Ixinity

Dosage Forms And Strengths

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

Storage And Handling

IXINITY is supplied as a lyophilized powder in single-use 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 or two single-use vials (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, vial adapter with filter, and a sterile 20 mL LUER-LOK Administration Syringe. All of the kit components are not 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.

REFERENCES

1. Srivastava A, et al. World Federation of Hemophilia, Guidelines for the management of hemophilia. Haemophilia. 2013; 19: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.

Manufactured by: Aptevo BioTherapeutics LLC Berwyn PA, 19312 U.S. Revised: Aug 2016

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• how you respond to this medication
• the severity of your factor IX deficiency
• your weight

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

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 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

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 (2). 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.

Read the entire FDA prescribing information for Ixinity ([Coagulation Factor IX (Recombinant)] for Injection)

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Your doctor may want to give your first dose of this medicine in a hospital or clinic setting to quickly treat any serious side effects that occur.

Coagulation factor IX is injected into a vein through an IV. You may be shown how to use an IV at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Coagulation factor IX is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

The mixture should appear clear, yellow, or colorless. Do not use the mixed medicine if it has changed colors or has particles in it. Prepare a new kit or call your pharmacist for a new supply of coagulation factor IX.

Gently swirl but do not shake the medicine bottle when mixing or you may ruin the medicine. Use the injection within 3 hours after mixing your dose.

Coagulation factor IX comes with patient instructions for proper mixing and storage. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Use a disposable needle only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

While using coagulation factor IX, you may need frequent blood tests.

Wear a medical alert tag or carry an ID card stating that you have hemophilia. Any medical care provider who treats you should know that you have a bleeding disorder.

If you store this medicine at home, carefully follow the directions on your medicine label about how to store the powder medicine and the diluent. Some forms of coagulation factor IX can be stored at room temperature, and others should be kept in a refrigerator. Do not freeze. Avoid exposing the medication to light.

Each single-use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Throw away any coagulation factor IX not used before the expiration date on the medicine label.

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

• Store in a refrigerator or at room temperature.
• Do not freeze.
• Be sure you know how long you can store Ixinity if stored in a refrigerator or at room temperature.
• If stored at room temperature, make a note of the date it was placed at room temperature.
• Do not put this medicine back in the refrigerator after it has been stored at room temperature.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• 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 Ixinity, 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 Ixinity. 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 Ixinity (factor IX (recombinant)).

Review Date: October 4, 2017

Pregnancy

Risk Summary

There are no data with Ixinity use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with Ixinity.

In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

Risk Summary

There is no information regarding the presence of Ixinity in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ixinity and any potential adverse effects on the breastfed infant from Ixinity or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of Ixinity in pediatric patients below the age of 12 years have not been established.

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)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

No macroscopic or microscopic pathologies in reproductive organs were observed in repeated dose toxicity studies of Ixinity in animals. Animal studies regarding impairment of fertility were not conducted.

No nonclinical investigations of genotoxicity, carcinogenicity, or toxicity to reproduction and development have been conducted with Ixinity.

1. Srivastava A, et al. World Federation of Hemophilia, Guidelines for the management of hemophilia. Haemophilia. 2013; 19: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.

• 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:
Aptevo BioTherapeutics LLC
Berwyn, PA 19312
U.S. License No. 2054

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:

• 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
• One sterile 20 mL LUER-LOK syringe (Administration Syringe)
• Sterile alcohol swabs
• Sterile infusion set
• Sterile gauze pad
• Sterile bandage

Ixinity is supplied in kits that include single-use 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), a sterile vial adapter with filter and a sterile 20 mL LUER-LOK syringe (Administration Syringe).

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 separate large 20 mL LUER-LOK syringe (Administration Syringe) from the 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.

If you are using more than three vials you may need a larger Administration Syringe (i.e. larger than 20 mL) which is not included.

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 counter clockwise 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 the 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 Aptevo BioTherapeutics LLC brand, product, service and feature names, logos, and slogans are trademarks or registered trademarks of Aptevo BioTherapeutics LLC 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:
Aptevo BioTherapeutics LLC
Berwyn, PA 19312
U.S. License No. 2054

More frequent side effects include: dizziness, nausea, skin rash, and urticaria. See below for a comprehensive list of adverse effects.