Limitation of Use:

ALPROLIX is not indicated for induction of immune tolerance in patients with hemophilia B.

2.1 Dose

• Dose and duration of treatment depend on the severity of the Factor IX deficiency, the location and extent of bleeding, the individual patient's pharmacokinetic profile, and/or 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.
• More frequent or higher doses may be needed in children <12 years of age, especially in children <6 years of age [see Use in Specific Populations (8.4)]. For patients 12 years of age or older, age-based dose adjustment is not usually required.
• In addition to the nominal (target) potency, the actual Factor IX potency in international units (IU), determined by the quality control laboratory at product release, is stated on each ALPROLIX vial label. ALPROLIX potency is assigned using a validated 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)].
  On average, one IU of ALPROLIX per kg body weight increases the circulating level of Factor IX by approximately 1% (IU/dL) in adults and children ≥6 years of age and by 0.6% (IU/dL) in children under 6 years of age. 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:

• Consider determining the patient's in vivo recovery (in IU/dL per IU/kg) prior to elective major surgery and verify that the target Factor IX level has been achieved prior to major surgery and for major bleeds.

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, containing the white to off-white lyophilized powder and the prefilled 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.

   

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.

   

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

   

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.

   

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.

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.

5.1 Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ALPROLIX.

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. 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 patient plasma Factor IX levels by performing a validated 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 has been shown to result in an underestimation of Factor IX levels.
• Monitor for the development of Factor IX inhibitors if the expected Factor IX levels in patient 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.

5.5 Nephrotic Syndrome

Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with Factor IX inhibitors and a history of allergic reactions to Factor IX. The safety and efficacy of using ALPROLIX for immune tolerance induction have not been established.

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during the postapproval use of ALPROLIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Factor IX inhibitor development

Immune system disorders: hypersensitivity, including anaphylaxis

For additional information, refer to the Warnings and Precautions 5.1 and 5.2.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety, efficacy, and pharmacokinetics of ALPROLIX have been evaluated in previously treated patients (PTPs) from the adult and adolescent study (12 to <17 years of age) and from the pediatric study (1 to 11 years of age) [see Adverse Reactions (6), Clinical Trials Experience (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. Safety of ALPROLIX has been evaluated in previously untreated patients (PUPs) less than 18 years of age (median: 0.6 year; range: 0.08–2 years) in the PUPs study [see Adverse Reactions (6), Clinical Trials Experience (6.1), and Clinical Pharmacology (12.3)].

No dose adjustment is required for adolescents. Children under 12 years of age may have higher Factor IX body weight-adjusted clearance and lower recovery. More frequent or higher doses may be needed in children <12 years of age. When calculating target peak doses for treatment of bleeding or surgery, use the average in vivo recovery value of 0.6 IU/dL per IU/kg, or individually determined in vivo recovery, for children under 6 years of age [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

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.

12.1 Mechanism of Action

ALPROLIX is a 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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

PK parameters for ALPROLIX were estimated based on the plasma FIX activity measured by the one-stage clotting assay.

13.1 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.

Adult and Adolescent Study (12 to 71 Years)

The non-randomized adult and adolescent study 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 to moderately severe hemophilia B (≤2% endogenous FIX activity) were followed for up to 77 weeks. Subjects who were on prophylaxis before the study were assigned to one of the prophylaxis arms. Subjects who were treating on-demand before the study were assigned to either one of the two prophylaxis arms or to the on-demand treatment arm. Treatment arm assignments were based on standard of care and discussion between the investigator and the subject.

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 (79%) 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 initially 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).

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 procedure 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.

Pediatric Study (1 to 11 Years)

The pediatric study enrolled a total of 30 previously treated male pediatric patients with severe to moderately severe hemophilia B (≤2% endogenous FIX activity). Subjects were less than 12 years of age (15 were 1 to 5 years of age and 15 were 6 to 11 years of age). All subjects received treatment with ALPROLIX and were followed for up to 52 weeks.

All 30 subjects were treated with ALPROLIX on an individualized prophylactic dose regimen starting with 50–60 IU/kg every 7 days, with adjustment of dose to a maximum of 100 IU/kg and dosing interval adjusted between once and twice weekly. The median dosing interval was 7.0 days (interquartile range: 6.9 to 7.0) with no difference between the age cohorts. The median average weekly dose of ALPROLIX was 59.4 IU/kg and (interquartile range: 53.0 to 64.8) for subjects 1 to 5 years of age and 57.8 IU/kg (interquartile range: 51.7 to 65.0) for subjects 6 to 11 years of age. At the end of the trial, the median prescribed once weekly prophylactic dose was 60 IU/kg across both pediatric age subgroups (range: 40 to 70 IU/kg).

On-demand Treatment and Control of Bleeding Episodes

Perioperative Management

Thirty-five major surgical procedures were performed in 22 subjects (age range: 10–63 years) in the adult and adolescent study and in the extension study. Of the 35 major surgeries, 28 surgeries (80.0%) required a single perioperative dose to maintain hemostasis during surgery. The median average dose per injection to maintain hemostasis during surgery was 94.7 IU/kg (range: 49 to 152). 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 after surgery. Assessment of intraoperative and postoperative hemostatic response for major surgeries in the adult and adolescent study and the ongoing extension study are summarized in Table 8.

There were an additional 62 minor surgical procedures in 37 subjects in the adult and adolescent study, the pediatric study, and the extension study. Hemostatic response was assessed for 38 minor surgeries; 36 minor surgeries were rated as excellent or good and 2 as fair.

Routine Prophylaxis

How Supplied

ALPROLIX is supplied as a kit comprising:

• one single-dose glass vial containing rFIXFc powder,
• one prefilled syringe containing 5 mL diluent and sealed with a plunger stopper and tip-cap, and
• one sterile vial adapter (reconstitution device).

ALPROLIX is available in 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU or 4000 IU nominal (approximate) dosage strengths. The actual Factor IX potency, expressed in IU, is stated on each rFIXFc vial and carton label. Not made with natural rubber latex.

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). Do not freeze. Freezing will damage the prefilled diluent syringe.
• ALPROLIX can be stored at room temperature, not to exceed 30°C (86°F), for a single period of up to 6 months within the expiration date printed on the carton and vial label. If stored at room temperature, record the date on the carton 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. The shelf-life then expires after storage at room temperature for 6 months, or after the expiration date on the product vial, whichever is earlier.
• 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.