IXINITY, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adults and children with hemophilia B for:

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

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

For intravenous use after reconstitution only.

IXINITY is available as a lyophilized white or almost white powder, in single-dose glass vials containing nominally 250, 500, 1000, 1500, 2000, or 3000 IU per vial.

IXINITY is contraindicated in patients who have known hypersensitivity to IXINITY or its excipients, including hamster protein [see Warnings and Precautions (5.1)].

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

IXINITY [coagulation factor IX (recombinant)] is a purified protein that has 415 amino acids. It has an amino acid sequence that is comparable to the Thr148 allelic form of plasma-derived factor IX. Coagulation factor IX (recombinant) is a single-chain glycoprotein with a molecular mass of about 55,000 Dalton that is secreted by a genetically engineered mammalian cell line derived from Chinese hamster ovary (CHO) cells. No human or animal proteins are added during any stage of manufacturing or formulation of IXINITY. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain hormones. The recombinant factor IX is purified by a chromatography purification process. The process includes three validated steps for virus inactivation and removal, namely, solvent/detergent treatment, a chromatographic step, and nanofiltration. The process also includes a validated step to reduce the presence of CHO proteins in the final drug product.

IXINITY is formulated as a sterile, nonpyrogenic lyophilized powder to be reconstituted with Sterile Water for Injection for intravenous administration. It does not contain any preservatives and is available in single-dose vials containing the labeled amount of factor IX activity, expressed in international units (IU). Each vial contains nominally 250, 500, 1000, 1500, 2000, or 3000 IU of recombinant coagulation factor IX. After reconstitution of the lyophilized powder, all dosage strengths yield a clear, colorless solution. The concentrations of excipients are:

Routine Prophylaxis

PTPs ≥ 12 years of age

The efficacy of IXINITY was evaluated in a prospective, open-label, uncontrolled multicenter study in which a total of 77 subjects (76 male, 1 female carrier in surgery study) were exposed to IXINITY for treatment of hemophilia B or for perioperative management. All male subjects either had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B, or had factor IX levels between 2-8 IU/dL and clinically severe hemophilia B with recurrent hemarthroses and required surgery (n = 3 in surgery study, one continued to treatment phase). Previously treated patients (PTPs) were defined as patients with a minimum of 150 exposures to another factor IX preparation. Of the 77 subjects, 68 PTPs between 7 and 64 years of age received IXINITY either as routine prophylaxis or on-demand treatment. Routine prophylaxis treatment was defined as PTPs who received a starting dose of 40-70 international units (IU) per kg twice weekly. Excluded from the study were patients with a history of a detectable factor IX inhibitor (≥ 0.6 BU), a history of hypersensitivity reactions following exposure to factor IX-containing products, a known allergic reaction to hamster proteins, evidence of severe liver impairment, evidence of impaired renal function, CD4 count < 400 cells/mm3, or any coagulation defect other than hemophilia B. In addition, there was a prospective, open-label, uncontrolled, multicenter substudy where 17 subjects (16 male, 1 female carrier) underwent surgeries (19 major procedures in males) receiving IXINITY for perioperative management; some of the surgery subjects also participated in the treatment trial.

Of the 68 PTPs in the treatment group, subjects were primarily prescribed a routine prophylaxis (n = 58) or an on-demand regimen (n = 9); one subject was not assigned a regimen. Subjects were allowed to switch regimens during the course of the study. As a result, 61 subjects were treated at some point with routine prophylaxis treatment and 12 were treated at some point with an on-demand regimen. Subjects in the routine prophylaxis therapy group received mean intravenous doses of 55 ± 12.8 IU/kg of IXINITY twice weekly. Subjects in the on-demand therapy group received mean doses of 60 ± 18.2 IU/kg (median 59.3, interquartile range 49.9, 71.8) for bleeding episodes. The mean number of exposure days (ED) was 138.2 (median 127.5), including 45 subjects with ≥ 100 ED and 55 subjects with ≥ 50 ED. Median duration on study for the on-demand group was 14.1 months (range 2.3-36.9).

Annualized bleeding rates for PTPs ≥12 years of age in prophylaxis arm are summarized in Table 7.

PTP < 12 years of age

The PK, safety and efficacy of IXINITY for treatment of hemophilia B was evaluated in a prospective multi-center, multi-country study of 21 previously treated patients (PTPs) (10 subjects < 6 years of age and 11 subjects 6 to < 12 years of age). PTP were defined as patients who were exposed to a factor IX containing product for ≥ 50 exposure days (ED). All subjects had severe to moderately severe (factor ≤ 2%). Subjects with history of hypersensitivity reactions following exposure to factor IX-containing products, a known allergic reaction to hamster proteins, evidence of severe liver impairment, evidence of impaired renal function, CD4 count < 400 cells/mm3, or any coagulation defect other than hemophilia B, evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC) were excluded from the trial.

Subjects received IXINITY prophylaxis once to twice weekly, the recommended dose range was 35 – 75 IU/kg. Subjects < 6 years received a mean intravenous dose of 58 (45-72) ± 8.9 IU/kg and subjects 6 to < 12 received a mean intravenous dose of 52 (46-60) ± 11.6 IU/kg. Twenty-one subjects completed the PK analysis, and 19 subjects completed a minimum of 50 ED. The mean number of ED was 159 (median 163), including 16 subjects with ≥ 100 ED and 7 subjects with ≥ 200 ED.

Annualized bleeding rates for PTPs <12 years of age are summarized in Table 8.

Control of Bleeding Episodes

PTPs ≥ 12 years of age

A total of 508 bleeding episodes were treated with IXINITY, of which 286 bleeds were recorded for subjects treated with the routine prophylaxis treatment regimen and 222 with the on-demand regimen. Bleeding resolved in 360 episodes (70.9%) after a single infusion of IXINITY and in 66 (13.0%) episodes after two infusions. For 24 bleeding episodes (4.7%), five or more infusions were required; these 24 bleeding episodes were predominantly related to trauma, target joints, or muscle bleeds.

Hemostatic efficacy to resolve a bleed was rated by subjects as excellent or good in 84% of treated bleeding episodes. Excellent was defined as a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size, and good was defined as pain relief or reduction in hemorrhage size that may have required an additional infusion for resolution.

PTP < 12 years of age

There were 52 bleeding episodes; nine did not require treatment and resolved with IXINITY routine prophylaxis once or twice-weekly treatment. In 45 of 52 (86.5%) of the episodes, hemostasis was achieved with zero to two infusions. For four bleeding episodes (7.7%) three infusions were required, two episodes (3.8%) four infusions were required, and one episode (1.9%) required five infusions for resolution.

Hemostatic efficacy to resolve a bleed was rated by subjects as excellent or good in 41 (95%) of the 43 bleeding episodes that required treatment; two bleeding episodes did not have efficacy assessments. Excellent was defined as a dramatic response with abrupt pain relief and clear reduction in joint or bleeding site size and good was defined as pain relief or reduction in bleeding site size that may have required an additional infusion for resolution.

Perioperative Management

The efficacy analysis of IXINITY in perioperative management included 19 major surgeries performed in 16 male PTPs between 12 and 56 years of age (female carrier not included in efficacy analysis). Efficacy of IXINITY for support of major surgery was based on the surgeon’s assessment of efficacy including: a) at the time of surgery as estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’; and b) at 12 and 24 hours post-surgical assessments of hemostasis as ‘adequate’, ‘better than adequate’, or ‘poorly controlled’. Transfusion requirements to support surgery were also monitored. There were no transfusions required during the procedures.

IXINITY was administered during major surgical procedures as bolus (n = 13) or continuous infusion (n = 6). IXINITY was rated as adequate or better in controlling hemostasis post-surgery as assessed by the surgeon when used in various procedures, including, knee arthroplasty (n = 8), elbow arthroplasty (n = 2), knee amputation (n = 1), percutaneous Achilles tendon lengthening (n = 1), open inguinal hernia repair (n = 1), tibiotalar fusion (n = 1), arthroscopic synovectomy (n = 2), and debridement (ankle, knee) (n = 3). In all instances, blood loss at surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon.

1. Srivastava A, et al. World Federation of Hemophilia, Guidelines for the management of hemophilia. Haemophilia. 2013; 19(1):e1–e47.
2. Ingerslev J, Christiansen K, Ravn HB, et al. Antibodies to heterologous proteins in hemophilia A patients receiving recombinant factor VIII (Recombinate™). Thromb Haemost. 2002; 87:626–634.

IXINITY is supplied as a lyophilized powder in single-dose glass vials containing the labeled amount of factor IX activity, expressed in international units (IU). The actual factor IX activity in IU is stated on the label of each vial.

Kits include one single-dose vial (containing nominally 250, 500, 1000, 1500, 2000, or 3000 IU per vial), a 10 mL syringe pre-filled with 5 mL of Sterile Water for Injection with plunger rod attached, and a vial adapter with filter. None of the kit components are made with natural rubber latex.

250 IU strength only; store at 2 to 8°C (36 to 46°F).

500, 1000, 1500, 2000, and 3000 IU strengths: store at 2 to 25°C (36 to 77°F).

Do not freeze.

Keep the vial in the carton and protect from light.

Infuse reconstituted solution immediately or within 3 hours of storage at room temperature after reconstitution. Do not refrigerate after reconstitution.

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Inform patients of the early signs of hypersensitivity reactions (including hives, generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Instruct patients to discontinue use of the product and contact their physician if these symptoms occur.
• Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of clinical response to factor IX replacement therapy, as in some cases this may be a manifestation of an inhibitor.

Manufactured by:
Medexus Pharma, Inc.
Chicago, IL 60606
U.S. License No. 2220

IXINITY® [coagulation factor IX (recombinant)]

This leaflet summarizes important information about IXINITY. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about IXINITY. If you have any questions after reading this, ask your healthcare provider.

What is IXINITY?

IXINITY is a medicine used to replace clotting factor (factor IX) that is missing in people with hemophilia B. Hemophilia B is also called congenital factor IX deficiency or Christmas disease. Hemophilia B is an inherited bleeding disorder that prevents clotting.

Your healthcare provider may give you IXINITY when you have surgery.

Who should not use IXINITY?

You should not use IXINITY if you:

• Are allergic to hamsters
• Are allergic to any ingredients in IXINITY

Tell your healthcare provider if you are pregnant or breastfeeding because IXINITY may not be right for you.

What should I tell my healthcare provider before using IXINITY?

You should tell your healthcare provider if you:

• Have or have had any medical problems
• Take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies
• Have any allergies, including allergies to hamsters
• Are breastfeeding. It is not known if IXINITY passes into your milk and if it can harm your baby
• Are pregnant or planning to become pregnant. It is not known if IXINITY may harm your baby
• Have been told that you have inhibitors to factor IX (because IXINITY may not work for you)

How should I infuse IXINITY?

IXINITY is given directly into the bloodstream. IXINITY should be administered as ordered by your healthcare provider. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. Many people with hemophilia B learn to infuse their IXINITY by themselves or with the help of a family member.

See the step-by-step guide (Instructions for Use) provided at the end of this leaflet.

Your healthcare provider will tell you how much IXINITY to use based on your weight, the severity of you hemophilia B, and where you are bleeding. You may have to have blood tests done after getting IXINITY to be sure that your blood level of factor IX is high enough to stop the bleeding. Call you healthcare provider right away if your bleeding does not stop after taking IXINITY.

What are the possible side effects of IXINITY?

Allergic reactions may occur with IXINITY. Call your healthcare provider or get emergency treatment right away if you get any of the following symptoms: rash, hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, light-headedness, dizziness, nausea, or fainting.

Tell your healthcare provider about any side effect that bothers you or does not go away.

The most common side effect of IXINITY in clinical trials was headache.

These are not all the side effects possible with IXINITY. You can ask your healthcare provider for information that is written for healthcare professionals.

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

What are the IXINITY dosage strengths?

IXINITY comes in vials containing six different dosage strengths: 250, 500, 1000, 1500, 2000 and 3000 international units (IU). The actual strength will be printed on the label of the vial and on the box. The six different strengths in the vials are color coded as follows:

Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider.

How should I store IXINITY?

250 IU strength only; store at 2 to 8°C (36 to 46°F). Do not freeze.

500, 1000, 1500, 2000, and 3000 IU strengths; store at 2 to 25°C (36 to 77°F). Do not freeze.

Do not use IXINITY after the expiration date printed on the label. Throw away any unused IXINITY and diluents after it reaches this date.

Reconstituted product (after mixing dry product with Sterile Water for Injection) must be used within 3 hours and cannot be stored or refrigerated. Discard any IXINITY left in the vial at the end of your infusion.

What else should I know about IXINITY?

Your body may form inhibitors to factor IX. An inhibitor is part of the body’s immune system. If you form inhibitors, it may stop IXINITY from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests to check for the development of inhibitors to factor IX. Consult your doctor promptly if bleeding is not controlled with IXINITY as expected.

Medicines are sometimes prescribed for purposes other than those listed here. Do not use IXINITY for a condition for which it is not prescribed. Do not share IXINITY with other people, even if they have the same symptoms as you.

Resources available to patients

For information on patient assistance programs that may be available to you, please call our IXINITY Patient Care Center at 1-855-IXINITY (1-855-494-6489).

Manufactured by:
Medexus Pharma, Inc.
Chicago, IL 60606
U.S. License No. 2220

IXINITY [coagulation factor IX (recombinant)]

For intravenous use after reconstitution only

Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using IXINITY. If you are unsure of the procedures, please call your healthcare provider before using IXINITY. Your healthcare provider will prescribe the dose that you should take.

Before starting reconstitution and administration you will need the following items that are included in each kit of IXINITY:

• One (or more) vial(s) of IXINITY 250, 500, 1000, 1500, 2000, or 3000 IU powder, as prescribed by your healthcare provider
• One (or more) 10 mL syringe(s), pre-filled with 5 mL of Sterile Water for Injection (pre-filled syringe) with plunger rod attached
• Sterile vial adapter with filter

In addition, you will need the following items that are not included in the kit:

• One sterile LUER-LOK syringe (administration syringe); additional or larger syringes may be required if pooling multiple vials
• Sterile alcohol swabs
• Sterile infusion set
• Sterile gauze pad
• Sterile bandage

IXINITY is supplied in kits that include single-dose vials which contain vials of IXINITY (250, 500, 1000, 1500, 2000, or 3000 IU of powder), a 10 mL syringe pre-filled with 5 mL of Sterile Water for Injection with plunger rod attached (to be used for reconstitution only), and a sterile vial adapter with filter.

RECONSTITUTION INSTRUCTIONS

Wash your hands and then clean a flat area before starting the steps for reconstituting IXINITY. Use an aseptic technique during reconstitution.

1. Remove the pre-filled syringe and IXINITY vial from storage and allow them to reach room temperature before use. Check the expiration date on the IXINITY vial.

2. Remove the plastic cap from the IXINITY vial and place the vial top up on the clean surface. You will see a rubber circle on the top of the vial.

3. Wipe the top of the IXINITY vial with a sterile alcohol swab and allow it to dry. After cleaning, do not touch the rubber circle with your hands or allow it to touch another object.

4. Peel back the paper cover of the vial adapter package. Be careful not to touch the LUER-LOK (tip) in the center of the vial adapter. Do not remove the adapter from the package.

5. Leave the vial adapter in the package and place it open end up on the clean surface with the LUER-LOK pointing up.

6. Twist off the tip cap counterclockwise from the pre-filled syringe. Do not touch the inside of the cap or the syringe tip.

7. While firmly holding the package containing the adapter with one hand and the barrel of the pre-filled syringe with the other, 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, turning clockwise until the syringe is secured.

8. Carefully lift up the combined syringe-and-vial-adapter and remove it from the plastic package and discard packaging.

9. With one hand, continue to hold the combined syringe-and-vial-adapter. With the other hand, hold the IXINITY vial tightly on the clean, flat surface. Do not touch the top of the IXINITY vial or the filter spike of the combined syringe and vial adapter.

10. Place the vial adapter over the IXINITY vial on the table; firmly push the filter spike of the vial adapter through the center of the IXINITY vial rubber circle until the clear plastic cap snaps onto the IXINITY vial.

11. Slowly push the plunger rod down to transfer all of the liquid from the syringe into the IXINITY vial.

• With the syringe and the vial still attached, gently swirl, in a circular motion, the IXINITY vial until the product is fully dissolved. IXINITY is a clear, colorless solution without visible particles. Inspect the final solution for specks before administration. Do not use contents of vial if specks or particles persist after proper reconstitution.

12. NOTE: If you use more than one vial of IXINITY per infusion, reconstitute each vial as per the previous instructions.

13. Remove the diluent syringe from the vial adapter by turning syringe counterclockwise until it is completely detached. Do not touch the luer tip of the vial adapter.

14. Remove the LUER-LOK syringe (administration syringe) from its sterile packaging, taking care to not touch the luer tip of the syringe. Attach to the reconstituted vial and vial adapter by turning syringe clockwise until it is securely attached.

15. Press and keep the plunger down and turn the IXINITY vial/vial adapter/administration syringe upside down to transfer the solution. Draw up the solution into the administration syringe slowly until all solution is transferred into the syringe. Inspect the vial to confirm as much liquid as possible has been extracted into the administration syringe. NOTE: If you use more than one vial of IXINITY per infusion, extract reconstituted liquid from each vial, as per the previous instructions.

16. Hold onto the vial adapter with one hand and firmly grasp the administration syringe with the other and unscrew the administration syringe from the vial adapter turning either counterclockwise. Do not touch the tip of the syringe to any object or surface. NOTE: If multiple reconstituted vials are required for infusion, do not detach the large LUER-LOK administration syringe from the first vial until you are ready to attach the next vial (with vial adapter attached).

17. Prior to administering the solution, invert the administration syringe so that the tip is pointed toward the ceiling and express any air in the syringe. Place the administration syringe containing the IXINITY solution on the clean surface, making sure that the tip does not touch anything.

The reconstituted solution should be infused immediately or within 3 hours of storage at room temperature after reconstitution. NOTE: The luer tip of the syringe must not be touched by any objects or surfaces, when disconnecting the syringe from the vial adapter, and when transferring the administration syringe to the infusion set.

If you are using more than one vial, stop here and proceed to the Pooling Instructions.

POOLING INSTRUCTIONS

POOLING is the process of combining two or more reconstituted vials into a larger administration syringe prior to intravenous administration.

Do not detach the large LUER-LOK administration syringe until you are ready to attach the next vial (with vial adapter attached).

Follow the instructions above for reconstitution of the second vial.

1. Remove the administration syringe from the first vial adapter by turning it counterclockwise until it is completely detached.
2. Attach the administration syringe to the second reconstituted vial by turning clockwise until it is securely attached.
3. Turn the IXINITY vial/vial adapter/administration syringe upside down, slowly pull on the plunger rod to draw the solution into the administration syringe (see Step 15 above).

Repeat this POOLING procedure with each vial you will be using.

Once you have pooled the required dose, proceed to administration using the administration syringe.

ADMINISTRATION INSTRUCTIONS

For intravenous use after reconstitution only.

IXINITY is administered by intravenous (IV) infusion after reconstitution with diluent (Sterile Water for Injection) supplied in the pre-filled syringe.

IXINITY must not be mixed with other medicinal products for infusion.

Reconstituted IXINITY must be pulled into an administration syringe prior to infusion.

IXINITY is normally administered intravenously over about 5 minutes at a maximum infusion rate of 10 mL per minute. The infusion rate should be adapted to the comfort level of each patient.

1. Attach the administration syringe containing the reconstituted IXINITY solution to the luer end of the sterile infusion set. Inspect for and remove any air bubbles in the infusion set and administration syringe. NOTE: The luer tip of the administration syringe and the luer connection of the infusion set must not be touched by any object or surface, prior to connection of the administration syringe.
2. Transfer IXINITY solution into the tube by pressing the syringe plunger until the tubing is completely filled. Once again, inspect for and remove any air bubbles in the infusion set and administration syringe.
3. Perform venipuncture as directed by your healthcare provider.
4. Limit the amount of blood entering the tubing. Blood must never enter the syringe. If blood is observed in the tubing or syringe, discard all material and resume administration with a new package.
5. Following completion of the infusion, remove the infusion set, press the sterile gauze on the infusion site until bleeding has stopped, then apply a sterile bandage. The amount of drug product remaining in the infusion set should be minimal. Log the batch number of the IXINITY used; it is located on the container.

Dispose of all unused solution, empty vials, and used needles and syringes in an appropriate container for throwing away medical waste as it may hurt others if not handled properly.

Contact your healthcare provider or local hemophilia treatment center if you experience any problems.

IXINITY® coagulation factor IX (recombinant) and any and all Medexus Pharma, Inc. brand, product, service and feature names, logos, and slogans are trademarks or registered trademarks of Medexus Pharma, Inc. in the United States or other countries. All rights reserved.

LUER-LOK™ is a trademark of Becton, Dickinson and Company. All other brand, product, service and feature names or trademarks are the property of their respective owners.

Manufactured by:
Medexus Pharma, Inc.
Chicago, IL 60606
U.S. License No. 2220