Data from FDA - Curated by Toby Galbraith - Last updated 18 April 2017

Licensing authority

FDA (Food and Drug Administration, USA)

Indication(s)

1 INDICATIONS AND USAGE IXINITY is a coagulation factor IX (recombinant) indicated in adults and children?

12 years of age with hemophilia B for control and prevention of bleeding episodes, and for perioperative management.

IXINITY is not indicated for induction of immune tolerance in patients with hemophilia B IXINITY is a coagulation factor IX (recombinant) indicated in adults and children?

12 years of age with hemophilia B for control and prevention of bleeding episodes, and for perioperative management (1) IXINITY is not indicated for induction of immune tolerance in patients with hemophilia B

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Advisory information

contraindications
4 CONTRAINDICATIONS IXINITY is contraindicated in patients who have known hypersensitivity to IXINITY or its excipients, including hamster protein [see Warnings and Precautions (5.1)]. Do not use in patients with known hypersensitivity to IXINITY or its excipients, including hamster protein (4)
Adverse reactions

6 ADVERSE REACTIONS The most common adverse reaction (> 2 %) reported in clinical trials was headache.

The most common adverse reaction observed in > 2 % of patients in clinical trials was headache (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Cangene Corporation at 1-800-768-2304 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 14 adverse reactions were reported following IXINITY administration among 6 of the 77 subjects who received at least one dose of IXINITY in trials of previously treated patients (PTPs), which included 11 subjects < 18 years of age.

A total of 9641 infusions of IXINITY were administered to the 77 subjects.

The adverse reactions that were assessed as probably or possibly related to study drug are provided in the table below.

Table 3 Summary of Adverse Reactions MedDRA Standard System Organ Class Adverse Reaction Number of Events Number of Patients (n = 77) (%) Congenital

familial and genetic disorders Hemophilia (i.e. lack of efficacy) 1 1 (1.3 %) General disorders and administration site conditions Asthenia 1 1 (1.3 %) Injection site discomfort 1 1 (1.3 %) Infections and infestations Influenza 1 1 (1.3 %) Nervous system disorders Headache 5 2 (2.6 %) Dysgeusia 1 1 (1.3 %) Lethargy 1 1 (1.3 %) Psychiatric disorders Apathy 1 1 (1.3 %) Depression 1 1 (1.3 %) Skin and subcutaneous tissue disorders Rash pruritic 1 1 (1.3 %) 6.2 Immunogenicity All subjects participating in the clinical trial were monitored for inhibitory and non-inhibitory antibodies to factor IX and antibodies for CHO proteins at the following time points; pre-infusion, after the first 5 exposure days, and then every 3 months thereafter.

No subjects in IXINITY clinical trials developed inhibitors to factor IX, including 55 subjects with more than 50 exposure days and 45 of those subjects with more than 100 exposure days.

Non-inhibitory factor IX binding antibodies were detected in 30 % (23/77) of subjects, including 5 subjects positive at baseline.

In three of the subjects, the non-inhibitory factor IX antibodies were persistent, while in the remainder the antibodies were sporadic and non-persistent.

No clinical adverse findings related to non-inhibitory factor IX antibody formation were identified.

Detection of non-inhibitory antibodies against factor IX has been reported following administration of other factor IX products.

The clinical significance of this finding is unknown.

In IXINITY clinical trials, 29 % (20/68) of subjects tested positive for antibodies against CHO cell proteins.

No clinical adverse findings were associated with these antibodies.

Reports have been published of sporadic detection of antibodies against

CHO cell proteins in subjects treated with other recombinant coagulation factor products produced in CHO cells, as well as in non-hemophilic subjects ().

The clinical significance of this is unknown.

The manufacturing process for IXINITY was modified to include an additional step to ensure increased clearance of CHO proteins to address the anti-CHO protein response seen in clinical trials.

The anti-CHO protein response status of the clinical trial subjects who transitioned to the modified product (n = 17) remained negative (n = 10), stable/nonspecific assay binding (n = 5), or declined (n = 2) after the transition to modified IXINITY for at least 3 months.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection and concomitant medications.

For these reasons, comparisons of the incidence of antibodies to IXINITY with the incidence of antibodies to other products may be misleading.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only.

For intravenous use after reconstitution only.

One international unit (IU) of IXINITY per kg body weight increases the circulating activity of factor IX by 0.98 IU/dL (2.1) Initial dose (2.1) Required factor IX units (IU) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL).

Maintenance dose: Depends upon the type of bleed or surgery, clinical response, and the severity of the underlying factor IX deficiency (2.1) 2.1 Dose Each vial of IXINITY has the recombinant factor IX (rFIX) potency in international units (IU) stated on the vial.

Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, the patient 's clinical condition, age, and pharmacokinetic parameters of factor IX, such as incremental recovery and half-life.

Initial Dose Calculate the initial dose of IXINITY based on the empirical finding that one international unit (IU) of IXINITY per kg body weight increases the circulating level of factor IX by 0.98 international units/dL (IU/dL) of plasma in adults and children?

12 years of age.

Initial Dose = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x reciprocal of observed recovery (IU/kg per IU/dL) Incremental Recovery in Previously Treated Patients (PTPs) Base calculation of the dose on the patient 's individual incremental recovery using serial factor IX activity assays, to account for the wide range of inter-individual differences in incremental recovery and the type of aPTT reagent used for the assay.

Titrate the dose based on the patient 's clinical response and individual pharmacokinetics, in particular incremental recovery and half-life.

For an incremental recovery of 0.98 IU/dL, the dose is calculated as follows:

Dose (IU) = body weight (kg) x desired factor IX increase (% of normal or IU/dL) x 1.02 dL/kg Examples (assuming patient 's baseline factor IX level is < 1 % of normal): A dose of 4550 international units (IUs) of IXINITY administered to a 70 kg patient should be expected to result in a peak post-infusion factor IX increase of 4550 IU x (0.98 IU/dL per IU/kg)/(70 kg) = 64 IU/dL (approximately 60 % of normal) A peak of 70 % is required in a 60 kg patient.

The appropriate dose would be (60 kg x 70 IU/dL)/(0.98 IU/dL per IU/kg) = 4286 IU Monitor factor IX activity to ensure that the desired factor IX activity level has been achieved [see Warnings and Precautions (5.5)].

Titrate doses using factor IX activity and pharmacokinetic parameters such as half-life and incremental recovery, as well as by taking the clinical situation into consideration, to adjust the dose and frequency of repeated infusions as appropriate.

Factor IX activity measurements in the clinical laboratory may be affected by the type of activated partial thromboplastin time (aPTT) reagent or laboratory standard used [see Warnings and Precautions (5.5)].Control and Prevention of Bleeding and Perioperative Management Control and Prevention of Bleeding and Perioperative Management Guides for dosing IXINITY in the control and prevention of bleeding episodes (Table 1) and perioperative management (Table 2) are provided in the tables below.

Individual patients may vary in their response to factor IX, and may demonstrate different levels of in_vivo recovery and different half-lives.

For surgical procedures, initiate treatment with IXINITY early enough pre-operatively to achieve and maintain the desired factor IX level before starting the procedure.

Table 1 Dosing for Control and Prevention of Bleeding Episodes Adapted from Srivastava et al. 2013 (1).

Type of Bleeding Episode Desired Peak Factor IX Level (% of normal or IU/dL) Dosing Interval (hours) Duration of therapy (days) Minor Early bleeds: uncomplicated hemarthroses and superficial muscle (except iliopsoas) with no neurovascular compromise, other soft tissue 30-60 24 1-3, until healing is achieved Moderate Hemarthrosis of longer duration, recurrent hemarthrosis, mucous membranes, deep lacerations, hematuria 40-60 24 2-7, until healing is achieved Major or Life Threatening Iliopsoas, deep muscle with neurovascular injury, substantial blood loss, CNS, pharyngeal, retropharyngeal, retroperitoneal 60-100 12-24 2-14, until healing is achieved Table 2 Dosing for Perioperative Management Adapted from Srivastava et al. 2013 (1).

Type of Surgery Desired Peak Factor IX Level (% of normal or IU/dL) Dosing Interval (hours) Duration of Therapy (days) Minor (including uncomplicated dental extractions) Pre-op 50-80 Post-op 30-80 24 1-5, depending on type of procedure Major Pre-op 60-80 Post-op 40-60 30-50 20-40 8-24 1-3 4-6 7-14 2.2 Preparation and Reconstitution The procedures below are provided as general recommendations for the preparation and reconstitution of IXINITY. Before starting reconstitution and administration you will need the following items: One (or more) vial(s) of IXINITY 500, 1000, or 1500 IU powder One (or more) 10 mL syringe(s)

pre-filled with 5 mL of Sterile Water for Injection (Pre-filled Syringe) with plunger rod attached One sterile vial adapter with filter One sterile 20 mL LUER-LOK™ syringe (Administration Syringe) Sterile alcohol swabs Sterile infusion set Sterile gauze pad Sterile bandage Always work on a clean surface and wash your hands before performing the following procedures: 1. Use aseptic technique during reconstitution procedure.

2.

Allow IXINITY and the Pre-filled Syringe to reach room temperature before use.

3.

Remove cap from the vial (See Figure A).

Peel back the cover of the vial adapter package (leave the vial adapter in the package).

Figure A 4.

Place the Administration Syringe and vial adapter on a clean flat work surface.

5.

Twist off the cap of the Pre-filled Syringe and place it on the clean flat surface (See Figure B).

Figure B 6.

Wipe the top of the

IXINITY vial with an alcohol swab (or similar germicidal solution) and allow it to dry.

Place on a clean, flat surface.

7.

Firmly hold the package containing the vial adapter on a clean, flat surface.

Connect the Pre-filled Syringe to the vial adapter by pushing the syringe tip down onto the LUER-LOK in the center of the vial adapter, and screw until the syringe is secured (See Figure C).

Figure C 8.

Carefully lift up the combined syringe-and-vial-adapter and remove it from the plastic package (See Figure D).

Figure D 9.

With one hand, continue to hold the combined syringe-and-vial-adapter.

With the other hand, hold the IXINITY vial tightly on a clean, flat surface.

In a continuous motion, place the vial adapter over the IXINITY vial; firmly push the filter spike of the vial adapter through the center of IXINITY vial 's rubber circle until the clear plastic cap snaps onto the IXINITY vial (See Figure E).

Push the plunger down to complete the transfer of all liquid from the syringe to the IXINITY vial.

Figure E 10.

With the syringe and the vial still attached, gently swirl, in a circular motion, the IXINITY vial until the product is fully dissolved/reconstituted (See Figure F).

Figure F 11.

Remove the Pre-filled Syringe (now empty) from the vial adapter by turning it counterclockwise until it is completely detached (See Figure G).

Figure G 12.

Remove the Administration Syringe (provided) from its packaging.

13.

Leave the vial adapter attached to the vial and attach the Administration Syringe to the vial adapter by turning clockwise until it is securely attached (See Figure H).

Figure H 14.

Keeping the Administration Syringe plunger pressed, turn the IXINITY vial upside down.

Draw the solution from the vial through the filter spike in the vial adapter by pulling the plunger back slowly until all solution is transferred into the Administration Syringe (See Figure I).

Figure I 15.

Keep the Administration Syringe plunger facing downwards and prevent it from moving.

With one hand hold the vial-and-vial-adapter, and with the other hand firmly grasp the barrel of the Administration Syringe and unscrew the syringe from the vial adapter (See Figure J).

Figure J 16.

If only dosing with a single vial, proceed to administer IXINITY via intravenous infusion; otherwise proceed to Pooling Instructions.

POOLING INSTRUCTIONS 1.

If two or more vials are required to achieve the required dose, remove the Pre-filled Syringe from the vial adapter on the reconstituted second vial by turning it counterclockwise until it is completely detached.

2.

Leave the vial adapter attached to the vial and attach the Administration Syringe containing the reconstituted IXINITY from the first vial by turning it clockwise until it is securely in place.

3.

Turn the IXINITY vial upside down and slowly pull on the plunger rod to draw the solution into the Administration Syringe (see Figure I).

The Administration Syringe provided with IXINITY may be used to pool up to three (3) vials.

If pooling is complete, proceed to administer IXINITY via intravenous infusion.

4.

If more than three (3) vials are required, use a larger (i.e. greater than 20 mL) sterile LUER-LOK syringe (not provided) and repeat Steps 1 to 3 above for all required vials of IXINITY. Once reconstituted product is pooled from all required vials, proceed to administer IXINITY via intravenous infusion.

After reconstitution of the lyophilized powder, all dosage strengths should yield a clear, colorless solution without visible particles.

Discard if visible particulate matter or discoloration is observed.

Infuse reconstituted solution immediately or within 3 hours of storage at room temperature after reconstitution.

Do not refrigerate after reconstitution.

Do not touch the syringe tip or the inside of the cap.

Place the syringe containing the IXINITY solution on the clean surface, making sure that the tip does not touch anything.

Dosing Figure A-1 Dosing Figure A-2 Dosing Figure B

Dosing Figure C Dosing

Figure D Dosing Figure E \Dosing Figure F Dosing Figure G Dosing Figure H Dosing Figure I Dosing Figure J 2.3 Administration For intravenous use after reconstitution only.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not mix IXINITY with other medicinal products for infusion.

Attach the Administration Syringe containing the reconstituted IXINITY solution to a sterile infusion set.

Adapt the infusion rate to the comfort level of each patient, not exceeding 10 mL per min. Record the name and batch number of the product in the patient record.

Dispose of any unused product or waste material in accordance with local requirements.

Use in special populations

8 USE IN SPECIFIC POPULATIONS Pregnancy: No human or animal data are available.

Use only if clearly needed (8.1).

8.1 Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with IXINITY.

It is also not known whether IXINITY can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

IXINITY should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers It is not known whether IXINITY is excreted into human milk.

Because many drugs are excreted into human milk, caution should be exercised when IXINITY is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of IXINITY in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use Clinical studies of IXINITY did not include subjects aged 65 and over.

It is not known whether elderly patients respond differently than younger patients.

Individualize dose selection for elderly patients [see

Dosage and

Administration (2.1)].

Pregnancy and lactation
8.3 Nursing Mothers It is not known whether IXINITY is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when IXINITY is administered to a nursing woman.

More information

Category Value
Authorisation number BLA125426
Orphan designation No
Product NDC 53270-0271,53270-0270,53270-0272
Date Last Revised 24-09-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 1666311
Marketing authorisation holder Cangene BioPharma