Antihemophilic Factor

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ADYNOVATE
[Antihemophilic Factor (Recombinant), PEGylated]

This leaflet summarizes important information about ADYNOVATE. 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 ADYNOVATE. If you have any questions after reading this, ask your healthcare provider.

What is the most important information I need to know about ADYNOVATE?

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

You must carefully follow your healthcare provider's instructions regarding the dose and schedule for infusing ADYNOVATE so that your treatment will work best for you.

What is ADYNOVATE?

ADYNOVATE is an injectable medicine used to replace clotting factor (factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally.

ADYNOVATE is used on-demand to control bleeding in patients 12 years of age and older with hemophilia A. ADYNOVATE can reduce the number of bleeding episodes when used regularly (prophylaxis).

ADYNOVATE is not used to treat von Willebrand disease.

Who should not use ADYNOVATE?

You should not use ADYNOVATE if you:

• Are allergic to mice or hamster protein
• Are allergic to any ingredients in ADYNOVATE or ADVATE

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

How should I use ADYNOVATE?

ADYNOVATE is given directly into the bloodstream.

You may infuse ADYNOVATE at a hemophilia treatment center, at your healthcare provider's office or in your home. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center. Many people with hemophilia A learn to infuse their ADYNOVATE by themselves or with the help of a family member.

Your healthcare provider will tell you how much ADYNOVATE to use based on your individual weight, level of physical activity, the severity of your hemophilia A, and where you are bleeding.

Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated. Discard any ADYNOVATE left in the vial at the end of your infusion as directed by your healthcare professional.

You may have to have blood tests done after getting ADYNOVATE to be sure that your blood level of factor VIII is high enough to clot your blood.

Call your healthcare provider right away if your bleeding does not stop after taking ADYNOVATE.

What should I tell my healthcare provider before I use ADYNOVATE?

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 overthe- counter medicines, supplements or herbal remedies.
• Have any allergies, including allergies to mice or hamsters.
• Are breastfeeding. It is not known if ADYNOVATE passes into your milk and if it can harm your baby.
• Are pregnant or planning to become pregnant.  It is not known if ADYNOVATE may harm your unborn baby.
• Have been told that you have inhibitors to factor VIII (because ADYNOVATE may not work for you).

What are the possible side effects of ADYNOVATE?

You can have an allergic reaction to ADYNOVATE.

Call your healthcare provider right away and stop treatment if you get a rash or hives, itching, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea or fainting.

The common side effect of ADYNOVATE is headache and nausea. Tell your healthcare provider about any side effects that bother you or do not go away.

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

What are the ADYNOVATE dosage strengths?

ADYNOVATE comes in four different dosage strengths: 250 International Units (IU), 500 IU, 1000 IU, and 2000 IU. The actual strength will be imprinted on the label and on the box. The four different strengths are color coded, as follows:

Dosage strength of approximately 250 International Units per vial (200-400 IU/vial)

Dosage strength of approximately 500 International Units per vial (401-800 IU/vial)

Dosage strength of approximately 1000 International Units per vial (801-1250 IU/vial)

Dosage strength of approximately 2000 International Units per vial (1251-2500 IU/vial)

Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider. Always check the expiration date printed on the box. Do not use the product after the expiration date printed on the box.

How do I store ADYNOVATE?

• Do not freeze.
• Store at refrigerated temperature 2°C to 8°C (36°F to 46°F).
• May store at room temperature not to exceed 30°C (86°F) for up to 1 month.
  • Write the date on the carton when ADYNOVATE is removed from refrigeration.
  • After storage at room temperature, do not return product back to the refrigerator.
• Do not use beyond the expiration date printed on the carton or vial.
• Store vials in their original box and protect them from extreme exposure to light.

What else should I know about ADYNOVATE and Hemophilia A?

Your body may form inhibitors to Factor VIII. An inhibitor is part of the body's normal defense system. If you form inhibitors, it may stop ADYNOVATE from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to Factor VIII.

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

Instructions for Use

ADYNOVATE
[Antihemophilic Factor (Recombinant), PEGylated] (For intravenous use only)

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

Step-by-step instructions for reconstituting ADYNOVATE are found at the end of this leafl et.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using ADYNOVATE. If you are unsure of the procedures, please call your healthcare provider before using.

Call your healthcare provider right away if bleeding is not controlled after using ADYNOVATE.

Your healthcare provider will prescribe the dose that you should take.

Reconstituted product (after mixing dry product with wet diluent) must be used within 3 hours and cannot be stored or refrigerated.

Your healthcare provider may need to take blood tests from time to time.

Talk to your healthcare provider before traveling. Plan to bring enough ADYNOVATE for your treatment during this time.

Dispose of all materials, including any leftover reconstituted ADYNOVATE product, in an appropriate container.

1. Prepare a clean fl at surface and gather all the materials you will need for the infusion.

• Check the expiration date, and let the vials with the ADYNOVATE concentrate and the Sterile Water for Injection, USP (diluent) warm up to room temperature.
• Wash your hands and put on clean exam gloves. If infusing yourself at home, the use of gloves is optional.
• If you are using more than one vial of ADYNOVATE, make sure you mix each vial of ADYNOVATE with the Sterile Water for Injection, USP that is provided in the box.
• Inspect the contents of the product and diluent vials. The ADYNOVATE powder should be white to off-white in color and the diluent should not contain particles. Do not use if discoloration or particles are seen.

2. Remove caps from the ADYNOVATE concentrate and diluents vials to expose the centers of the rubber stoppers.

3. Disinfect the stoppers with a sterile alcohol prep pad (or other suitable solution suggested by your healthcare provider or hemophilia center) by rubbing the stoppers firmly for several seconds and allow them to dry prior to use. Place the vials on a flat surface.

4. Open the BAXJECT II Hi-Flow device package by completely peeling away the lid, without touching the inside of the package. Do not remove the BAXJECT II Hi-flow device from the package.

5. Turn the package with the BAXJECT II Hi-Flow device upside down and place it over the top of the diluent vial. Fully insert the clear plastic spike of the device into the center of the diluent vial's stopper by pushing straight down. Grip the package at its edge and lift it off the device. Be careful not to touch the purple plastic spike. Do not remove the blue cap from the BAXJECT II Hi-Flow device. The diluent vial now has the BAXJECT II Hi-Flow device connected to it and is ready to be connected to the ADYNOVATE vial.

6. To connect the diluent vial to the ADYNOVATE vial, turn the diluent vial over and place it on top of the vial containing ADYNOVATE concentrate. Fully insert the purple plastic spike into the ADYNOVATE vial's stopper by pushing straight down. Diluent will flow into the ADYNOVATE vial. This should be done right away to keep the liquid free of germs.

7. Swirl the connected vials gently and continuously until the ADYNOVATE is completely dissolved. Do not shake.

8. Take off the blue cap from the BAXJECT II Hi-Flow device and connect the syringe. Use of a Luer-lock syringe is recommended. Be careful to not inject air.

9. Turn over the connected vials so that the ADYNOVATE vial is on top. Draw the ADYNOVATE solution into the syringe by pulling back the plunger slowly. Disconnect the syringe from the vials. Attach the infusion needle to the syringe using a winged (butterfly) infusion set, if available. Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle. The ADYNOVATE solution should look clear and colorless. If not, do not use it and notify Baxalta immediately.

10. If you are using more than one vial of ADYNOVATE, the contents of more than one vial may be drawn into the same syringe (Following Steps 1-9). You will need a separate BAXJECT II Hi-Flow device to mix each additional vial of ADYNOVATE. Apply a tourniquet and get the injection site ready by wiping the skin well with a sterile alcohol prep pad (or other suitable solution suggested by your healthcare provider or hemophilia center).

11. Insert the needle into the vein and remove the tourniquet. Slowly infuse the ADYNOVATE. Do not infuse any faster than 10 mL per minute.

12. Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes.

13. Do not recap the needle. Place it with the used syringe in a hard-walled Sharps container for proper disposal.

14. Remove the peel-off label from the ADYNOVATE vial and place it in your logbook. Clean any spilled blood with a freshly prepared mixture of 1 part bleach and 9 parts water, soap and water, or any household disinfecting solution.

15. Dispose of the used vials and BAXJECT II Hi-Flow device in your hard-walled sharps container without taking them apart. Do not dispose of these supplies in ordinary household trash.

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

Monoclate-P® is supplied in a single dose vial with Sterile Water for Injection, USP, double-ended needle for reconstitution, vented filter spike for withdrawal, filter needle for withdrawal, winged infusion set and alcohol swabs. Factor VIII activity in IU is stated on the label of each vial.

Each product package consists of the following:

Bibliography

Hershman, R.J., Naconti, S.B., and Shulman, N.R. Prophylactic Treatment of Factor VIII Defi ciency. Blood 35, (1970), p. 189.

Kasper, C.K. Dietrich, S.I. and Rapaport, S.K. Hemophilia Prophylaxis in Factor VIII Concentrate. Arch Int Med 125, (1970), p. 1004.

Biggs, R. ed. The Treatment of Hemophilia A and B and von Willebrands Disease. Oxford: Blackwell, 1978.

Fulcher, C.A., Zimmerman, T.S., Characterization of the Human Factor VIII Procoagulant Protein With A Heterologous Precipitating Antibody. Proc Natl Acad Sci 79 (1982), pp. 1648-1652. Levine, P.H., Factor VIII C Purifi ed from Plasma Via Monoclonal Antibodies Human Studies. Semin Hematol 25 (2 Suppl. 1), 1988, pp. 38-41.

REFERENCES

10. C.F. Abilgaard, J.V. Simone, J.J. Corrigan, et al., Treatment of Hemophilia with Glycine - Precipitated Factor VIII, New Eng J Med, 275 (1966), p. 471.

11. C.K. Kasper, Hematologic Care, Comprehensive Management of Hemophilia, ed. Boone, D.C., Philadelphia, F.A. Davis Co., (1976) pp. 2-20.

Manufactured by: CSL Behring LLC, Kankakee, IL 60901 USA, US License No. 1767. Revised: Feb, 2014

Mechanism Of Action

Kogenate FS temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.

Pharmacodynamics

The aPTT is prolonged in patients with hemophilia. Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay for biological activity of factor VIII. Treatment with Kogenate FS normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetic properties of Kogenate FS were investigated in two separate studies in previously treated patients, adults and children.

Pharmacokinetic studies with Kogenate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A in North America. The pharmacokinetic parameters for Kogenate FS were measured in a randomized, crossover clinical trial with the predecessor KOGENATE product with a single dose administration of 50 IU/kg. After 24 weeks, the same dose of Kogenate FS was administered to the same patients. The recovery and half-life data for Kogenate FS were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition. [See Table 9.]

Table 9 : Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE

The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4-18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. This might be explained by differences in body composition such as body surface area and plasma volume. The pharmacokinetic parameters are depicted in Table 10.

Table 10 : Pharmacokinetic Parameters for Kogenate FS in Children

Clinical Studies

Previously Treated Patients

A total of 73 patients with severe ( ≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54-months in open label studies with Kogenate FS in Europe and North America. A total of 5,684 bleeding episodes were treated during the studies. Patients could be treated on demand or on prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week). [See Table 11.]

Table 11 : Previously Treated Patients (PTPs) Clinical Trial Results

A total of 30 patients received Kogenate FS for 41 surgical procedures during the PTP studies. There were both minor and major surgery types, 16 and 25 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent”, “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Previously Untreated And Minimally Treated Patients

Kogenate FS has been used in the treatment of bleeding episodes in pediatric previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe ( < 2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Kogenate FS for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated.

Table 12 : Previously Untreated and Minimally Treated Patients (PUPs and MTPs) Clinical Trial Results

A total of 27 surgical procedures were performed in 22 patients during the PUPs and MTPs study. There were both minor and major surgery types, 21 and 6 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent,” “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Table 13 : Surgical Procedures Performed During PTPs and PUPs/MTPs Clinical Trials

Pediatric Prophylaxis And Joint Damage Risk Reduction

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU/kg every other day (primary prophylaxis; n=32) or at least 3 doses totaling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n=33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p=0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).

As shown in Table 14 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.

To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.,22 and X-rays were scored using the method of Pettersson et al.23 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥ 1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

Table 14 : Subjects with Joint Damage (Subjects with Available Baseline and Endpoint Data)

Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy.

P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups.

As shown in Table 15 below, the assessment of endpoints in all randomized subjects assuming that those without complete baseline and endpoint data are treatment failures (intention-to-treat analysis). The incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group, with similar pvalues, when assessed by MRI, or either MRI or radiography.

Table 15 : Subjects with Joint Damage (All Randomized Subjects Assuming Subjects without Complete Baseline and Endpoint Data as Treatment Failures)

Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy.

P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups.

REFERENCES

22. Nuss R, Kilcoyne RF, Geraghty S, et al: MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia 6:162-169, 2000.

23. Pettersson H, Ahlberg A, Nilsson IM: A radiologic classification of hemophilia arthropathy. Clin Orthop Relat Res 149:153-159, 1980.

During the clinical studies conducted in the previously treated patient group, there were 13 infusion related minor adverse reactions reported out of 10,446 infusions (0.12%).

One patient experienced flushing and nausea during his first infusion which abated on decreasing the infusion rate. A second patient experienced mild fatigue during and following one infusion and a third patient had a series of eleven nose bleeds with a periodicity associated with the infusions.

The protein in greatest concentration in RECOMBINATE (antihemophilic factor (recombinant)) rAHF is Albumin (Human). Reactions associated with intravenous administration of albumin are extremely rare, although nausea, fever, chills or urticaria have been reported. Other allergic reactions could theoretically be encountered in the use of this Antihemophilic Factor preparation. See Information for Patients.

ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a sterile, non-pyrogenic, lyophilized powder for reconstitution for intravenous injection. The product is supplied in single use vials containing nominal potencies of 250, 500, 750, 1000, 1500, 2000 or 3000 international units (IU). Each vial of ELOCTATE is labeled with the actual content in IU. The powder for injection is reconstituted with 3 mL sterile water for injection (SWFI) supplied in a sterile prefilled syringe. The reconstituted product contains the excipients: sucrose, sodium chloride, L-histidine, calcium chloride and polysorbate 20. ELOCTATE contains no preservatives.

B-domain deleted recombinant Factor VIII, Fc fusion protein (BDD-rFVIIIFc) is the active ingredient in ELOCTATE. BDD-rFVIIIFc is a recombinant protein consisting of a B-domain deleted analogue of human Coagulation Factor VIII covalently linked to the human immunoglobulin G1 (IgG1) Fc domain sequence. The Factor VIII portion of the molecule has a 90 kDa heavy chain and an 80 kDa light chain (similar to endogenous Factor VIII), which are linked by 14 (of 908) amino acids from the central B-domain. The FVIII portion has post-translational modifications comparable to endogenous Factor VIII. The Fc domain of the molecule contains the hinge, CH2, and CH3 regions of IgG1. BDD-rFVIIIFc contains 1890 amino acids with an apparent molecular weight of 220 kDa. The majority of the expressed protein is proteolytically processed to a two chain molecule; however ELOCTATE may also contain up to 39% of a single chain, non-processed form. Both molecules have been shown to have comparable Factor VIII activity.

BDD-rFVIIIFc is produced by recombinant DNA technology from a human embryonic kidney (HEK) cell line, which has been extensively characterized. The HEK cell line expresses BDD-rFVIIIFc into a defined, cell culture medium that does not contain any proteins derived from animal or human sources. BDD-rFVIIIFc is purified using a series of chromatography steps, including affinity capture with a recombinant, single chain antibody fragment produced in a yeast expression system. No human or animal derived proteins are used in the purification or formulation processes. The production process also incorporates two dedicated viral clearance steps - a detergent treatment step for inactivation and a 15 nm filtration step for removal of viruses.

Do not use this medicine if you have ever had a severe allergic reaction to antihemophilic factor in the past, or if you are allergic to mouse proteins.

Before using human antihemophilic factor, your specific blood clotting disorder must be diagnosed as factor VIII deficiency. Human antihemophilic factor will not treat von Willebrand disease.

FDA pregnancy category C. It is not known whether antihemophilic factor will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether human antihemophilic factor passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

This medicine is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Your doctor may want you to receive a hepatitis vaccination before you start using human antihemophilic factor.

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© Helixate FS Patient Information is supplied by Cerner Multum, Inc. and Helixate FS Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Do not use this medication if you have ever had a severe allergic reaction to antihemophilic factor in the past, or if you are allergic to mouse or beef proteins.

Before using recombinant antihemophilic factor, your specific blood clotting disorder must be diagnosed as factor VIII deficiency. Recombinant antihemophilic factor will not treat von Willebrand disease.

FDA pregnancy category C. It is not known whether recombinant antihemophilic factor will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether recombinant antihemophilic factor passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

• Hemophilia