Alprolix

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with coagulation factor IX, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Included as part of the PRECAUTIONS section.

Mechanism Of Action

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.

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.

Pharmacokinetics

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)

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

Clinical Studies

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

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

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 is part of the drug class:

• Blood coagulation factors

Serious side effects have been reported with Alprolix. “Drug Precautions” section.

Common side effects of Alprolix include:

• headache
• tingling and/or numbness in the mouth
• bad breath
• dizziness
• pain at site of injection
• low blood pressure

This is not a complete list of Alprolix side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you take too much Alprolix call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Coagulation factor IX is a man-made protein similar to a natural protein in the body that helps the blood to clot.

Coagulation factor IX is used to treat or prevent bleeding in people with hemophilia B. This medication is not for treating people with hemophilia A factor VIII deficiency.

Coagulation factor IX may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Alprolix, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Alprolix. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Alprolix (factor IX (recombinant [fc fusion protein])).

Review Date: October 4, 2017

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

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™.

Read the entire FDA prescribing information for Alprolix ([Coagulation Factor IX (Recombinant), Fc Fusion Protein], Lyophilized Powder for Solution For Intravenous Injection)