Alprolix information, interactions and side effects, 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:
- Control and prevention of bleeding episodes,
- Perioperative management,
- Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
ALPROLIX™ is not indicated for induction of immune tolerance in patients with hemophilia B.
DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only
- Initiate treatment with ALPROLIX™ under the supervision of a qualified healthcare professional experienced in the treatment of hemophilia B.
- Dose and duration of treatment depend on the severity of the Factor IX deficiency, the location and extent of bleeding, and the patient’s clinical condition.
- Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Base the dose and frequency of ALPROLIX™ on the individual clinical response. Each vial label for ALPROLIX™ states the Factor IX potency in international units (IU). ALPROLIX™ 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.
- Factor IX activity measurements in the clinical laboratory may be affected by the type of aPTT reagent or reference standard used.
One IU of ALPROLIX™ per kg body weight increases the circulating level of Factor IX by 1% [IU/dL]. Estimate the required dose or the expected in vivo peak increase in Factor IX level expressed as IU/dL (or % of normal) using the following formulas:
IU/dL (or % of normal) = [Total Dose (IU)/Body Weight (kg)] x Recovery (IU/dL per IU/kg)
Dose (IU) = Body Weight (kg) x Desired Factor IX Rise (IU/dL or, % of normal) x Reciprocal of Recovery (IU/kg per IU/dL)
- Dose adjustment may be necessary in pediatric patients under 12 years of age. For patients 12 years of age or older, dose adjustment is not usually required.
Control and Prevention of Bleeding Episodes
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
||Repeat every 48 hours if there is further evidence of bleeding
For example: Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss; Pharyngeal, retropharyngeal, retroperitoneal, CNS
||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.
||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.
- The recommended starting regimens are either 50 IU/kg once weekly, or 100 IU/kg once every 10 days.
- Adjust dose based on individual response.
- Use aseptic technique (clean and germ-free) and a flat work surface during the reconstitution procedure.
- Allow the vial of ALPROLIX™ and the pre-filled diluent syringe to reach room temperature before use.
- Remove the plastic cap from the vial and wipe the rubber stopper of the vial with an alcohol wipe. Allow the rubber stopper to dry.
- Completely remove the backing from the vial adapter package by peeling back the lid. Do not remove the vial adapter from the package or touch the inside of the package of the adapter.
- Keeping the vial on a flat surface, hold the vial adapter package with one hand, and using the other hand, place the vial adapter over the vial. Place the adapter spike directly above the center of the rubber stopper and push the adapter straight down until the spike punctures the center of the vial stopper and is fully inserted.
- Lift the package cover away from the vial adapter and discard the cover.
- Hold the plunger rod at the circular disk. Place the tip of the plunger rod into the end of the syringe. Turn clockwise until it is securely attached. Only use the diluent syringe provided in the ALPROLIX™ package.
- With one hand, hold the diluent syringe by the ridged part directly under the cap, with the cap pointing up. Do not use if the cap has been removed or is not securely attached.
- With your other hand, grasp the cap and bend it at a 90° angle until it snaps off. After the cap snaps off, you will see the glass tip of the syringe. Do not touch the glass tip of the syringe or the inside of the cap.
- With the vial sitting on a flat surface, insert the tip of the syringe into the adapter opening. Turn the syringe clockwise until it is securely attached to the adapter.
- Slowly depress the plunger rod to inject all of the diluent into the vial. The plunger rod may rise slightly after this process. This is normal.
- With the syringe still connected to the adapter, gently swirl the vial until the product is completely dissolved. The final solution should be clear to slightly opalescent and colorless. Do not shake. Do not use the reconstituted ALPROLIX™ if it contains visible particles or is cloudy.
- Make sure the plunger rod is completely depressed. Turn the vial upside-down. Slowly pull on the plunger rod to draw the solution into the syringe. Be careful not to pull the plunger rod completely out of the syringe.
- Gently unscrew the syringe from the vial adapter and dispose of the vial with the adapter still attached. Do not touch the syringe tip or the inside of the cap.
- Use the reconstituted ALPROLIX™ as soon as possible, but no later than 3 hours after reconstitution. Protect from direct sunlight. Do not refrigerate after reconstitution.
To combine two or more vials of ALPROLIX™, follow the following pooling steps.
- Leave the vial adapter attached to the vial, as it is needed for attaching a large luer lock syringe. Do not detach the diluent syringe or the large luer lock syringe until ready to attach the large luer lock syringe to the next vial (with vial adapter attached).
- Remove the diluent syringe from the vial adapter by turning it counterclockwise until it is completely detached.
- Attach a separate, large luer lock syringe by turning clockwise until it is securely in place.
- Slowly pull on the plunger rod to draw the solution into the syringe.
- Repeat this pooling procedure with each vial necessary to obtain the required dose. Once you have pooled the required dose, proceed to administration using the large luer lock syringe.
For intravenous injection only
- Inspect the reconstituted ALPROLIX™ solution visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.
- Do not administer reconstituted ALPROLIX™ in the same tubing or container with other medications.
- Attach the syringe to the connector end of the infusion set tubing by turning clockwise until it is securely in place.
- Depress the plunger until all air is removed from the syringe and ALPROLIX™ has reached the end of the infusion set tubing. Do not push ALPROLIX™ through the needle.
- Remove the protective needle cover from the infusion set tubing.
- Perform intravenous bolus infusion. The rate of administration should be determined by the patient’s comfort level, and no faster than 10 ml per minute.
- After infusing ALPROLIX™, remove and properly discard the infusion set.
Dosage Forms And Strengths
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:
- one single-use rFIXFc vial,
- one pre-filled syringe containing 5 mL diluent and sealed with a plunger stopper and tip-cap, and
- one sterile vial adapter (reconstitution device).
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.
||Kit NDC Number
Storage And Handling
- Store ALPROLIX™ in the original package in order to protect it from light.
- Store ALPROLIX™ at 2°C to 8°C (36°F to 46°F). ALPROLIX™ may also be stored at room temperature, not to exceed 30°C (86°F) for a single 6 month period. On the carton, record the date when the product was removed from refrigeration. Use the product before the end of this 6 month period or discard it. Do not place the product back into refrigeration after warming to room temperature.
- Do not freeze. Freezing will damage the pre-filled diluent syringe.
- Do not use product or diluent after the expiration date printed on the carton, vial or syringe.
- Reconstituted product may be stored at room temperature, not to exceed 30°C (86°F) for no longer than 3 hours. Protect from direct sunlight. Discard any product not used within 3 hours after reconstitution.
Common adverse reactions (incidence ≥ 1%) reported in clinical trials were headache and oral paresthesia.
Clinical Trials Experience
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 (%)
|Nervous system disorders
|General disorders and administration site conditions
|Infusion site pain
|Renal and urinary disorders
|*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™.
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.
Neutralizing Antibodies (Inhibitors)
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.
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. The safety of ALPROLIX™ administration by continuous infusion has not been studied.
Monitoring Laboratory Tests
- To confirm adequate Factor IX levels have been achieved and maintained, monitor plasma Factor IX activity by performing the one-stage clotting assay. Factor IX results can be affected by the type of aPTT reagent used. Measurement with a one-stage clotting assay using a kaolin-based aPTT reagent will likely result in an underestimation of activity level.
- Monitor for the development of Factor IX inhibitors if the expected Factor IX activity levels in plasma are not attained, or if bleeding is not controlled with the recommended dose of ALPROLIX™. Perform a Bethesda assay to determine if Factor IX inhibitors are present.
Patient Counseling Information
- Advise patient to read the FDA-approved patient labeling.
- Advise patients to report any adverse reactions or problems following ALPROLIX™ administration to their physician or healthcare provider.
- Advise patients to contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to Factor IX therapy, as this may indicate the development of an inhibitor.
- Inform patients of the early signs of hypersensitivity reactions (including hives, chest tightness, wheezing, difficulty breathing and swelling of the face) and anaphylaxis. Instruct patients to discontinue use of the product and contact their healthcare provider if these symptoms occur.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
Use In Specific Populations
Pregnancy Category C
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.
Labor And Delivery
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.
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.
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.
ALPROLIX™ is contraindicated in individuals who have a known history of hypersensitivity reactions, including anaphylaxis, to the product or its excipients.