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ALPROLIX™
[Coagulation Factor IX (Recombinant), Fc Fusion Protein], Lyophilized Powder for Solution For Intravenous Injection
Coagulation Factor IX (Recombinant), Fc Fusion Protein [rFIXFc], the active ingredient in ALPROLIX™, is a fully recombinant coagulation Factor IX protein consisting of the human coagulation Factor IX sequence covalently linked to the Fc domain of human immunoglobulin G1 (IgG1). The Factor IX portion of rFIXFc has a primary amino acid sequence that is identical to the Thr148 allelic form of plasma derived Factor IX and has structural and functional properties similar to endogenous Factor IX. The Fc domain of rFIXFc contains the hinge, CH2, and CH3 regions of IgG1. rFIXFc contains 867 amino acids with a molecular weight of approximately 98 kilodaltons.
ALPROLIX™ is not derived from human blood and contains no preservatives. The recombinant Factor IX Fc fusion protein is expressed in a human embryonic kidney (HEK) cell line, which produces rFIXFc into a defined cell culture medium that does not contain proteins derived from animal or human sources. The purification process for rFIXFc does not include use of a monoclonal antibody reagent. To enhance viral safety, the purification process incorporates a nanofiltration step and a column chromatography purification step that have been validated for viral clearance. The content of activated Factor IX Fc fusion protein (FIXaFc) is limited to ≤ 0.035 mole percent FIXaFc/FIXFc.
ALPROLIX™ is a sterile, non-pyrogenic, preservative-free, white to off-white, lyophilized powder to cake for reconstitution with the provided diluent, for intravenous injection. After reconstitution, the solution has a clear to slightly opalescent appearance and contains the excipients: sucrose, mannitol, sodium chloride, L-histidine and polysorbate 20. ALPROLIX™ is available in single-use vials containing the labeled amount of Factor IX activity, expressed in international units. Each vial contains nominally 500 IU, 1000 IU, 2000 IU or 3000 IU.
ALPROLIX™, Coagulation Factor IX (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, coagulation Factor IX concentrate indicated in adults and children with hemophilia B (congenital Factor IX deficiency) for:
ALPROLIX™ is not indicated for induction of immune tolerance in patients with hemophilia B [see WARNINGS AND PRECAUTIONS].
For intravenous use after reconstitution only
ALPROLIX™ dosing for the control and prevention of bleeding episodes is provided in Table 1.
Table 1: Dosing for Control and Prevention of Bleeding
Episodes
| Type of Bleeding | Circulating Factor IX Level Required (IU/dL or % of normal) | Dosing Interval (hours) |
| Minor and Moderate For example: Uncomplicated hemarthroses, superficial muscle (except iliopsoas) without neurovascular compromise, superficial soft tissue, mucous membranes |
30-60 | Repeat every 48 hours if there is further evidence of bleeding |
| Major For example: Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss; Pharyngeal, retropharyngeal, retroperitoneal, CNS |
80-100 | Consider a repeat dose after 6-10 hours and then every 24 hours for the first 3 days. Due to the long half-life of ALPROLIX™, the dose may be reduced and frequency of dosing may be extended after day 3 to every 48 hours or longer until bleeding stops and healing is achieved. |
ALPROLIX™ dosing for perioperative management is provided in Table 2 .
Table 2: Dosing for Perioperative Management
| Type of Surgery | Circulating Factor IX Level Required (IU/dL or % of normal) | Dosing Interval (hours) |
| Minor (including uncomplicated dental extraction) | 50 to 80 | A single infusion may be sufficient. Repeat as needed after 24-48 hours until bleeding stops and healing is achieved. |
| Major | 60 to 100 (initial level) | Consider a repeat dose after 6-10 hours and then every 24 hours for the first 3 days. Due to the long half-life of ALPROLIX™, the dose may be reduced and frequency of dosing in the post-surgical setting may be extended after day 3 to every 48 hours or longer until bleeding stops and healing is achieved. |
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To combine two or more vials of ALPROLIX™, follow the following pooling steps.
For intravenous injection only
ALPROLIX™ is available as a lyophilized powder in single use vials containing nominally 500, 1000, 2000, or 3000 international units (IU) per vial. The actual Factor IX potency is stated on each ALPROLIX™ vial.
ALPROLIX™ is supplied as a kit comprising:
ALPROLIX™ vials are available in 500, 1000, 2000, or 3000 IU nominal dosage strengths. The actual Factor IX potency, expressed in IU is stated on every rFIXFc vial and kit carton label.
| Strength | Kit NDC Number | |
| 500 IU | 64406-911-01 | |
| 1000 IU | 64406-922-01 | |
| 2000 IU | 64406-933-01 | |
| 3000 IU | 64406-944-01 | |
Manufactured by : Biogen Idec, Inc. 14 Cambridge Center, Cambridge, MA 02142
Common adverse reactions (incidence ≥ 1%) reported in clinical trials were headache and oral paresthesia.
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.
In the multi-center, prospective, open-label clinical trial with ALPROLIX™, 123 previously treated patients (PTPs, exposed to a Factor IX containing product for ≥ 100 exposure days) were evaluated, with 115 subjects treated for at least 26 weeks and 56 subjects treated for at least 52 weeks.
Adverse reactions (ARs) were reported in 10 of 119 (8.4%) subjects treated with routine prophylaxis or episodic (on-demand) therapy. They are summarized in Table 3.
No subject was withdrawn from study due to an adverse reaction. In the study, no inhibitors were detected and no events of anaphylaxis were reported.
Table 3: Summary of Adverse Reactions
| System Organ Class | Adverse Reactions (AR) | Number of Subjects (%) N=119* |
| Nervous system disorders | Headache | 2 (1.7) |
| Dizziness | 1 (0.8) | |
| Dysgeusia | 1 (0.8) | |
| Gastrointestinal disorders | Paresthesia oral | 2 (1.7) |
| Breath odor | 1 (0.8) | |
| General disorders and administration site conditions | Fatigue | 1 (0.8) |
| Infusion site pain | 1 (0.8) | |
| Cardiac disorders | Palpitations | 1 (0.8) |
| Renal and urinary disorders | Obstructive uropathy | 1 (0.8) |
| Vascular disorders | Hypotension | 1 (0.8) |
| *119 previously treated patients (PTPs) on routine prophylaxis or episodic (on-demand) therapy | ||
Obstructive uropathy was reported in one subject with hematuria who developed an obstructing clot in the urinary collecting system. The event resolved with hydration and the subject continued prophylactic treatment with ALPROLIX™.
No information provided.
Included as part of the PRECAUTIONS section.
Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with Factor IX replacement products, and are possible with ALPROLIX™. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, parasthesia, restlessness, wheezing and dyspnea. Discontinue use of ALPROLIX™ if hypersensitivity symptoms occur, and initiate appropriate treatment.
Formation of neutralizing antibodies (inhibitors) to Factor IX has been reported during factor replacement therapy in the treatment of hemophilia B. Monitor all patients regularly for the development of inhibitors by appropriate clinical observations and laboratory tests [see Monitoring Laboratory Tests].
An association between the occurrence of a Factor IX inhibitor and allergic reactions has been reported1. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Closely observe patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of exposure to the product.
Individuals with Factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with ALPROLIX™.
The use of Factor IX products has been associated with the development of thromboembolic complications, especially in individuals receiving continuous infusion through a central venous catheter. ALPROLIX™ should be administered as bolus infusion over several minutes [see DOSAGE AND ADMINISTRATION]. The safety of ALPROLIX™ administration by continuous infusion has not been studied.
Long-term studies in animals to evaluate the carcinogenic potential of ALPROLIX™, or studies to determine the effects of ALPROLIX™ on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of ALPROLIX™ was completed and no carcinogenic risk from product use has been identified.
Animal reproductive studies have not been conducted with ALPROLIX™. It is also not known whether ALPROLIX™ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ALPROLIX™ should be given to a pregnant woman only if clearly needed.
There is no information available on the effect of Factor IX replacement therapy on labor and delivery. Use only if the potential benefit justifies the potential risk.
It is not known if ALPROLIX™ is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised if ALPROLIX™ is administered to nursing women.
Safety, efficacy, and pharmacokinetics of ALPROLIX™ have been evaluated in previously treated pediatric patients 12 years of age and older. No dose adjustment is required for adolescents.
Children under 12 years of age may have higher Factor IX bodyweight-adjusted clearance, shorter half-life, and lower recovery. Higher dose per kilogram bodyweight or more frequent dosing may be needed in these patients [see CLINICAL PHARMACOLOGY].
The use of ALPROLIX™ in children younger than 12 years of age is supported by the clinical study of ALPROLIX™ in subjects 12 years of age and older and interim pharmacokinetic and safety data from a study of pediatric subjects including 8 subjects 2 to 5 years of age and 15 subjects 6 to 11 years of age who were exposed for a median of 21.3 weeks (1.1 to 45.7 weeks). The safety profile in subjects under 12 years of age is acceptable. Efficacy data can be extrapolated from pharmacokinetic data to subjects < 2 years of age. [See CLINICAL PHARMACOLOGY]
Clinical studies of ALPROLIX™ did not include a sufficient number of subjects age 65 and over to determine whether or not they respond differently than younger subjects.
REFERENCES
1. Chitlur M, Warrier I, Rajpurkar M, et al. Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia. 2009;15(5):1027-31.
No information provided.
ALPROLIX™ is contraindicated in individuals who have a known history of hypersensitivity reactions, including anaphylaxis, to the product or its excipients [see DESCRIPTION].
ALPROLIX™ is a fully recombinant, fusion protein that temporarily replaces the missing coagulation Factor IX needed for effective hemostasis. ALPROLIX™ contains the Fc region of human IgG1, which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation, and prolonging their plasma half-life.
Hemophilia B is a bleeding disorder characterized by a deficiency of functional coagulation Factor IX (FIX), which leads to a prolonged clotting time in the activated partial thromboplastin time (aPTT) assay, an established in vitro test for the biological activity of Factor IX. Treatment with ALPROLIX™ shortens the aPTT over the effective dosing period.
The pharmacokinetics (PK) of ALPROLIX™ (rFIXFc) were evaluated in 22 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters (Table 4) were based on plasma FIX activity measured by the one-stage clotting assay. Blood samples for PK analysis were collected prior to dosing and at 11 time points up to 240 hours (10 days) after dosing. The PK data demonstrate that ALPROLIX™ has a prolonged circulating half-life. 12
Table 4: Pharmacokinetic Parameters (Arithmetic Mean,
CV)
| PK Parameters | rFIXFc (50 IU/kg) (N = 22) |
| Cmax (IU/dL) | 46.04 (68.3%) |
| AUCinf (h*IU/dL) | 1619.1 (26.1%) |
| CL (mL/kg/h) | 3.304 (28.4%) |
| Vss (mL/kg) | 327.0 (28.2%) |
| Terminal T½ (h) | 86.52 (37.2%) |
| MRT (h) | 101.96 (29.7%) |
| IR (IU/dL per IU/kg) | 1.0154 (58.7%) |
| Time to 1% FIX activity (d) | 11.489 (23.8%) |
| Abbreviations: IR = incremental recovery; AUCinf = area under the FIX activity time curve; T½ = elimination half-life; MRT = mean residence time; CL = bodyweight adjusted clearance; Vss = bodyweight adjusted volume of distribution at steady-state, Time to 1% FIX activity = estimated time in days after dose when FIX activity has declined to approximately 1 IU/dL above baseline | |
The ALPROLIX™ PK profile was stable over repeated dosing as shown by comparable PK parameters at Week 26.
The PK parameters following a 100 IU/kg dose of ALPROLIX™ were evaluated in a subset of 27 subjects. For this subset, the mean drug clearance (CL) was 2.65 (21.7%) mL/kg/h, the maximum activity (Cmax) was 99.89 IU/dL (20.1%) and the time to 1% FIX activity was 15.8 days (21.3%).
Pharmacokinetic (PK) parameters of ALPROLIX™ (rFIXFc) were determined for adolescents (12 to 17 years of age) and children (2 to 11 years of age) in open-label, multi-center studies of previously treated patients [see Use in Specific Populations].
Pharmacokinetic parameters were evaluated following a 10 minute intravenous infusion in 11 evaluable adolescents who received a single dose of ALPROLIX™. PK samples were collected prior to dosing and at multiple time points up to 336 hours (14 days) after dosing. In a separate study, PK parameters were evaluated following a 10 minute intravenous infusion in 18 evaluable children (2 to 11 years of age) who received a single dose of ALPROLIX™. PK samples were collected prior to dosing and at multiple time points up to 168 hours (7 days) after dosing. PK parameters for ALPROLIX™ were estimated based on the plasma FIX activity over time profile.
Table 5 presents the PK parameters calculated from the pediatric data of 29 subjects 2 to 17 years of age. Compared to adults, incremental recovery appeared to be lower and bodyweight- adjusted clearance appeared to be higher in children under 12 years of age. This may result in a need for per kg bodyweight dose adjustments in children under 12 years of age. [see Use In Specific Populations]
Table 5: Comparison of Pharmacokinetic Parameters of
rFIXFc by Age Category
| PK parameters1 | 2 to 5 years (N = 5) |
6 to 11 years (N = 13) |
12 to 17 years (N = 11) |
| IR (IU/dL per IU/kg) | 0.5980 (15.7%) | 0.7422 (29.2%) | 0.8929 (36.4%) |
| AUC/Dose (IU•h/dL per IU/kg) | 23.18 (15.9%) | 29.38 (26.6%) | 30.23 (22.2%) |
| T½ (h) | 66.40 (32.1%) | 72.23 (23.1%) | 83.59 (19.1%) |
| MRT (h) | 80.52 (22.3%) | 84.06 (18.6%) | 95.13 (19.4%) |
| CL (mL/h/kg) | 4.406 (16.8%) | 3.613 (25.1%) | 3.483 (25.6%) |
| Vss (mL/kg) | 349.0 (19.2%) | 303.0 (28.5%) | 326.0 (24.9%) |
| 1PK parameters are presented in arithmetic
mean (CV%) Abbreviations: IR = incremental recovery; AUC = area under the FIX activity time curve; T ½= elimination half-life; MRT = mean residence time; CL = bodyweight adjusted clearance; Vss = bodyweight adjusted volume of distribution at steady-state |
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The safety and efficacy of ALPROLIX™ was evaluated in a multi-center, prospective, open-label clinical trial that compared each of two prophylactic treatment regimens (fixed weekly and individualized interval) to episodic (on-demand) treatment; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management of subjects undergoing major surgical procedures. A total of 123 previously treated patients (PTPs) with severe hemophilia B ( ≤ 2% endogenous FIX activity), ages 12-71, were followed for up to 77 weeks.
Sixty three subjects in the fixed weekly interval arm received ALPROLIX™ for routine prophylaxis starting at an initial dose of 50 IU/kg. The dose was adjusted to maintain FIX trough level between 1% and 3% above baseline or higher, as clinically indicated to prevent bleeding. Fifty subjects required at least one dose adjustment and the median number of dose adjustments was one. The overall median dose on study was 45.2 IU/kg (interquartile range: 38.1, 53.7). The median weekly dose during the last 6 months on study in 58 subjects who were on study for at least 9 months was 40.7 IU/kg (interquartile range: 32.3, 54.1).
Twenty nine subjects in the individualized interval arm received ALPROLIX™ for routine prophylaxis at a dose of 100 IU/kg every 10 days, with the interval adjusted to maintain FIX trough level between 1% and 3% above baseline or higher, as clinically indicated to prevent bleeding. The overall median interval on study was 12.5 days (interquartile range: 10.4, 13.4). The median interval during the last 6 months in 26 subjects who were on study for at least 9 months was 13.8 days (interquartile range: 10.5, 14.0). 14
Twenty seven subjects received ALPROLIX™ as needed for the treatment of bleeding episodes in the episodic (on-demand) treatment arm.
Twelve subjects received ALPROLIX™ for perioperative management in 14 major surgical procedures. Major surgery was defined as any surgical procedures with or without general anesthesia in which a major body cavity was penetrated and exposed, or a substantial impairment of physical or physiological functions was produced. Four subjects in this arm did not participate in the other arms.
A total of 636 bleeding events were observed by 114 subjects in the fixed weekly interval prophylaxis, individualized interval prophylaxis, and the episodic (on-demand) arms. The median total dose to treat a bleeding episode was 46.99 IU/kg (interquartile range: 33.33, 62.50). Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. Efficacy in control of bleeding episodes is summarized in Table 6.
Table 6: Efficacy in Control of Bleeding
| New Bleeding Episodes | (n=636) |
| Number of injections to treat bleeding episodes | |
| 1 injection | 575 (90.4%) |
| 2 injections | 44 (6.9%) |
| 3 injections | 17 (2.7%) |
| Response* to first injection | (n=613) |
| Excellent or good | 513 (83.7%) |
| Moderate | 90 (14.7%) |
| No response | 10 (1.6%) |
| *Excellent: abrupt pain relief and/or improvement in signs of bleeding; Good: definite pain relief and/or improvement in signs of bleeding but possibly requiring another injection in 1-2 days; Moderate: probable or slight beneficial effect and requiring more than one injection; No response: no improvement, or worsening. Response evaluated at approximately 8 hours after treatment. | |
Using a negative binomial model, a reduction in annualized bleeding rate (ABR) of 83% (76-89%) for subjects in the fixed weekly interval arm and a reduction of 87% (80-92%) for subjects in the individualized interval arm compared to the episodic (on-demand) treatment arm was observed.
The median duration of treatment on study was 51.4 weeks (range < 1-77). A comparison of the ABRs in subjects evaluable for efficacy is summarized in Table 7.
Table 7: Median Annualized Bleeding Rate (ABR) by
Treatment Arm
| Bleeding Episode Etiology | Prophylaxis Fixed Weekly Interval (N=61) |
Prophylaxis Individualized Interval (N=26) |
Episodic (On Demand) (N=27) |
| Overall ABR (IQR)* | 2.95 (1.01, 4.35) |
1.38 (0.00, 3.43) |
17.69 (10.77, 23.24) |
| Spontaneous ABR (IQR)* | 1.04 (0.00, 2.19) |
0.88 (0.00, 2.30) |
11.78 (2.62, 19.78) |
| * IQR=interquartile range Five subjects (2 in prophylaxis fixed weekly interval arm, 3 in prophylaxis individualized interval arm) did not have sufficient data to be included in the efficacy analysis. |
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Fourteen major surgical procedures were performed in 12 subjects, including 5 knee replacements, abdominal surgery and a complex dental procedure. Perioperative Factor IX replacement with ALPROLIX™ was by bolus infusion only. The safety of continuous infusion was not evaluated. Hemostasis was assessed by the investigator at 24 hours after surgery using a 4-point scale of excellent, good, fair, and none. The hemostatic response was rated as excellent (n=13) or good (n=1) in 100% of major surgeries. There were an additional 15 minor surgical procedures in 13 subjects. There was no clinical evidence of thrombotic complications in any of the subjects.
ALPROLIX™ /all' pro liks /
[Coagulation Factor IX (Recombinant), Fc Fusion Protein]
Please read this Patient Information carefully before using ALPROLIX™ and each time you get a refill, as there may be new information. This Patient Information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is ALPROLIX™?
ALPROLIX™ is an injectable medicine that is used to help control and prevent bleeding in people with hemophilia B. Hemophilia B is also called congenital Factor IX deficiency.
Your healthcare provider may give you ALPROLIX™ when you have surgery.
Who should not use ALPROLIX™?
You should not use ALPROLIX™ if you are allergic to ALPROLIX™ or any of the other ingredients in ALPROLIX™. Tell your healthcare provider if you have had an allergic reaction to any Factor IX product prior to using ALPROLIX™.
What should I tell my healthcare provider before using ALPROLIX™?
Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal medicines.
Tell your doctor about all of your medical conditions, including if you:
How should I use ALPROLIX™?
ALPROLIX™ should be administered as ordered by your healthcare provider. You should be trained on how to do infusions by your healthcare provider. Many people with hemophilia B learn to infuse their ALPROLIX™ by themselves or with the help of a family member.
See the Instructions for Use for directions on infusing ALPROLIX™. The steps in the Instructions for Use are general guidelines for using ALPROLIX™. Always follow any specific instructions from your healthcare provider. If you are unsure of the procedure, please ask your healthcare provider. Do not use ALPROLIX™ as a continuous intravenous infusion.
Contact your healthcare provider immediately if bleeding is not controlled after using ALPROLIX™.
What are the possible side effects of ALPROLIX™?
Common side effects of ALPROLIX™ include headache and abnormal sensation in the mouth. 19
Allergic reactions may occur. Call your healthcare provider or get emergency treatment right away if you have any of the following symptoms: hives, chest tightness, wheezing, difficulty breathing, or swelling of the face.
ALPROLIX™ may increase the risk of forming abnormal blood clots in your body if you have risk factors for developing blood clots.
Your body can also make antibodies called, “inhibitors,” against ALPROLIX™, which may stop ALPROLIX™ from working properly. Your healthcare provider may need to test your blood from time to time.
These are not all the possible side effects of ALPROLIX™.
Talk to your healthcare provider about any side effect that bothers you or that does not go away.
How should I store ALPROLIX™?
Store ALPROLIX™ vials at 2°C to 8°C (36°F to 46°F). Do not freeze.
ALPROLIX™ vials may also be stored at room temperature up to 30°C (86°F) for a single 6 month period.
If you choose to store ALPROLIX™ at room temperature:
Do not use product or diluent after the expiration date printed on the carton, vial or syringe.
After Reconstitution:
What else should I know about ALPROLIX™?
Medicines are sometimes prescribed for purposes other than those listed here. Do not use ALPROLIX™ for a condition for which it was not prescribed. Do not share ALPROLIX™ with other people, even if they have the same symptoms that you have.
