediatric subjects (1 to 17 years old) were treated with REBINYN for 137 bleeding episodes. Results are provided in Table 4.
Table 4: Efficacy in treatment of bleeding episodes in
pediatric subjects by age
| New bleeding episodes | ≤ 6 years n=11 |
7-12 years n=31 |
13-17 years n=95* |
| Efficacy assessment** | |||
| Excellent or good | 10 (91%) | 29 (94%) | 91 (97%) |
| Moderate or poor | 1 (9%) | 2 (6%) | 3 (3%) |
| Number of injections to treat a bleeding episode | |||
| 1 injection | 9 (82%) | 27 (87%) | 78 (82%) |
| 2 injections | 1 (9%) | 4 (13%) | 12 (13%) |
| > 2 injections | 1 (9%) | - | 5 (5%) |
| *Efficacy assessment was missing for one bleeding
episode. **Efficacy assessment [Response] was assessed according to a four-point scale using: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection; Good: Noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection; Moderate: Probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours; Poor: No improvement, or worsening of symptoms within 8 hours after the second of two injections. |
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Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus [see Animal Toxicology and/or Pharmacology]. The potential clinical implications of these animal findings are unknown. No adverse neurologic effects of PEG have been reported in infants, children, and adolescents exposed to REBINYN during clinical trials. The potential consequences of long term exposure have not been fully evaluated [see Section 6.3].
Clinical studies of REBINYN did not include sufficient numbers of subjects age 65 and over to determine whether or not they respond differently than younger subjects.
Animals administered repeat doses of REBINYN showed accumulation of PEG in the choroid plexus [see Animal Toxicology and/or Pharmacology]. The potential clinical implications of these animal findings are unknown. No adverse neurologic effects of PEG have been reported in adults exposed to REBINYN during clinical trials, however use in older adults with baseline cognitive dysfunction has not been fully evaluated [see ADVERSE REACTIONS].
No information provided.
REBINYN is contraindicated in patients who have known hypersensitivity to REBINYN or its components (including hamster proteins) [see WARNINGS AND PRECAUTIONS and DESCRIPTION]
Patients with hemophilia B are deficient in coagulation Factor IX, which is required for effective hemostasis. Treatment with REBINYN temporarily replaces the missing coagulation Factor IX.
The Factor IX in REBINYN is conjugated to a 40-kDa polyethylene glycol molecule, which slows down its removal from the blood circulation.
The administration of REBINYN increases plasma levels of Factor IX and can temporarily correct the coagulation defect in hemophilia B patients, as reflected by a decrease in aPTT.
Pharmacokinetic (PK) parameters of REBINYN were evaluated in previously treated subjects, including a subset of subjects in the adult/adolescent trial and all subjects in the main phase of the pediatric trial [see Clinical Studies]. PK samples were collected prior to dosing and at multiple time points up to 168 hours after dosing. The analysis of plasma samples was conducted using the one-stage clotting assay.
Steady state pharmacokinetic parameters for adolescents and adults following once-weekly prophylactic treatment of REBINYN 40 IU/kg are shown in Table 5.
Table 5: Steady-state pharmacokinetic parameters of
REBINYN (40 IU/kg) in adolescents and adults (geometric mean (CV))
| PK Parameter | 13-17 years N=3 |
≥ 18 years N=6 |
| Half-life (hours) | 103.1 (14.2) | 114.9 (9.7) |
| Incremental Recovery30min (IU/dL per IU/kg) | 1.82 (28.2) | 1.92 (19.6) |
| AUC0-168 (IU*hours/dL) | 9072 (22) | 9280 (15) |
| Clearance (mL/hour/kg) | 0.4 (16.7) | 0.4 (11.4) |
| Mean residence time (hours) | 144.4 (15.3) | 158.1 (9.6) |
| Vss (mL/kg) | 60.5 (31.1) | 65.8 (11.9) |
| Factor IX activity 168 h after dosing (%) | 28.9 (18.6) | 32.4 (17.1) |
| Abbreviations: AUC = area under plasma concentration-time curve; Vss= volume of distribution at steady state; CV=coefficient of variation. | ||
The mean steady state pre-dose trough levels and post-dose peak levels across the clinical trials for all previously treated subjects are shown in Table 6.
Table 6: Factor IX peak and trough levels of REBINYN
(40 IU/kg) by age at steady state
| ≤ 6 years N=12 |
7-12 years N=13 |
13-17 years N=9 |
≥ 18years N=20 |
|
| Mean Factor IX peak level (%) (95% CI) | 65.5 (60.6; 70.7) | 71.4 (66.3; 77.0) | 82.8 (70.7; 96.9) | 97.9 (87.7; 109.3) |
| Mean Factor IX trough level* (%) (95% CI) | 15.4 (13.2; 17.9) | 18.7 (16.2; 21.6) | 23.7 (19.9; 28.2) | 29.3 (26.0; 33.0) |
| Min, Max** | 9.2; 24.5 | 8.3; 28.3 | 18.6; 34.6 | 21.3; 42.2 |
| * Factor IX activity from samples collected at clinical
site visits just prior to administration of next weekly dose **Individual geometric mean trough values |
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Single-dose pharmacokinetic parameters of REBINYN in children, adolescents and adults are listed in Table 7.
Table 7: Single Dose Pharmacokinetic Parameters of
REBINYN (40 IU/kg) in children, adolescents and adults (geometric mean (CV))
| PK Parameter | ≤ 6 years N=12 |
7-12 years N=13 |
13-17 years N=3 |
≥ 18 years N=6 |
| Half-life (hours) | 69.6 (15.8) | 76.3 (25.5) | 89.4 (24.1) | 83.0 (22.5) |
| Incremental Recovery30min (IU/dL per IU/kg) | 1.51 (7.31) | 1.59 (16.2) | 1.96 (14.7) | 2.34 (11.3) |
| AUCinf (IU*h/dL) | 4617 (14) | 5618 (19) | 7986 (35) | 9063 (16) |
| Clearance (mL/hour/kg) | 0.8 (13.0) | 0.6 (21.9) | 0.5 (30.4) | 0.4 (14.7) |
| Mean residence time (hours) | 95.4 (15.3) | 105.1 (24.2) | 124.2 (24.4) | 115.5 (21.8) |
| Vss (mL/kg) | 72.3 (14.8) | 68.3 (21.7) | 58.6 (7.8) | 47.0 (15.9) |
| Factor IX activity 168 h after dosing (%) | 8.4 (16.3) | 10.9 (18.9) | 14.6 (59.6) | 16.8 (30.6) |
| Abbreviations: AUC = area under plasma concentration-time curve; Vss = volume of distribution at steady state; CV = coefficient of variation. | ||||
Pharmacokinetics were investigated in 9 subjects in the adult/adolescent trial, of which 5 were normal weight (body mass index (BMI) 18.5 to 24.9 kg/m²) and 4 were overweight (BMI 25 to < 29.9 kg/m²). The pharmacokinetic parameters were not affected by BMI.
The Factor IX activity following 80 IU/kg infusion in major surgery is shown in Table 8.
Table 8: Factor IX activity following 80 IU/kg bolus
for major surgery
| 30 minutes N=13 |
8 hours1 N=12 |
24 hours1 N=12 |
48 hours2 N=7 |
|
| Factor IX activity (%) Median (Range) | 143 (123-224) | 138 (101-175) | 112 (62-146) | 73(40-110) |
| 1 Excludes one subject with no Factor IX
activity measurement obtained. 2 Excludes two subjects with no Factor IX activity measurement obtained and additionally 4 subjects re-dosed prior to second day after surgery for whom the Factor IX activity at 24 hours were 84%, 112%, 131% and 134%. The 48 hours measurement reflects a measurement on the 2nd day after surgery (range 47-57 hours). |
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REBINYN was intraveneously administered in repeat-dose toxicity studies in immune-deficient rats (40-1200 IU/kg/week for 26 weeks) and immune-competent monkeys (350-3750 IU/kg/week for four weeks). Accumulation of the 40-kDa polyethylene-glycol (PEG) was detected by immunohistochemical staining in epithelial cells of the choroid plexus in the brain of the majority of animals. This finding was not associated with morphological changes or abnormal clinical signs.
Four multicenter, non-controlled trials were conducted to evaluate the safety and efficacy of REBINYN in routine treatment, on-demand treatment and control of bleeding episodes, and perioperative management in previously treated male patients with hemophilia B (Factor IX activity ≤ 2%). Previously treated patients were defined as patients receiving treatment with other Factor IX products for ≥ 150 exposure days for adolescents and adults, and ≥ 50 exposure days for pediatric patients. The key exclusion criteria across trials included known or suspected hypersensitivity to trial or related products, known history of Factor IX inhibitors or current inhibitor ≥ 0.6 BU, HIV-positive with a viral load ≥ 400,000 copies/mL or CD4+ lymphocyte count ≤ 200/μL, additional congenital or acquired coagulation disorders, previous arterial thrombotic events, and recipients of immune modulating or chemotherapeutic medication.
The efficacy evaluation included 105 subjects: 62 adults (18 to 65 years old), 18 adolescents (13 to 17 years old), and 25 children (1 to 12 years old).
A total of 597 bleeding episodes were reported in 79 out of 105 subjects in the clinical program in previously treated patients. Bleeding episodes were treated with REBINYN at 40 IU/kg for minor or moderate bleeds or 80 IU/kg for major bleeds, with additional doses of 40 IU/kg as needed. The median dose to treat a bleeding episode was 42.3 IU/kg.
An overall assessment of efficacy was performed by the subject (for home treatment) or the study site investigator (for treatment under medical supervision) using a 4-point scale of excellent, good, moderate, or poor. The overall success rate (defined as excellent or good) for treatment of bleeding episodes was 93.2% as shown in Table 9.
The success rate and dose needed for treatment of bleeding episodes were independent of the location of the bleeding. The success rate for treatment of bleeding episodes was also independent of whether the bleed was traumatic or spontaneous.
Table 9: Efficacy in treatment of bleeding episodes in
previously treated patients
| New Bleeding Episodes | n = 597 |
| Efficacy assessment* | |
| Excellent or Good | 551 (93%) |
| Moderate or Poor | 40 (7%) |
| Number of injections to treat a bleeding episode | |
| 1 injection | 521 (87%) |
| 2 injections | 60 (10%) |
| > 2 injections | 16 (3%) |
| *Efficacy assessment was based on 591 evaluated bleeding
episodes (data missing for six bleeding episodes). Efficacy was assessed
according to a four-point scale using: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection; Good: Noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection; Moderate: Probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours; Poor: No improvement, or worsening of symptoms within 8 hours after the second of two injections. |
|
In the on-demand arm there were 143 bleeding episodes in 14 of 15 subjects. The overall success rate was 95.1% (135 of 142 evaluated bleeds). A total of 120 bleeds (83.9%) of the 143 bleeding episodes were treated with one injection, and 20 (14.0%) were treated with two injections.
In the surgery trial, the efficacy analysis of REBINYN in perioperative management included 13 surgical procedures of which 9 were major and performed in 13 previously treated adolescent and adult patients. The procedures included 9 orthopedic, 1 gastrointestinal and 3 in the oral cavity.
The hemostatic effect during surgery was evaluated on a four-point scale of excellent, good, moderate, or poor. The intraoperative hemostatic effect was rated as excellent or good for the 13 surgeries, for a success rate of 100%. A pre-operative dose of 80 IU/kg REBINYN was effective, and no subjects required additional doses on the day of surgery. The median number of additional 40 IU/kg doses in the post-operative period was 2.0 for Days 1 to 6, 1.5 for Days 7-13, and 3.0 for Days 1 to 13. The mean total consumption of REBINYN in the pre- and post-operative period was 241 IU/kg (range: 81 to 460 IU/kg). There was no unexpected postoperative bleeding.
Three additional major surgeries and 18 minor surgery procedures were evaluated in the extension trial for REBINYN in previously treated patients. The hemostatic effect during major and minor surgery was confirmed with a success rate of 100%.
REBINYN (reh-be-NINE)
Coagulation Factor IX (Recombinant), GlycoPEGylated
Read the Patient Product Information and the Instructions For Use that come with REBINYN before you start taking this medicine and each time you get a refill. There may be new information.
This Patient Product Information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about REBINYN after reading this information, ask your healthcare provider.
What is the most important information I need to know about REBINYN?
Do not attempt to do an infusion yourself unless you have been taught how by your healthcare provider or hemophilia treatment center.
You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing REBINYN so that your treatment will work best for you.
What is REBINYN?
REBINYN is an injectable medicine used to replace clotting Factor IX that is missing in patients with hemophilia B. Hemophilia B is an inherited bleeding disorder in all age groups that prevents blood from clotting normally.
REBINYN is used to treat and control bleeding in people with hemophilia B.
Your healthcare provider may give you REBINYN when you have surgery.
Who should not use REBINYN?
You should not use REBINYN if you
If you are not sure, talk to your healthcare provider before using this medicine.
Tell your healthcare provider if you are pregnant or nursing because REBINYN might not be right for you.
What should I tell my healthcare provider before I use REBINYN?
You should tell your healthcare provider if you
How should I use REBINYN?
Treatment with REBINYN should be started by a healthcare provider who is experienced in the care of patients with hemophilia B.
REBINYN is given as an infusion into the vein.
You may infuse REBINYN at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your hemophilia treatment center or healthcare provider. Many people with hemophilia B learn to infuse the medicine by themselves or with the help of a family member.
Your healthcare provider will tell you how much REBINYN to use based on your weight, the severity of your hemophilia B, and where you are bleeding. Your dose will be calculated in international units, IU.
Call your healthcare provider right away if your bleeding does not stop after taking REBINYN.
If your bleeding is not adequately controlled, it could be due to the development of Factor IX inhibitors. This should be checked by your healthcare provider. You might need a higher dose of REBINYN or even a different product to control bleeding. Do not increase the total dose of REBINYN to control your bleeding without consulting your healthcare provider.
Use in children
REBINYN can be used in children. Your healthcare provider will decide the dose of REBINYN you will receive.
If you forget to use REBINYN
If you forget a dose, infuse the missed dose when you discover the mistake. Do not infuse a double dose to make up for a forgotten dose. Proceed with the next infusions as scheduled and continue as advised by your healthcare provider.
If you stop using REBINYN
Do not stop using REBINYN without consulting your healthcare provider.
If you have any further questions on the use of this product, ask your healthcare provider.
What if I take too much REBINYN?
Always take REBINYN exactly as your healthcare provider has told you. You should check with your healthcare provider if you are not sure. If you infuse more REBINYN than recommended, tell your healthcare provider as soon as possible.
What are the possible side effects of REBINYN?
Common Side Effects Include:
Other Possible Side Effects:
You could have an allergic reaction to coagulation Factor IX products. Call your healthcare provider right away or get emergency treatment right away if you get any of the following signs of an allergic reaction: hives, chest tightness, wheezing, difficulty breathing, and/or swelling of the face.
Your body can also make antibodies called “inhibitors” against REBINYN, which may stop REBINYN from working properly. Your healthcare provider may need to test your blood for inhibitors from time to time.
You may be at an increased risk of forming blood clots in your body, especially if you have risk factors for developing blood clots. Call your healthcare provider if you have chest pain, difficulty breathing, leg tenderness or swelling.
These are not all of the possible side effects from REBINYN. Ask your healthcare provider for more information. You are encouraged to report side effects to FDA at 1-800-FDA-1088.
Tell your healthcare provider about any side effect that bothers you or that does not go away.
What are the REBINYN dosage strengths?
REBINYN comes in three different dosage strengths. The actual number of international units (IU) of Factor IX in the vial will be imprinted on the label and on the box. The three different strengths are as follows:
| Cap Color Indicator | Nominal Strength |
| Red | 500 IU per vial |
| Green | 1000 IU per vial |
| Yellow | 2000 IU per vial |
Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider.
How should I store REBINYN?
Prior to Reconstitution (mixing the dry powder in the vial with the diluent):
Store in original package in order to protect from light. Do not freeze REBINYN.
REBINYN vials can be stored in the refrigerator (36-46°F [2°C - 8°C]) for up to 24 months until the expiration date, or at room temperature (up to 86°F [30°C]) for a single period not more than 6 months.
If you choose to store REBINYN at room temperature:
Do not use this medicine after the expiration date which is on the outer carton and the vial. The expiration date refers to the last day of that month.
After Reconstitution:
The reconstituted (the final product once the powder is mixed with the diluent) REBINYN should appear clear without visible particles.
The reconstituted REBINYN should be used immediately.
If you cannot use the reconstituted REBINYN immediately, it should be used within 4 hours when stored at or below 86°F (30°C). Store the reconstituted product in the vial.
Keep this medicine out of the sight and out of reach of children.
What else should I know about REBINYN and hemophilia B?
Medicines are sometimes prescribed for purposes other than those listed here. Do not use REBINYN for a condition for which it is not prescribed. Do not share REBINYN with other people, even if they have the same symptoms that you have.
For more information about REBINYN, please call Novo Nordisk at 1-844-REB-INYN.
Instructions on how to use REBINYN® MixPro®
READ THESE INSTRUCTIONS CAREFULLY BEFORE USING REBINYN.
REBINYN is supplied as a powder. Before infusion (administration) it must be mixed (reconstituted) with the liquid diluent supplied in the syringe. The liquid diluent is a histidine solution. The mixed REBINYN must be infused into your vein (intravenous infusion). The equipment in this package is designed to mix and infuse REBINYN.
You will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads, and bandages.
Don't use the equipment without proper training from your doctor or nurse.
Always wash your hands and ensure that the area around you is clean.
When you prepare and infuse medication directly into the veins, it is important to use a clean and germ free (aseptic) technique. Improper technique can introduce germs that can infect the blood.
Don't open the equipment until you are ready to use it.
Don't use the equipment if it has been dropped, or if it is damaged. Use a new package instead.
Don't use the equipment if it is expired. Use a new package instead. The expiration date is printed on the outer carton and on the vial, the vial adapter and the pre-filled syringe.
Don't use the equipment if you suspect it is contaminated. Use a new package instead.
Don't dispose of any of the items until after you have infused the mixed solution.
The equipment is for single use only.
Content
The package contains:
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1. Prepare the vial and the syringe
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2. Attach the vial adapter
Don't take the vial adapter out of the protective cap with your fingers. If you touch the spike on the vial adapter germs from your fingers can be transferred.
If the protective paper is not fully sealed or if it is broken, don't use the vial adapter.
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Once attached, don't remove the vial adapter from the vial.
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Don't lift the vial adapter from the vial when removing the protective cap.
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3. Attach the plunger rod and the syringe
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Don't touch the syringe tip under the syringe cap. If you touch the syringe tip germs from your fingers can be transferred.
If the syringe cap is loose or missing, don't use the pre-filled syringe.
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4. Mix the powder with the diluent
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REBINYN is recommended to be used immediately after it is mixed.
If you cannot use the mixed REBINYN solution immediately, it should be used within 4 hours when stored at room temperature at or below 86°F (30°C). Store the reconstituted product in the vial.
Do not freeze mixed REBINYN solution or store it in syringes.
Keep mixed REBINYN solution out of direct light.
If your dose requires more than one vial, repeat step A to J with additional vials, vial adapters and pre-filled syringes until you have reached your required dose.
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Don't touch the syringe tip. If you touch the syringe tip germs from your fingers can be transferred.
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Caution: The pre-filled diluent syringe is made of glass with an internal tip diameter of 0.037 inches, and is compatible with a standard Luer-lock connector.
Some needleless connectors for intravenous catheters are incompatible with the glass diluent syringes (for example, certain connectors with an internal spike, such as Clave®/MicroClave®, InVision-Plus®, InVision-Plus CS®, Invision-PlusJunior®, Bionector®).
The use of these needleless connectors can damage the connector and affect administration.
To administer REBINYN through incompatible needleless connectors, withdraw reconstituted product into a standard 10 mL sterile Luer-lock plastic syringe.
If you have encountered any problems with attaching the pre-filled histidine diluent syringe to any Luer-lock compatible device, please contact Novo Nordisk at (844) 303-4448.
5. Infuse the mixed solution
REBINYN is now ready to infuse into your vein.
Infusing the solution via a central venous access device (CVAD) such as a central venous catheter or subcutaneous port:
The peel-off label found on the REBINYN vial can be used to record the lot number.
Disposal
After infusion, safely dispose of all unused REBINYN solution, the syringe with the infusion set, the vial with the vial adapter, and other waste materials in an appropriate container for throwing away medical waste.
Don't throw it out with the ordinary household trash.
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Don't disassemble the vial and vial adapter before disposal.
Don't reuse the equipment.
Important information
Contact your healthcare provider or local hemophilia treatment center if you experience any problems.
