ALPROLIX: Package Insert and Label Information

ALPROLIX- coagulation factor ix (recombinant), fc fusion protein
Biogen Inc.

1 INDICATIONS AND USAGE

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:

  • On demand treatment and control of bleeding episodes,
  • Perioperative management of bleeding,
  • Routine prophylaxis to reduce the frequency of bleeding episodes.

Limitation of Use

ALPROLIX is not indicated for induction of immune tolerance in patients with hemophilia B [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only

2.1 Dosing Guidelines

  • 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 laboratory standard used.[see Warnings and Precautions (5.4)]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)
OR
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 [see Use in Specific Populations (8.4)]. For patients 12 years of age or older, dose adjustment is not usually required.

On Demand Treatment and Control of Bleeding Episodes

ALPROLIX dosing for the 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 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.

Perioperative Management

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.

Routine Prophylaxis

  • The recommended starting regimens are either 50 IU/kg once weekly, or 100 IU/kg once every 10 days.
  • Adjust dosing regimen based on individual response.

2.2 Reconstitution

  1. Use aseptic technique (clean and germ-free) and a flat work surface during the reconstitution procedure.
  2. Allow the vial of ALPROLIX and the pre-filled diluent syringe to reach room temperature before use.
  3. 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.
  4. 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.

    Figure

  5. Place the vial on a flat surface and use one hand to hold the vial steady. Use the other hand to 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.

    Figure

  6. Lift the package cover away from the vial adapter and discard the cover.

    Figure

  7. 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.

    Figure

  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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, after step 12 above, follow these pooling steps:

  1. Remove the diluent syringe from the vial adapter by turning it counterclockwise until it is completely detached. 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).
  2. Leave the vial adapter attached to the vial, as it is needed for attaching a large luer lock syringe.
  3. Attach a separate, large luer lock syringe by turning clockwise until it is securely in place.
  4. Slowly pull on the plunger rod to draw the solution into the syringe.
  5. 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.
Figure Figure Figure Figure

2.3 Administration

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.

Administration Steps:

  1. Attach the syringe to the connector end of the infusion set tubing by turning clockwise until it is securely in place.
  2. 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.
  3. Remove the protective needle cover from the infusion set tubing.
  4. 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.

3 DOSAGE FORMS AND STRENGTHS

ALPROLIX is available as a lyophilized powder in single use vials containing nominally 250, 500, 1000, 2000, 3000, or 4000 international units (IU) per vial. The actual Factor IX potency is stated on each ALPROLIX vial.

4 CONTRAINDICATIONS

ALPROLIX is contraindicated in individuals who have a known history of hypersensitivity reactions, including anaphylaxis, to the product or its excipients (sucrose, mannitol, sodium chloride, L-histidine and polysorbate 20) .

.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions have been reported with ALPROLIX. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with Factor IX replacement products.

The presence of inhibitors has been associated with allergic reactions with Factor IX replacement therapies, including with ALPROLIX. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. Discontinue use of ALPROLIX if hypersensitivity symptoms occur, and initiate appropriate treatment.

5.2 Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to Factor IX has been reported following administration of ALPROLIX, including in previously untreated patients. Monitor all patients regularly for the development of inhibitors by appropriate clinical observations and laboratory tests [see Warnings and Precautions (5.4)].

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.

5.3 Thromboembolic Complications

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 (2.3)]. The safety of ALPROLIX administration by continuous infusion has not been studied.

5.4 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 [see Dosage and Administration (2.1)]. 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.

6 ADVERSE REACTIONS

Common adverse reactions (incidence ≥1%) reported in clinical trials were headache and oral paresthesia.

6.1 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 the trial due to an adverse reaction. In the trial, no inhibitors were detected and no events of anaphylaxis were reported.

Table 3: Summary of Adverse Reactions

*119 previously treated patients (PTPs) on routine prophylaxis or episodic (on-demand) therapy

System Organ Class Adverse Reactions (AR) Number of Subjects (%) N=119*
Nervous system disorders HeadacheDizzinessDysgeusia 2 (1.7)1 (0.8)1 (0.8)
Gastrointestinal disorders Paresthesia oralBreath odor 2 (1.7)1 (0.8)
General disorders and administration site conditions FatigueInfusion site pain 1 (0.8)1 (0.8)
Cardiac disorders Palpitations 1 (0.8)
Renal and urinary disorders Obstructive uropathy 1 (0.8)
Vascular disorders Hypotension 1 (0.8)

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. A causal relationship of clot formation to ALPROLIX was not established.

Immunogenicity

Previously-treated patients participating in clinical trials were monitored for neutralizing antibodies to Factor IX. No subjects developed neutralizing antibodies to Factor IX.

The detection of antibodies that are reactive to Factor IX is highly dependent on many factors, including the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease.

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