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Please see full Prescribing Information at the end of this document.Bayer, the Bayer Cross, and KOVALTRY are registered trademarks of Bayer. © 2016 Bayer. All rights reserved.06/16 PP-675-US-0464

1. Indications and Usage

2. Dosage and Administration

3. Dosage Forms and Strengths 4. Contraindications 5. Warnings

and Precautions 6. Adverse Reactions 8. Use in Specific Populations

11. Description 12. Clinical Pharmacology

13. Nonclinical Toxicology 14. Clinical Studies 16. How Supplied /

Storage and Handling17. Patient Counseling

Information

Highlights of Prescribing Information

KOVALTRY® Indications and Important Safety Information

KOVALTRY® Prescribing Information

INDICATIONS KOVALTRY® Antihemophilic Factor (Recombinant) is a recombinant human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A for:

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

KOVALTRY® is not indicated for the treatment of von Willebrand disease.

IMPORTANT SAFETY INFORMATION KOVALTRY® is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins. Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY®. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY® if symptoms occur and seek immediate emergency treatment. KOVALTRY® may contain trace amounts of mouse and hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY®. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor. Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII. Catheter-related infections may occur when KOVALTRY® is administered via central venous access devices (CVADs). These infections have not been associated with the product itself. The most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus.

For additional important risk and use information, please see full Prescribing Information at the end of this document.You are encouraged to report negative side effects or quality complaints of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

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Please see full Prescribing Information at the end of this document.Bayer, the Bayer Cross, and KOVALTRY are registered trademarks of Bayer. © 2016 Bayer. All rights reserved.06/16 PP-675-US-0464

Tabbed Prescribing Information Tool











Information

Please see full Prescribing Information at the end of this document.

These highlights do not include all the information needed to use KOVALTRY safely and effectively. See full prescribing information for KOVALTRY.KOVALTRY [Antihemophilic Factor (Recombinant)]Lyophilized Powder for Solution for Intravenous Injection – Reconstitution with Vial AdapterInitial U.S. Approval: 2016

INDICATIONS AND USAGEKOVALTRY®, Antihemophilic Factor (Recombinant) is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for:


KOVALTRY is not indicated for the treatment of von Willebrand disease (1).

DOSAGE AND ADMINISTRATIONFor intravenous use after reconstitution only.Control of bleeding episodes and perioperative management (2.1)

Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL) x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg). Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg).

Routine prophylaxis (2.1) Adults and adolescents: 20-40 IU/kg 2 or 3 times per week. Children ≤12 years old: 25-50 IU/kg 2 times per week, 3 times per week or every other day.

DOSAGE FORMS AND STRENGTHSKOVALTRY is available as lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000, and 3000 IU. Each vial of KOVALTRY contains the labeled amount of recombinant Factor VIII in IU (3).

CONTRAINDICATIONSDo not use in patients who have history of hypersensitivity reactions to the active substance, mouse or hamster protein, or other constituents of the product (4).

WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, discontinue treatment with KOVALTRY and administer appropriate treatment (5.1). Development of Factor VIII neutralizing antibodies can occur. Perform an assay that measures Factor VIII inhibitor concentration if expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled as expected with administered dose (5.2, 5.5).

ADVERSE REACTIONSThe most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus (6).

To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONSPediatric Use: Due to higher clearance (body weight adjusted) in children ≤12 years of age, higher or more frequent dosing may be needed (8.4).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling of the full Prescribing Information

Revised: 3/2016

HIGHLIGHTS OF PRESCRIBING INFORMATION < 1/2 >











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FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dose 2.2 Preparation and Reconstitution 2.3 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions 5.2 Neutralizing Antibodies 5.3 Cardiovascular Risk Factors 5.4 Catheter-related Infections 5.5 Monitoring Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 On-demand Treatment and Control of Bleeding Episodes 14.2 Perioperative Management 14.3 Routine Prophylaxis

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed

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INDICATIONS AND USAGE

1 INDICATIONS AND USAGEKOVALTRY, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for:


KOVALTRY is not indicated for the treatment of von Willebrand disease.

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DOSAGE AND ADMINISTRATION

2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only.

2.1 Dose Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. Each vial label of KOVALTRY states the Factor VIII potency in international units (IU). One IU is defined by the current WHO (World Health Organization) international standard (IS) for Factor VIII concentrate. Potency assignment for KOVALTRY is determined using a chromogenic substrate assay. A field study involving 41 clinical laboratories from around the world measured recoveries of KOVALTRY spiked into hemophilic plasma. The results of the field study indicated that the Factor VIII activity of KOVALTRY can be accurately measured in plasma using either a one-stage clotting or chromogenic substrate assay according to routine methods of the testing laboratory. The required dose for a desired Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL)

x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg)

The expected in vivo peak increase of Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

Estimated increment of Factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)

Examples (assuming patient’s baseline Factor VIII is <1%):1. A peak of 50% is required in a 20 kg child. In this situation, the required

dose of KOVALTRY would be 20 kg x 50 IU/dL x 0.5% (for recovery of 2 IU/dL per IU/dL) = 500 IU

2. A dose of 2000 IU of KOVALTRY administered to a 50 kg patient should be expected to result in post-infusion Factor VIII increase of 2000 IU / 50 kg (body weight) x 2 IU/dL per IU/kg = 80 IU/dL (80% of normal)

Adjust dose to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, incremental recovery) and clinical responses to KOVALTRY.

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On-demand Treatment and Control of Bleeding Episodes A guide for dosing KOVALTRY for the on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

Table 1: Dosing for Control of Bleeding Episodes

Degree of Bleeding

Factor VIII Level Required (IU/dL or % of

normal)

Frequency of Doses(hours)

Duration of Therapy

(days)

Minor (Early hemarthrosis, minor muscle, oral bleeds) 20–40 Repeat every

12–24 hours

At least 1 day, until bleeding episode as indicated by pain is resolved or healing is achieved

Moderate (More extensive hemarthrosis, muscle bleeding, or hematoma)

30–60 Repeat every 12–24 hours

3 to 4 days or more until pain and acute disability are resolved

Major (intracranial, intra-abdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, life or limb threatening hemorrhage)

60–100 Repeat every 8–24 hours

Until bleeding is resolved

DOSAGE AND ADMINISTRATION (CONT’D)

Perioperative Management of Bleeding A guide for dosing KOVALTRY during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate laboratory tests, including serial Factor VIII activity assays, is highly recommended [see Warnings and Precautions (5.5)].

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DOSAGE AND ADMINISTRATION (CONT’D)

2.2 Preparation and Reconstitution Reconstitute and administer KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component. For any questions about the handling, reconstitution and administration of KOVALTRY, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).

The procedures below are provided as general guidelines for the reconstitution of KOVALTRY using the sterile vial adapter with a 15 micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

Usability Testing of Vial AdapterUsability testing was conducted with 60 users, including 15 pediatric hemophilia A patients (between 10-17 years of age), 15 adult hemophilia A patients (≥18 years of age), 15 caregivers, and 15 healthcare providers. To mimic real life, the pediatric and adult patients and the caregivers were given minimal training, which included participants performing a supervised reconstitution and later performing a single unaided reconstitution. Healthcare providers were untrained in this study and could learn the procedure from the provided Instructions for Use. All participants were able to successfully and safely use the vial adapter device for reconstitution.

Table 2: Dosing for Perioperative Management

Type of Surgery


normal)

Frequency of Doses(hours)

Duration of Therapy

(days)

Minor (Such as tooth extraction)

30–60 (pre- and post-

operative)

Repeat every 24 hours

At least 1 day until healing is achieved

Major (Such as intracranial, intra- abdominal, intrathoracic, or joint replacement surgery)


operative)

Repeat every 8–24 hours

Until adequate wound healing is complete, then continue therapy for at least another 7 days to maintain FVIII activity of 30–60% (IU/dL)

Routine Prophylaxis Individualize the patient’s dose based on clinical response. Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or three times per week. Children ≤12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice weekly, three times weekly, or every other day according to individual requirements [see Use in Specific Populations (8.4)].

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Reconstitution Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures. Reconstitute KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component. Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.

1. Warm both unopened KOVALTRY vial and prefilled diluent syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F).

8. Inject the diluent slowly by pushing down on the plunger rod (G).

Pooling If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. Use a larger plastic syringe (not provided) to combine the content of the vials into the syringe.

DOSAGE AND ADMINISTRATION (CONT’D) < 4/5 >

Note: follow instructions for infusion set provided.

2. Remove the protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper.

3. Place the product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.

4. Holding the syringe by the barrel, snap the syringe cap off the tip (C). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use.

5. Now remove and discard the adapter plastic housing (D).

6. Attach the prefilled syringe to the vial adapter thread by turning clockwise (E).

7. Remove the clear plastic plunger rod from the carton. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Attach the plunger rod by turning it clockwise into the threaded rubber stopper of the prefilled syringe (F).

9. Swirl vial gently until all powder on all sides of the vial is dissolved (H). Do not shake vial. Be sure that all powder is completely dissolved. Do not use if solution contains visible particles or is cloudy.

10. Push down on the plunger to push all air back into the vial. Then while holding the plunger down, turn the vial with syringe upside-down (invert) so the vial is now above the syringe (I).

11. Withdraw all the solution into the syringe by pulling the plunger rod back slowly and smoothly (J). Tilt the vial to the side and back to make sure all the solution has been drawn toward the large opening in the rubber stopper and into the syringe. Remove as much air as possible before removing the syringe from the vial by slowly and carefully pushing the air back into the vial.

12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K).











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2.3 AdministrationFor intravenous use only.

Inspect reconstituted KOVALTRY visually for particulate matter and discoloration prior to administration. Do not use if you notice any particulate matter or discoloration and immediately contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937). Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours. Infuse KOVALTRY intravenously over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient.

DOSAGE AND ADMINISTRATION (CONT’D) < 5/5 >











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3 DOSAGE FORMS AND STRENGTHSKOVALTRY is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000, 2000, or 3000 IU of recombinant Factor VIII per vial.Each vial of KOVALTRY is labeled with actual Factor VIII potency expressed in IU determined using a chromogenic substrate assay. This potency assignment employs a Factor VIII concentrate standard that is referenced to the current WHO International Standard for Factor VIII concentrate, and is evaluated by appropriate methodology to ensure accuracy of the results.

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4 CONTRAINDICATIONSKOVALTRY is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins [see Description (11)].

CONTRAINDICATIONS < 1/1 >











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5 WARNINGS AND PRECAUTIONS5.1 Hypersensitivity ReactionsHypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY if symptoms occur and seek immediate emergency treatment.KOVALTRY may contain trace amounts of mouse and hamster proteins [see Description (11)]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

5.2 Neutralizing AntibodiesNeutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products [see Adverse Reactions (6.1)]. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor (neutralizing antibody) [see Warnings and Precautions (5.5)].

5.3 Cardiovascular Risk FactorsHemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII.

5.4 Catheter-related InfectionsCatheter-related infections may be observed when KOVALTRY is administered via central venous access devices (CVADs). These infections have not been associated with the product itself.

5.5 Monitoring Laboratory Tests Monitor plasma Factor VIII activity levels using a validated test to confirm that adequate Factor VIII levels have been achieved and maintained [see Dosage and Administration (2.1)]. Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of KOVALTRY. Use Bethesda Units (BU) to report inhibitor titers.

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6 ADVERSE REACTIONSThe most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus (see Table 3).

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety profile of KOVALTRY was evaluated in 193 previously treated patients (PTPs) (inclusive of 51 pediatric patients <12 years of age) with at least three months of exposure to KOVALTRY. The safety analysis was done using a pooled database from three multi-center, prospective, open-label clinical studies. The median time on study for patients ≥12 years of age was 372 days with a median of 159 exposure days (EDs). The median time on study for patients <12 years of age was 182 days with a median of 73 EDs. Subjects who received KOVALTRY for perioperative management (n=5) with treatment period of 2 to 3 weeks and those who received single doses of KOVALTRY for PK studies (n=6) were excluded from safety analysis. Table 3 lists the adverse reactions reported during clinical studies. The frequency, type, and severity of adverse reactions in children are similar to those in adults.

ADVERSE REACTIONS < 1/2 >

Table 3: Adverse Reactions in Previously Treated Patients (N=193)

MedDRA Primary System Organ ClassPreferred term

Frequency N (%)

Blood and the Lymphatic System DisordersLymphadenopathy

2 (1.0%)

Cardiac DisordersPalpitationSinus tachycardia

2 (1.0%)2 (1.0%)

Gastrointestinal DisordersAbdominal painAbdominal discomfortDyspepsia

4 (2.1%)3 (1.6%)4 (2.1%)

Table 3: Adverse Reactions in Previously Treated Patients (N=193) (CONT’D)

MedDRA Primary System Organ ClassPreferred term

Frequency N (%)

General Disorders and Administration Site ConditionsPyrexiaChest discomfortInjection site reactionsa

8 (4.1%)2 (1.0%)5 (2.6%)

Immune System DisordersHypersensitivity 1 (0.5%)

Nervous System DisordersDizzinessDysgeusiaHeadache

2 (1.0%)1 (0.5%)

14 (7.3%)

Psychiatric DisordersInsomnia 5 (2.6%)

Skin and Subcutaneous Tissue DisordersDermatitis allergicPruritusRashb

Urticaria

2 (1.0%)6 (3.1%)5 (2.6%)1 (0.5%)

Vascular disordersFlushing 1 (0.5%)

aIncludes injection site extravasation and hematoma, infusion site pain, pruritus, and swelling bIncludes rash, rash erythematous, and rash pruritic











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ImmunogenicityAll clinical trial subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY, at defined intervals during the studies and at the completion visit. Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A (Factor VIII <1%) with previous exposure to Factor VIII concentrates ≥50 EDs, and no history of inhibitors. In the completed studies, no PTP developed neutralizing antibodies to Factor VIII. In an ongoing extension study, a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute infection and positive IgG anticardiolipin antibodies. The Factor VIII recovery was 2.2 IU/dL per IU/kg, annualized bleeding rate (ABR) was zero, and no change in therapy was required.

ADVERSE REACTIONS (CONT’D)

In an actively enrolling clinical trial in PUPs, 6 of 14 treated subjects (42.9% with a 95% Confidence Interval of 17.7-71.1%) developed an inhibitor. Of these, 3 subjects (21.4%) had high titer inhibitors, and 3 subjects (21.4%) had transient low titer inhibitors for which no change in therapy was required. The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to other products.

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8.1 PregnancyRisk Summary There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using KOVALTRY. It is not known whether KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. KOVALTRY should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 LactationRisk Summary There is no information regarding the presence of KOVALTRY in human milk, the effects 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 KOVALTRY and any potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal condition.

USE IN SPECIFIC POPULATIONS

8.4 Pediatric UseSafety and efficacy studies with KOVALTRY have been performed in pediatric PTPs. Body weight adjusted clearance of Factor VIII in children ≤12 years of age is higher than in adults and adolescents. Consider higher or more frequent dosing in children to account for this difference in clearance [see Clinical Pharmacology (12.3)].

8.5 Geriatric UseClinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or not they respond differently from younger patients. However, clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients. As with any patient receiving rFVIII, dose selection for an elderly patient should be individualized.

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Kogenate® FS Prescribing Information








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DESCRIPTION

KOGENATE® FS, ANTIHEMOPHILIC FACTOR (RECOMBINANT) INDICATIONS AND IMPORTANT SAFETY INFORMATIONINDICATIONS

Kogenate® FS is an Antihemophilic Factor (Recombinant) indicated for: On-demand treatment and control of bleeding episodes in adults and children with hemophilia A. Perioperative management of bleeding in adults and children with hemophilia A. Routine prophylaxis to reduce the frequency of bleeding episodes in children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage. Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A.

Kogenate FS is not indicated for the treatment of von Willebrand disease.

IMPORTANT SAFETY INFORMATION Kogenate FS Antihemophilic Factor (Recombinant) is contraindicated in patients who have life-threatening hypersensitivity reactions, including anaphylaxis to mouse or hamster protein or other constituents of the product. Hypersensitivity reactions, including anaphylaxis have been reported with Kogenate FS. Reported symptoms included facial swelling, flushing, hives, decrease in blood pressure, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, and vomiting. Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment. Neutralizing antibodies (inhibitors) have been reported following administration of Kogenate FS predominately in previously untreated patients. Carefully monitor patients for the development of factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII. Serious adverse reactions seen with Kogenate FS are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII. The most common adverse reactions (≥4%) observed in clinical trials were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions, infusion site reactions, and central venous access device (CVAD) associated infections.

For additional important risk and use information, please see full Prescribing Information at the end of this document.You are encouraged to report negative side effects or quality complaints of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

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Kogenate® FS Prescribing Information








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DESCRIPTION

11 DESCRIPTIONKOVALTRY, Antihemophilic Factor (Recombinant), is a sterile, non-pyrogenic, white to slightly yellow powder for reconstitution contained in a single-use vial. The final product does not contain any preservative. The reconstituted product is indicated for intravenous administration. The product is available in 250 IU, 500 IU, 1000 IU, 2000 IU, or 3000 IU nominal potencies; however, for each dosage strength the actual, assayed Factor VIII potency is directly printed on each vial label. The container closure system consists of a 10 mL, Type I glass vial sealed with a bromobutyl grey stopper and an aluminum crimp seal with plastic flip-off cap plus vial adapter. The vial adapter was designed to connect with the sterile water for injection (sWFI), prefilled diluent syringe. KOVALTRY is formulated with the following excipients: 2.2% glycine, 1% sucrose, 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM histidine and 80 ppm polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0. Intravenous administration of sucrose contained in KOVALTRY will not affect blood glucose level.The active substance in KOVALTRY is the unmodified full length recombinant Factor VIII glycoprotein comprising the human derived amino acid sequence. Post-translational modifications are similar to those of endogenous Factor VIII including glycosylation sites and sulfation of tyrosine sites. Manufacturing and quality controls ensure that both galactose-alpha-1,3-galactose (alpha-Gal) and N-glycolyl neuraminic acid (NGNA) content are below the 1% limit of detection established for each analytical method.

KOVALTRY is produced by a genetically engineered Baby Hamster Kidney (BHK) cell line into which the human FVIII gene was introduced together with the human heat shock protein 70 (HSP 70) gene. HSP 70 is an intracellular protein that improves proper folding of the FVIII protein. While KOVALTRY and Kogenate FS have the same protein backbone, human- and animal-derived raw materials are not added to the cell culture, purification, or formulation processes for KOVALTRY. In the manufacturing process for KOVALTRY, rFVIII is secreted into cell culture medium and is purified from process- and product-related impurities using a series of chromatography and filtration steps. The production process incorporates two dedicated viral clearance steps: (1) a detergent treatment step for inactivation and (2) a 20 nanometer filtration step for removal of viruses and potential protein aggregates.

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12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionKOVALTRY temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

12.2 PharmacodynamicsPlasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT.

12.3 PharmacokineticsThe pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of KOVALTRY are presented in Table 4 (one-stage clotting assay) and Table 5 (chromogenic substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 subjects following 6 to 12 months of prophylaxis).

Table 4: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), One-Stage Clotting Assay

Parameter [unit]12 to 17 yrs

(N=5)≥18 yrs (N=21)

AUC [IU*h/dL] 1013.9 ± 286.8 1601.3 ± 520.0

Cmax [IU/dL] 91.7 ± 28.7 99.7 ± 14.9

t½ [h] 11.7 ± 1.11 14.3 ± 3.7

MRTIV [h] 16.1 ± 0.8 19.8 ± 5.7

Vss [dL/kg] 0.85 ± 0.24 0.63 ± 0.11

CL [dL/h/kg] 0.053 ± 0.017 0.035 ± 0.012

AUC: area under the curveCmax: maximum drug concentration in plasma after single dose concentrationt½: terminal half-lifeMRTIV: mean residence time after an IV administrationVss: apparent volume distribution at steady-stateCL: clearance

The PK parameters of KOVALTRY for 8 subjects in age group 0 to <6 years and 10 subjects in age group 6 to <12 years are shown in Table 5. In general, children <12 years of age demonstrated lower plasma concentrations when compared to PTP children ≥12 years of age.

CLINICAL PHARMACOLOGY < 1/2 >











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Table 5: Pharmacokinetic Parameters [Arithmetic Mean ± SD] for KOVALTRY (50 IU/kg dose), Chromogenic Substrate Assay

Parameter [unit]0 to <6 yrs

(N=8)6 to <12 yrs

(N=10)b12 to 17 yrs

(N=5)≥18 yrs (N=21)

AUC [IU*h/dL] 1544.7 ± 387.1a

1214.5 ± 395.1

1572.0 ± 448.0

2103.4 ± 702.8

Cmax [IU/dL] 89.6 ± 27.4

81.6 ± 17.8

132.5 ± 46.3

133.1 ± 20.4

t½ [h] 12.1 ± 2.7a

12.0 ± 2.1

14.4 ± 5.5

14.2 ± 3.5

MRTIV [h] 17.7 ± 3.6a

17.8 ± 2.9

19.8 ± 5.8

19.9 ± 4.9

Vss [dL/kg] 0.57 ± 0.13a

0.79 ± 0.23

0.71 ± 0.39

0.50 ± 0.11

CL [dL/h/kg] 0.033 ± 0.009a

0.045 ± 0.016

0.034 ± 0.010

0.027 ± 0.010

an=7 bOne subject considered PK outlier was excluded

Table 6: Incremental Recovery in PTPs

0 to <6 yrs N=25

6 to 12 yrs N=25

≥12 yrs N=115

Chromogenic substrate assay resultsa

Median (Q1; Q3) (IU/dL per IU/kg)

1.6 (1.3; 1.9) 1.7 (1.4; 2.0) 2.3 (1.8; 2.6)

One-stage assay resultsa

Median (Q1; Q3) (IU/dL per IU/kg)

– – 2.2 (1.8; 2.4)

aStart of study

CLINICAL PHARMACOLOGY (CONT’D) < 2/2 >

Incremental Recovery analysis after 6 months of prophylactic treatment yielded comparable results with incremental recovery after the first dose (see Table 6).











Information


13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term studies in animals to evaluate the carcinogenic potential of KOVALTRY or other studies to determine the effects of KOVALTRY on fertility have not been performed. KOVALTRY was negative in the modified in-vitro (Mammalian Mutation and Chromosome Aberration Assay with Mouse Lymphoma Cells) genotoxicity test. KOVALTRY is expected to have no mutagenic potential.

NONCLINICAL TOXICOLOGY < 1/1 >











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14 CLINICAL STUDIESThe safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A (<1% FVIII) was evaluated in three international (including U.S.) clinical studies. Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤1%) and no history of FVIII inhibitors were eligible for the trials.Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥12 years to <65 years) PTPs (≥150 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week in which the dosing frequency was assigned by the investigator based on the subject’s individual requirements.Study 2: a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age ≥12 years to <65 years) PTPs (≥150 EDs) evaluated the superiority of prophylaxis over on-demand treatment with KOVALTRY over a one-year treatment period (See Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 30 IU/kg two times per week or 30 to 40 IU/kg three times per week and the treatment group was assigned by randomization.

Study 3: a multi-center, open-label, uncontrolled study in pediatric (age ≤12 years) PTPs (≥50 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 8). The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours of previous prophylaxis infusion. ABR during prophylaxis, independent of time of infusion, was also analyzed. The prophylactic regimen was 25 to 50 IU/kg at frequencies of either 2 times per week, 3 times per week or every other day and could be adapted to individual subject’s need by the investigator.In all studies, treatment of breakthrough bleeds and peri-operative management was at the investigator’s discretion based on standard of care.A total of 204 subjects were enrolled in the completed clinical trials, 153 subjects ≥12 years of age and 51 subjects <12 years of age. One hundred-forty (140) subjects were treated for at least 12 months, and 43 of these subjects were treated for 24 months.

CLINICAL STUDIES < 1/7 >











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Table 7: Overview of Study 1 (Prophylaxis Treatment Phase) and Study 2

Study 1 (N=62)

Study 2(N=80)

Age: mean ± SD 31.5 ± 12.7 years 29.6 ± 11.0 years

Previous treatment: % Prophylaxis: 80.6% On-demand: 100%

Number of Target joints at baseline: mean ± SD 1.4 ± 1.3 3.0 ± 2.1

Joint hemorrhage history(during 12 months prior to study):mean ± SD of joint bleeds

8.0 ± 11.9 32.1 ± 23.8

Table 8: Overview of Study 3

Study 3

PTPs 0 to <6 years (N=25)

PTPs 6 to 12 years(N=26)

Age: mean ± SD (range) 3.8 ± 1.3 years (1-5) 8.8 ± 1.8 years (6-11)

Previous treatment: % Prophylaxis: 92.0% Prophylaxis: 65.4%

Number of Target joints at baseline: mean ± SD 0.2 ± 0.4 0.7 ± 1.1

CLINICAL STUDIES (CONT’D) < 2/7 >











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14.1 On-demand Treatment and Control of Bleeding Episodes Adolescents and AdultsA total of 1892 bleeding episodes in 110 subjects were treated with KOVALTRY in Study 1 and Study 2 (see Table 9). The majority of the bleeding episodes were spontaneous, localized in joints, and mild to moderate in severity.In Study 1 and Study 2, the treatment responses in a total of 1859 treated bleeds were assessed by the subjects compared to their previous treatment experience.

Table 9: On-demand Treatment and Control of Bleeding Episodes in Adolescents and Adults Treated with KOVALTRY

Characteristics of Bleeding Episodes

Study 1 Study 2

Prophylaxis Main Study

N=62

Prophylaxis Extension

N=55Prophylaxis

N=59On-demand

N=21

Total number of bleeds 241 154 293 1204

Spontaneous: n/total (%)

153/241 (63.5%)

79/150a (52.7%)

209/283a (73.9%)

943/1202a (78.5%)

Trauma: n/total (%)

79/241 (32.8%)

70/150a (46.7%)

74/283a (26.1%)

258/1202a (21.5%)

Joint bleeds: n/total (%)

191/241 (79.3%)

120/154 (77.9%)

255/293 (87.0%)

924/1197a (77.2%)

Mild/moderate: n/total (%)

215/241 (89.2%)

130/153a (84.9%)

260/293 (88.8%)

1092/1196a (91.3%)

% of bleeds treated with ≤2 infusions 87.0% 96.2% 95.3%

Response to treatment of bleeds assessed as “Excellent” or “Good”: n/totalb (%)

190/235 (80.9%)

107/149 (71.8%)

172/279 (61.6%)

834/1196 (69.7%)

Median dose per infusion (range)

31.6 IU/kg (14-67 IU/kg)

29.4 IU/kg (19-49 IU/kg)

22.0 IU/kg (11-35 IU/kg)

aTotal number excluding uncharacterized bleeds bThe % is calculated from number of treated bleeds assessed for response












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Table 10: On-demand Treatment and Control of Bleeding Episodes in Children Treated with KOVALTRY


Study 3

PTPs 0 to <6 yrs(N=25)

PTPs 6 to 12 yrs(N=26)

PTPs 0 to 12 yrs (N=51)

Total number of bleeds 52 45 97

Spontaneous: n/total (%) 8/44a (18.2%) 12/37a (32.4%) 20/81a (24.7%)

Trauma: n/total (%) 36/44a (81.8%) 23/37a (62.2%) 59/81a (72.8%)

Joint bleeds: n/total (%) 10/52 (19.2%) 22/45 (48.9%) 32/97 (33.0%)

Mild/moderate: n/total (%) 50/52 (96.2%) 44/45 (97.8%) 94/97 (96.9%)

% bleeds treated with ≤2 infusions 92.4% 86.7% 89.7%

Response to treatment ofbleeds assessed as “Excellent”or “Good”: n/totalb (%)

43/44 (97.8%) 30/37 (81.0%) 73/81 (90.1%)


38.7 IU/kg(20.8–71.6 IU/kg)

32.4 IU/kg(21.7–50.0 IU/kg)

36.9 IU/kg(20.8–71.6 IU/kg)

aTotal number of treated bleeds bThe % is calculated from number of treated bleeds assessed for response

Children 12 Years of Age and YoungerA total of 97 bleeding episodes in 28 pediatric subjects were treated with KOVALTRY. Majority (96.9%) of the bleeds were mild to moderate in severity. Fifty-nine (72.8%) bleeds were trauma related. During the 6 month treatment period, the median dose of KOVALTRY for the treatment of breakthrough bleeds was 36.94 IU/kg per infusion (range 20.8–71.6 IU/kg).Assessment of response to treatment of bleeds was as follows:Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no additional infusion administered; Good: Definite pain relief and/or improvement in signs of bleeding but possibly requiring more than one infusion for complete resolution; Moderate: Probable or slight improvement in signs of bleeding with at least one additional infusion for complete resolution; Poor: No improvement at all between infusions or condition worsens.The hemostatic efficacy in on-demand treatment of bleeds was assessed as either “good” or “excellent” in 90.1% of cases (97.8% in the younger age group and 81.0% in the older age group). Majority of bleeds (89.7%) were successfully treated with ≤2 infusions. Response to treatment was similar for children aged 0 to <6 compared to 6 to 12 years of age (see Table 10).












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Table 11: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment Exposure

Study 1 (N=62)a

Study 2(N=59)

Median nominal prophylaxis dose/infusion (range)

All 31.2 IU/kg (21-43 IU/kg) 31.7 IU/kg (21-42 IU/kg)

Prophylaxis 2 times per week 35.0 IU/kg (21-42 IU/kg) 30.4 IU/kg (21-34 IU/kg)

Prophylaxis 3 times per week 31.1 IU/kg (24-43 IU/kg) 37.4 IU/kg (30-42 IU/kg)

Treatment duration 1 year main study 1 year

The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, respectively. In Study 2, comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference (p<0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as compared to subjects receiving prophylaxis (2 bleeds per year). In Study 2, mean ABR in subjects receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis.

14.2 Perioperative ManagementA total of 14 major and 46 minor surgeries were performed in 44 previously treated subjects (43 adults and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY dose administered was 2500 IU (108.7 IU/kg).The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood loss similar to the non-hemophilic patient).

14.3 Routine ProphylaxisAdolescents and Adults A total of 140 subjects were treated with KOVALTRY for at least 12 months with median (range) 157 EDs (25-178) in Study 1, [305 EDs (25-355) inclusive of extension phase] and 153 EDs (103-187) in Study 2 (see Table 11). In both studies, subjects in the Intent-to-Treat (ITT) population received 95% to 100% of the prescribed number of prophylaxis infusions.


Study 1: 2 times per week (n=18); 3 times per week (n=44)Study 2: 2 times per week (n=28); 3 times per week (n=31)

a Study 1 included PK, safety and efficacy of prophylaxis and hemostasis during surgeries. Prophylaxis phase data are presented.











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Table 12: ABR in Adolescent and Adult Patients

Study 1 (N=62) Study 2 (N=59)

2 times per week

(n=18)

3 times per week

(n=44)

2 times per week

(n=28)

3 times per week

(n=31)

ABR median (IQRa Q1; Q3)

All Bleeds 1.0 (0.0; 8.0) 2.0 (0.5; 5.0}4.0 (0.0; 8.0)

Month 1-6b: 4.1; Month 7-12b: 1.1

2.0 (0.0; 4.9) Month 1-6b: 2.0; Month 7-12b: 2.0

Spontaneous Bleeds 0.5 (0.0; 2.0) 1.0 (0.0; 3.9) 2.0 (0.0; 6.5) 0.0 (0.0; 3.0)

Joint Bleeds 0.5 (0.0; 7.0) 1.8 (0.0; 3.0) 2.5 (0.0; 7.5) 1.0 (0.0; 4.0)

Subjects with Zero Bleeding Episodesc % (n)

37.5% (6/16d)

62.5% (10/16d)

28.6% (8/28e)

25.8% (8/31e)

aIQR = Interquartile RangebMonth 1-6 refers to the first six months of the treatment period and Month 7-12 refer to the second six months of the treatment period

cObservation of one-year treatment perioddn=total number of patients with zero bleedsen=total number of patients randomized to treatment arms

The ABR for subjects (n=21) receiving on-demand therapy in Study 2 [median (IQR Q1; Q3)] for all bleeds: 60 (41.7; 76.3); spontaneous bleeds: 42.1 (24.3; 61.3); joint bleeds: 38.8 (24.3; 60.0).

Children 12 Years of Age and YoungerA total of 51 subjects were treated with KOVALTRY for at least 6 months with median (range) of 73 EDs (37-103) (see Table 13). Subjects received >95% of the prescribed number of prophylaxis infusions.

Table 13: Prophylaxis Treatment with KOVALTRY in Children 12 Years of Age or Younger – Treatment Exposure

Study 3

PTPs 0 to <6 yrs (N=25)

PTPs 6 to 12 yrs (N=26)

Treatment regimena during study (6 months) n (%)

2 times per week 9 (36%) 13 (50%)

3 times per week or every other day 16 (64%) 13 (50%)

Nominal prophylaxis dose per infusion median (range)

36.4 IU/kg (21-58 IU/kg)

31.8 IU/kg (22-50 IU/kg)

aTreatment regimen at the start of the study. Study duration was six months.

In children 12 years of age and younger (n=51), the median (IQR Q1; Q3) ABR within 48 hours after prophylactic infusion was 0 (0; 4) for all bleeds, and 0 (0; 0) for spontaneous and joint bleeds. The median (IQR Q1; Q3) ABR during prophylactic treatment independent of time of infusion was 1.9 (0; 6) for all bleeds, 0 (0; 0) for spontaneous bleeds and 0 (0; 2) for joint bleeds. The mean ABR within 48 hours after prophylactic infusion was 2.04 ± 2.91. The mean ABR at any time during the prophylaxis regimen was 3.75 ± 4.98.












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In both age groups (0 to <6 years and 6 to 12 years), the ABR for spontaneous bleeds and joint bleeds within 48 hours after prophylactic treatment [ABR median (IQR Q1; Q3)] was 0 (0; 0). The median (IQR Q1; Q3) annualized number of spontaneous bleeds during prophylactic treatment independent of time of infusion was 0 (0; 0). The median (IQR Q1; Q3) annualized number of joint bleeds during prophylactic treatment independent of time of infusion was 0 (0; 1.9) in 0 to <6 years age group and 0 (0; 2.1) in 6 to 12 years age group (see Table 14).The majority (32/53) of bleeds that occurred within 48 hours after a previous prophylaxis infusion were trauma related. Twenty-three (45.1%) subjects reported no bleeds during the six-month prophylaxis period.

CLINICAL STUDIES (CONT’D)

Table 14: ABR in Children 12 Years of Age or Younger

Study 3

PTPs 0 to <6 yrs (N=25)

PTPs 6 to 12 yrs(N=26)

All bleedsABR Median(IQRa Q1; Q3)

Within 48 hrs after prophylactic treatment

During prophylactic treatmentb

Within 48 hrs after prophylactic treatment


1.9 (0.0; 4.0) 2.0 (0.0; 6.0) 0.0 (0.0; 2.0) 0.9 (0.0; 5.8)

Number of Patients with Zero Bleeding Episodes %

10 (40%) 13 (50%)

aIQR = Interquartile Rangebindependent of time of infusion

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16 HOW SUPPLIED/STORAGE AND HANDLINGHow SuppliedKOVALTRY is available as a lyophilized powder in single-use glass vials, one vial per carton. It is supplied with a sterile vial adapter with 15-micrometer filter and a prefilled diluent glass barrel syringe, which together serve as a needleless reconstitution system. The prefilled diluent syringe contains Sterile Water for Injection, USP. An administration set is also provided in the package. Available sizes:

Nominal Strength (IU) Diluent (mL)Kit NDC Number Color Code

250 2.5 0026-3821-25 Blue

500 2.5 0026-3822-25 Green

1000 2.5 0026-3824-25 Red

2000 5.0 0026-3826-50 Yellow

3000 5.0 0026-3828-50 Gray

Actual Factor VIII activity in IU is stated on the label of each KOVALTRY vial.The product vial and diluent syringe are not made with natural rubber latex.

Storage and Handling

Product as Packaged for Sale Store KOVALTRY at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Do not freeze. Within this period, KOVALTRY may be stored for a single period of up to 12 months at temperatures up to +25°C or 77°F. Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature for 12 months, or after the expiration date on the product vial, whichever is earlier. Do not use KOVALTRY after the expiration date indicated on the vial. Protect KOVALTRY from extreme exposure to light and store the vial with the lyophilized powder in the carton prior to use.

Product After Reconstitution Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours. Do not use KOVALTRY if the reconstituted solution is cloudy or has particulate matter.

Use the administration set provided.

HOW SUPPLIED / STORAGE AND HANDLING < 1/1 >











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PATIENT COUNSELING INFORMATION < 1/1 >

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Hypersensitivity reactions are possible with KOVALTRY [see Warnings and Precautions (5.1)]. Warn patients of the early signs of hypersensitivity reactions (including tightness of the chest or throat, dizziness, mild hypotension and nausea during infusion) which can progress to anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.

Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A [see Warnings and Precautions (5.2)]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to Factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

Advise patients to discard all equipment, including any unused product, in an appropriate container.

Advise patients to consult with their healthcare provider prior to travel. Advise patients to bring an adequate supply of KOVALTRY while traveling based on their current regimen of treatment.











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INDICATIONS KOVALTRY®, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A for:


KOVALTRY® is not indicated for the treatment of von Willebrand disease.

IMPORTANT SAFETY INFORMATION KOVALTRY® is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins. Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY®. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY® if symptoms occur and seek immediate emergency treatment. KOVALTRY® may contain trace amounts of mouse and hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY®. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor.

IMPORTANT SAFETY INFORMATION

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII. Catheter-related infections may occur when KOVALTRY® is administered via central venous access devices (CVADs). These infections have not been associated with the product itself. The most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus.

For additional important risk and use information, please see full Prescribing Information at the end of this document.

You are encouraged to report negative side effects or quality complaints of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

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1

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KOVALTRY safely and effectively. See full prescribing information for KOVALTRY.

KOVALTRY [Antihemophilic Factor (Recombinant)] Lyophilized Powder for Solution for Intravenous Injection – Reconstitution with Vial Adapter Initial U.S. Approval: 2016

--------------------------- INDICATIONS AND USAGE -------------------------- KOVALTRY®, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes

KOVALTRY is not indicated for the treatment of von Willebrand disease (1).

---------------------- DOSAGE AND ADMINISTRATION ---------------------- For intravenous use after reconstitution only.

Control of bleeding episodes and perioperative management (2.1) Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of

normal or IU/dL) x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg).

Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg).

Routine prophylaxis (2.1) Adults and adolescents: 20-40 IU/kg 2 or 3 times per week.

Children ≤12 years old: 25-50 IU/kg 2 times per week, 3 times per week or every other day.

--------------------- DOSAGE FORMS AND STRENGTHS -------------------- KOVALTRY is available as lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000, or 3000 IU. Each vial of KOVALTRY contains the labeled amount of recombinant Factor VIII in IU (3).

------------------------------ CONTRAINDICATIONS ----------------------------- Do not use in patients who have history of hypersensitivity reactions to the active substance, mouse or hamster protein, or other constituents of the product (4).

----------------------- WARNINGS AND PRECAUTIONS ---------------------- Hypersensitivity reactions, including anaphylaxis, are possible. Should

symptoms occur, discontinue treatment with KOVALTRY and administer appropriate treatment (5.1).

Development of Factor VIII neutralizing antibodies can occur. Perform an assay that measures Factor VIII inhibitor concentration if expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled as expected with administered dose (5.2, 5.5).

------------------------------ ADVERSE REACTIONS ----------------------------- The most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus (6).


----------------------- USE IN SPECIFIC POPULATIONS ---------------------- Pediatric Use: Due to higher clearance (body weight adjusted) in children ≤12 years of age, higher or more frequent dosing may be needed (8.4).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 3/2016

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION


3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions 5.2 Neutralizing Antibodies 5.3 Cardiovascular Risk Factors 5.4 Catheter-related Infections 5.5 Monitoring Laboratory Tests

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES 14.1 On-demand Treatment and Control of Bleeding Episodes 14.2 Perioperative Management 14.3 Routine Prophylaxis

16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

HOME KOVALTRY® Prescribing Information

2

FULL PRESCRIBING INFORMATION


KOVALTRY, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes

KOVALTRY is not indicated for the treatment of von Willebrand disease.


For intravenous use after reconstitution only.

2.1 Dose

Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.

Each vial label of KOVALTRY states the Factor VIII potency in international units (IU). One IU is defined by the current WHO (World Health Organization) international standard (IS) for Factor VIII concentrate.

Potency assignment for KOVALTRY is determined using a chromogenic substrate assay. A field study involving 41 clinical laboratories from around the world measured recoveries of KOVALTRY spiked into hemophilic plasma. The results of the field study indicated that the Factor VIII activity of KOVALTRY can be accurately measured in plasma using either a one-stage clotting or chromogenic substrate assay according to routine methods of the testing laboratory.

The required dose for a desired Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL) x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg)

The expected in vivo peak increase of Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formula:

Estimated increment of Factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)

Examples (assuming patient’s baseline Factor VIII is <1%):

1. A peak of 50% is required in a 20 kg child. In this situation, the required dose of KOVALTRY would be 20 kg x 50 IU/dL x 0.5% (for recovery of 2 IU/dL per IU/kg) = 500 IU

2. A dose of 2000 IU of KOVALTRY administered to a 50 kg patient should be expected to result in post-infusion Factor VIII increase of 2000 IU / 50 kg (body weight) x 2 IU/dL per IU/kg = 80 IU/dL (80% of normal)

Adjust dose to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, incremental recovery) and clinical responses to KOVALTRY.


3

On-demand Treatment and Control of Bleeding Episodes

A guide for dosing KOVALTRY for the on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

Table 1: Dosing for Control of Bleeding Episodes

Degree of Bleeding

Factor VIII Level Required

(IU/dL or % of normal)

Frequency of Doses (hours) Duration of Therapy (days)

Minor (Early hemarthrosis, minor muscle, oral bleeds) 20–40 Repeat every

12–24 hours

At least 1 day, until bleeding episode as indicated by pain is resolved or healing is achieved

Moderate (More extensive hemarthrosis, muscle bleeding, or hematoma) 30–60 Repeat every

12–24 hours 3 to 4 days or more until pain and acute disability are resolved

Major (intracranial, intra-abdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, life or limb threatening hemorrhage)

60–100 Repeat every 8–24 hours Until bleeding is resolved

Perioperative Management of Bleeding

A guide for dosing KOVALTRY during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate laboratory tests, including serial Factor VIII activity assays, is highly recommended [see Warnings and Precautions (5.5)].

Table 2: Dosing for Perioperative Management

Type of Surgery

Factor VIII Level Required

(IU/dL or % of normal)

Frequency of Doses (hours) Duration of Therapy (days)

Minor (Such as tooth extraction) 30–60

(pre- and post-operative)

Repeat every 24 hours

At least 1 day until healing is achieved

Major (Such as intracranial, intra-abdominal, intrathoracic, or joint replacement surgery)


operative)

Repeat every 8–24 hours

Until adequate wound healing is complete, then continue therapy for at least another 7 days to maintain Factor VIII activity of 30–60% (IU/dL)

Routine Prophylaxis

Individualize the patient’s dose based on clinical response.

Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or three times per week.


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Children ≤12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice weekly, three times weekly, or every other day according to individual requirements [see Use in Specific Populations (8.4)].

2.2 Preparation and Reconstitution

Reconstitute and administer KOVALTRY with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

For any questions about the handling, reconstitution and administration of KOVALTRY, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).

The procedures below are provided as general guidelines for the reconstitution of KOVALTRY using the sterile vial adapter with a 15 micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

Usability Testing of Vial Adapter

Usability testing was conducted with 60 users, including 15 pediatric hemophilia A patients (between 10-17 years of age), 15 adult hemophilia A patients (≥18 years of age), 15 caregivers, and 15 healthcare providers. To mimic real life, the pediatric and adult patients and the caregivers were given minimal training, which included participants performing a supervised reconstitution and later performing a single unaided reconstitution. Healthcare providers were untrained in this study and could learn the procedure from the provided Instructions for Use. All participants were able to successfully and safely use the vial adapter device for reconstitution.

Reconstitution

Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures. Reconstitute KOVALTRY with the components provided with each package. If any component of the package is

opened or damaged, do not use this component. Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is achieved by using the

vial adapter.

1. Warm both unopened KOVALTRY vial and prefilled diluent syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F).

2. Remove the protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper.

3. Place the product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.


5









6


12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K).

Note: follow instructions for infusion set provided.

Pooling

If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. Use a larger plastic syringe (not provided) to combine the content of the vials into the syringe.

2.3 Administration

For intravenous use only.

Inspect reconstituted KOVALTRY visually for particulate matter and discoloration prior to administration. Do not use if you notice any particulate matter or discoloration and immediately contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).

Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no longer than 3 hours.

Infuse KOVALTRY intravenously over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient.


KOVALTRY is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000, 2000, or 3000 IU of recombinant Factor VIII per vial.

Each vial of KOVALTRY is labeled with actual Factor VIII potency expressed in IU determined using a chromogenic substrate assay. This potency assignment employs a Factor VIII concentrate standard that is referenced to the current WHO International Standard for Factor VIII concentrate, and is evaluated by appropriate methodology to ensure accuracy of the results.

4 CONTRAINDICATIONS

KOVALTRY is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, to any of the excipients, or to mouse or hamster proteins [see Description (11)].


5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. Discontinue KOVALTRY if symptoms occur and seek immediate emergency treatment.


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KOVALTRY may contain trace amounts of mouse and hamster proteins [see Description (11)]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

5.2 Neutralizing Antibodies

Neutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products [see Adverse Reactions (6.1)]. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor (neutralizing antibody) [see Warnings and Precautions (5.5)].

5.3 Cardiovascular Risk Factors

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII.

5.4 Catheter-related Infections

Catheter-related infections may be observed when KOVALTRY is administered via central venous access devices (CVADs). These infections have not been associated with the product itself.

5.5 Monitoring Laboratory Tests

Monitor plasma Factor VIII activity levels using a validated test to confirm that adequate Factor VIII levels have been achieved and maintained [see Dosage and Administration (2.1)].

Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of KOVALTRY. Use Bethesda Units (BU) to report inhibitor titers.

6 ADVERSE REACTIONS

The most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and pruritus (see Table 3).

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

The safety profile of KOVALTRY was evaluated in 193 previously treated patients (PTPs) (inclusive of 51 pediatric patients <12 years of age) with at least three months of exposure to KOVALTRY. The safety analysis was done using a pooled database from three multi-center, prospective, open-label clinical studies. The median time on study for patients ≥12 years of age was 372 days with a median of 159 exposure days (EDs). The median time on study for patients <12 years of age was 182 days with a median of 73 EDs. Subjects who received KOVALTRY for perioperative management (n=5) with treatment period of 2 to 3 weeks and those who received single doses of KOVALTRY for PK studies (n=6) were excluded from safety analysis. Table 3 lists the adverse reactions reported during clinical studies. The frequency, type, and severity of adverse reactions in children are similar to those in adults.


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Table 3: Adverse Reactions in PTPs (N=193)

MedDRA Primary System Organ Class Preferred term

Frequency N (%)

Blood and the Lymphatic System Disorders Lymphadenopathy 2 (1.0%)

Cardiac Disorders Palpitation Sinus tachycardia

2 (1.0%) 2 (1.0%)

Gastrointestinal Disorders Abdominal pain Abdominal discomfort Dyspepsia

4 (2.1%) 3 (1.6%) 4 (2.1%)

General Disorders and Administration Site Conditions Pyrexia Chest discomfort Injection site reactionsa

8 (4.1%) 2 (1.0%) 5 (2.6%)

Immune System Disorders Hypersensitivity 1 (0.5%) Nervous System Disorders Dizziness Dysgeusia Headache

2 (1.0%) 1 (0.5%) 14 (7.3%)

Psychiatric Disorders Insomnia 5 (2.6%) Skin and Subcutaneous Tissue Disorders Dermatitis allergic Pruritus Rashb Urticaria

2 (1.0%) 6 (3.1%) 5 (2.6%) 1 (0.5%)

Vascular disorders Flushing 1 (0.5%) aIncludes injection site extravasation and hematoma, infusion site pain, pruritus, and swelling bIncludes rash, rash erythematous, and rash pruritic

Immunogenicity

All clinical trial subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY, at defined intervals during the studies and at the completion visit.

Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A (Factor VIII <1%) with previous exposure to Factor VIII concentrates ≥50 EDs, and no history of inhibitors.

In the completed studies, no PTP developed neutralizing antibodies to Factor VIII. In an ongoing extension study, a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute infection and positive IgG anticardiolipin antibodies. The Factor VIII recovery was 2.2 IU/dL per IU/kg, annualized bleeding rate (ABR) was zero, and no change in therapy was required.


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In an actively enrolling clinical trial in PUPs, 6 of 14 treated subjects (42.9% with a 95% Confidence Interval of 17.7-71.1%) developed an inhibitor. Of these, 3 subjects (21.4%) had high titer inhibitors, and 3 subjects (21.4%) had transient low titer inhibitors for which no change in therapy was required.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to other products.


8.1 Pregnancy

Risk Summary

There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using KOVALTRY. It is not known whether KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. KOVALTRY should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of KOVALTRY in human milk, the effects 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 KOVALTRY and any potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal condition.

8.4 Pediatric Use

Safety and efficacy studies with KOVALTRY have been performed in pediatric PTPs. Body weight adjusted clearance of Factor VIII in children ≤12 years of age is higher than in adults and adolescents. Consider higher or more frequent dosing in children to account for this difference in clearance [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Clinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or not they respond differently from younger patients. However, clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients. As with any patient receiving recombinant Factor VIII, dose selection for an elderly patient should be individualized.

11 DESCRIPTION

KOVALTRY, Antihemophilic Factor (Recombinant), is a sterile, non-pyrogenic, white to slightly yellow powder for reconstitution contained in a single-use vial. The final product does not contain any preservative. The reconstituted product is indicated for intravenous administration. The product is available in 250 IU, 500 IU, 1000 IU, 2000 IU, or 3000 IU nominal potencies; however, for each dosage strength the actual, assayed Factor VIII potency is directly printed on each vial label. The container closure system consists of a 10 mL, Type I glass vial sealed with a bromobutyl grey stopper and an aluminum crimp seal with plastic flip-off cap plus vial adapter. The vial adapter was designed to connect with the sterile water for injection (sWFI), prefilled diluent syringe. KOVALTRY is formulated with the following excipients: 2.2% glycine, 1% sucrose, 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM histidine and 80 ppm polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0. Intravenous administration of sucrose contained in KOVALTRY will not affect blood glucose level.


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The active substance in KOVALTRY is the unmodified full length recombinant Factor VIII glycoprotein comprising the human derived amino acid sequence. Post-translational modifications are similar to those of endogenous Factor VIII including glycosylation sites and sulfation of tyrosine sites. Manufacturing and quality controls ensure that both galactose-alpha-1,3-galactose (alpha-Gal) and N-glycolyl neuraminic acid (NGNA) content are below the 1% limit of detection established for each analytical method.

KOVALTRY is produced by a genetically engineered Baby Hamster Kidney (BHK) cell line into which the human Factor VIII gene was introduced together with the human heat shock protein 70 (HSP 70) gene. HSP 70 is an intracellular protein that improves proper folding of the Factor VIII protein. While KOVALTRY and Kogenate FS have the same protein backbone, human- and animal-derived raw materials are not added to the cell culture, purification, or formulation processes for KOVALTRY. In the manufacturing process for KOVALTRY, recombinant Factor VIII is secreted into cell culture medium and is purified from process- and product-related impurities using a series of chromatography and filtration steps. The production process incorporates two dedicated viral clearance steps: (1) a detergent treatment step for inactivation and (2) a 20 nanometer filtration step for removal of viruses and potential protein aggregates.


12.1 Mechanism of Action

KOVALTRY temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

12.2 Pharmacodynamics

Plasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT.

12.3 Pharmacokinetics

The pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of KOVALTRY are presented in Table 4 (one-stage clotting assay) and Table 5 (chromogenic substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 subjects following 6 to 12 months of prophylaxis).

Table 4: Pharmacokinetic Parameters [Arithmetic Mean SD] for KOVALTRY (50 IU/kg dose), One-Stage Clotting Assay

Parameter [unit] 12 to 17 yrs

(N=5) ≥18 yrs (N=21)

AUC [IU*h/dL] 1013.9 ± 286.8 1601.3 ± 520.0 Cmax [IU/dL] 91.7 ± 28.7 99.7 ± 14.9 t½ [h] 11.7 ± 1.11 14.3 ± 3.7 MRTIV [h] 16.1 ± 0.8 19.8 ± 5.7 Vss [dL/kg] 0.85 ± 0.24 0.63 ± 0.11 CL [dL/h/kg] 0.053 ± 0.017 0.035 ± 0.012

AUC: area under the curve Cmax: maximum drug concentration in plasma after single dose t½ : terminal half-life MRTIV: mean residence time after an IV administration Vss: apparent volume distribution at steady-state CL: clearance

The PK parameters of KOVALTRY for 8 subjects in age group 0 to <6 years and 10 subjects in age group 6 to <12 years are shown in Table 5. In general, children <12 years of age demonstrated lower plasma concentrations when compared to PTP children ≥12 years of age.


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Table 5: Pharmacokinetic Parameters [Arithmetic Mean SD] for KOVALTRY (50 IU/kg dose), Chromogenic Substrate Assay

Parameter [unit] 0 to <6 yrs

(N=8) 6 to <12 yrs

(N=10)b 12 to 17 yrs

(N=5) ≥18 yrs (N=21)

AUC [IU*h/dL] 1544.7 ± 387.1a 1214.5 ± 395.1 1572.0 ± 448.0 2103.4 ± 702.8 Cmax [IU/dL] 89.6 ± 27.4 81.6± 17.8 132.5 ± 46.3 133.1 ± 20.4 t½ [h] 12.1 ± 2.7a 12.0 ± 2.1 14.4 ± 5.5 14.2 ± 3.5 MRTIV [h] 17.7 ± 3.6a 17.8 ± 2.9 19.8 ± 5.8 19.9 ± 4.9 Vss [dL/kg] 0.57 ± 0.13a 0.79 ± 0.23 0.71 ± 0.39 0.50 ± 0.11 CL [dL/h/kg] 0.033 ± 0.009a 0.045 ± 0.016 0.034 ± 0.010 0.027 ± 0.010

a n=7 b One subject considered PK outlier was excluded

Incremental Recovery analysis after 6 months of prophylactic treatment yielded comparable results with incremental recovery after the first dose (see Table 6).

Table 6: Incremental Recovery in PTPs

0 to <6 yrs

N=25 6 to 12 yrs

N=25 ≥12 yrs N=115

Chromogenic substrate assay resultsa Median (Q1; Q3) (IU/dL per IU/kg)

1.6 (1.3; 1.9) 1.7 (1.4; 2.0) 2.3 (1.8; 2.6)

One-stage assay resultsa Median (Q1; Q3) (IU/dL per IU/kg)

- - 2.2 (1.8; 2.4)

aStart of study


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of KOVALTRY or other studies to determine the effects of KOVALTRY on fertility have not been performed. KOVALTRY was negative in the modified in-vitro (Mammalian Mutation and Chromosome Aberration Assay with Mouse Lymphoma Cells) genotoxicity test. KOVALTRY is expected to have no mutagenic potential.

14 CLINICAL STUDIES

The safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A (<1% Factor VIII) was evaluated in three international (including U.S.) clinical studies. Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤1%) and no history of Factor VIII inhibitors were eligible for the trials.

Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥12 years to <65 years) PTPs (≥150 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week in which the dosing frequency was assigned by the investigator based on the subject’s individual requirements.

Study 2: a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age ≥12 years to <65 years) PTPs (≥150 EDs) evaluated the superiority of prophylaxis over on-demand treatment with KOVALTRY over a


12

one-year treatment period (see Table 7). The primary efficacy variable was ABR. The prophylactic regimen was 20 to 30 IU/kg two times per week or 30 to 40 IU/kg three times per week and the treatment group was assigned by randomization.

Study 3: a multi-center, open-label, uncontrolled study in pediatric (age ≤12 years) PTPs (≥50 EDs) evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 8). The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours following previous prophylaxis infusion. ABR during prophylaxis, independent of time of infusion, was also analyzed. The prophylactic regimen was 25 to 50 IU/kg at frequencies of either 2 times per week, 3 times per week or every other day and could be adapted to individual subject’s need by the investigator.

In all studies, treatments of breakthrough bleeds and perioperative management were at the investigator’s discretion based on standard of care.

A total of 204 subjects were enrolled in the completed clinical trials, 153 subjects ≥12 years of age and 51 subjects <12 years of age. One hundred-forty (140) subjects were treated for at least 12 months, and 43 of these subjects were treated for 24 months.

Table 7: Overview of Study 1 (Prophylaxis Treatment Phase) and Study 2

Study 1 (N=62)

Study 2 (N=80)

Age: mean SD 31.5 12.7 years 29.6 11.0 years Previous treatment: % Prophylaxis: 80.6% On-demand: 100% Number of Target joints at baseline: mean SD 1.4 1.3 3.0 2.1

Joint hemorrhage history (during 12 months prior to study): mean SD of joint bleeds

8.0 11.9

32.1 ± 23.8

Table 8: Overview of Study 3

Study 3 PTPs 0 to <6 yrs

(N=25) PTPs 6 to 12 yrs

(N=26) Age: mean SD (range) 3.8 1.3 years (1-5) 8.8 1.8 years (6-11) Previous treatment: % Prophylaxis: 92.0% Prophylaxis: 65.4% Number of Target joints at baseline: mean SD

0.2 0.4 0.7 1.1

14.1 On-demand Treatment and Control of Bleeding Episodes

Adolescents and Adults

A total of 1892 bleeding episodes in 110 subjects were treated with KOVALTRY in Study 1 and Study 2 (see Table 9). The majority of the bleeding episodes were spontaneous, localized in joints, and mild to moderate in severity.

In Study 1 and Study 2, the treatment responses in a total of 1859 treated bleeds were assessed by the subjects compared to their previous treatment experience.


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Table 9: On-demand Treatment and Control of Bleeding Episodes in Adolescents and Adults Treated with KOVALTRY


Study 1 Study 2 Prophylaxis Main Study

N=62

Prophylaxis Extension

N=55 Prophylaxis

N=59 On-demand

N=21 Total number of bleeds 241 154 293 1204

Spontaneous: n/total (%) 153/241 (63.5%) 79/150a (52.7%) 209/283a (73.9%) 943/1202a (78.5%)

Trauma: n/total (%) 79/241 (32.8%) 70/150a (46.7%) 74/283a (26.1%) 258/1202a (21.5%) Joint bleeds: n/total (%) 191/241 (79.3%) 120/154 (77.9%) 255/293 (87.0%) 924/1197a (77.2%) Mild/moderate: n/total (%) 215/241 (89.2%) 130/153a (84.9%) 260/293 (88.8%) 1092/1196a (91.3%) % of bleeds treated with ≤2 infusions 87.0% 96.2% 95.3%


190/235 (80.9%) 107/149 (71.8%) 172/279 (61.6%) 834/1196 (69.7%)


31.6 IU/kg (14-67 IU/kg)

29.4 IU/kg (19-49 IU/kg)

22.0 IU/kg (11-35 IU/kg)

aTotal number excluding uncharacterized bleeds bThe % is calculated from number of treated bleeds assessed for response

Children 12 Years of Age and Younger

A total of 97 bleeding episodes in 28 pediatric subjects were treated with KOVALTRY. Majority (96.9%) of the bleeds were mild to moderate in severity. Fifty-nine (72.8%) bleeds were trauma related. During the 6 month treatment period, the median dose of KOVALTRY for the treatment of breakthrough bleeds was 36.94 IU/kg per infusion (range 20.8–71.6 IU/kg).

Assessment of response to treatment of bleeds was as follows:

Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no additional infusion administered; Good: Definite pain relief and/or improvement in signs of bleeding but possibly requiring more than one infusion for complete resolution; Moderate: Probable or slight improvement in signs of bleeding with at least one additional infusion for complete resolution; Poor: No improvement at all between infusions or condition worsens.

The hemostatic efficacy in on-demand treatment of bleeds was assessed as either “good” or “excellent” in 90.1% of cases (97.8% in the younger age group and 81.0% in the older age group). Majority of bleeds (89.7%) were successfully treated with ≤2 infusions. Response to treatment was similar for children aged 0 to <6 compared to 6 to 12 years of age (see Table 10).


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Table 10: On-demand Treatment and Control of Bleeding Episodes in Children Treated with KOVALTRY





(N=51) Total number of bleeds 52 45 97

Spontaneous: n/total (%) 8/44a (18.2%) 12/37a (32.4%) 20/81a (24.7%) Trauma: n/total (%) 36/44a (81.8%) 23/37a (62.2%) 59/81a (72.8%)

Joint bleeds: n/total (%) 10/52 (19.2%) 22/45 (48.9%) 32/97 (33.0%)

Mild/moderate: n/total (%) 50/52 (96.2%) 44/45 (97.8%) 94/97 (96.9%) % of bleeds treated with ≤2 infusions 92.4% 86.7% 89.7%


43/44 (97.8%) 30/37 (81.0%) 73/81 (90.1%)


38.7 IU/kg (20.8–71.6 IU/kg)

32.4 IU/kg (21.7–50.0 IU/kg)

36.9 IU/kg (20.8–71.6 IU/kg)

aTotal number of treated bleeds bThe % is calculated from number of treated bleeds assessed for response

14.2 Perioperative Management

A total of 14 major and 46 minor surgeries were performed in 44 previously treated subjects (43 adults and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY dose administered was 2500 IU (108.7 IU/kg).

The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood loss similar to the non-hemophilic patient).

14.3 Routine Prophylaxis

Adolescents and Adults

A total of 140 subjects were treated with KOVALTRY for at least 12 months with median (range) 157 EDs (25-178) in Study 1, [305 EDs (25-355) inclusive of extension phase], and 153 EDs (103-187) in Study 2 (see Table 11). In both studies, subjects in the Intent-to-Treat (ITT) population received 95% to 100% of the prescribed number of prophylaxis infusions.


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Table 11: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment Exposure

Study 1 (N=62)a

Study 2 (N=59)

Median nominal prophylaxis dose/ infusion (range)

All

Prophylaxis 2 times per week

Prophylaxis 3 times per week

31.2 IU/kg (21-43 IU/kg)

35.0 IU/kg (21-42 IU/kg)

31.1 IU/kg (24-43 IU/kg)

31.7 IU/kg (21-42 IU/kg)

30.4 IU/kg (21-34 IU/kg)

37.4 IU/kg (30-42 IU/kg) Treatment duration 1 year main study 1 year Study 1: 2 times per week (n=18); 3 times per week (n=44) Study 2: 2 times per week (n=28); 3 times per week (n=31) a Study 1 included PK, safety and efficacy of prophylaxis and hemostasis during surgeries. Prophylaxis phase data are presented.

The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, respectively. In Study 2, comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference (p<0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as compared to subjects receiving prophylaxis (2 bleeds per year). In Study 2, mean ABR in subjects receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis.

Table 12: ABR in Adolescent and Adult Subjects

Study 1 (N=62)

Study 2 (N=59)

2 times per week (n=18)




ABR Median (IQRa Q1; Q3)

All Bleeds 1.0 (0.0; 8.0) 2.0 (0.5; 5.0) 4.0 (0.0; 8.0) Month 1-6b: 4.1; Month 7-12b: 1.1

2.0 (0.0; 4.9) Month 1-6b: 2.0; Month 7-12b: 2.0

Spontaneous Bleeds 0.5 (0.0; 2.0) 1.0 (0.0; 3.9) 2.0 (0.0; 6.5) 0.0 (0.0; 3.0) Joint Bleeds 0.5 (0.0; 7.0) 1.8 (0.0; 3.0) 2.5 (0.0; 7.5) 1.0 (0.0; 4.0)

Subjects with Zero Bleeding Episodesc % (n) 37.5% (6/16d) 62.5% (10/16d) 28.6% (8/28e) 25.8% (8/31e)

aIQR = Interquartile Range bMonth 1-6 refers to the first six months of the treatment period and Month 7-12 refer to the second six months of the treatment period cObservation of one-year treatment period dn=total number of subjects with zero bleeds en=total number of subjects randomized to treatment arms

The ABR for subjects (n=21) receiving on-demand therapy in Study 2 [median (IQR Q1; Q3)] for all bleeds: 60 (41.7; 76.3); spontaneous bleeds: 42.1 (24.3; 61.3); joint bleeds: 38.8 (24.3; 60.0).

Children 12 Years of Age and Younger

A total of 51 PTPs were treated with KOVALTRY for at least 6 months with median (range) 73 EDs (37-103) (see Table 13). Subjects received >95% of the prescribed number of prophylaxis infusions.


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Table 13: Prophylaxis Treatment with KOVALTRY in Children 12 Years of Age or Younger – Treatment Exposure



(N=26) Treatment regimena during study (6 months) n (%)

2 times per week

3 times per week or every other day

9 (36%)

16 (64%)

13 (50%)

13 (50%) Nominal prophylaxis dose per infusion, median (range) 36.4 IU/kg (21-58 IU/kg) 31.8 IU/kg (22-50 IU/kg) aTreatment regimen at the start of the study. Study duration was six months.

In children 12 years of age and younger (n=51), the median (IQR Q1; Q3) ABR within 48 hours after prophylactic infusion was 0 (0; 4) for all bleeds, and 0 (0; 0) for spontaneous and joint bleeds. The median (IQR Q1; Q3) ABR during prophylactic treatment independent of time of infusion was 1.9 (0; 6) for all bleeds, 0 (0; 0) for spontaneous bleeds and 0 (0; 2) for joint bleeds. The mean ABR within 48 hours after prophylactic infusion was 2.04 ± 2.91. The mean ABR at any time during the prophylaxis regimen was 3.75 ± 4.98.

In both age groups (0 to <6 years and 6 to 12 years), the ABR for spontaneous bleeds and joint bleeds within 48 hours after prophylactic treatment [ABR median (IQR Q1; Q3)] was 0 (0; 0). The median (IQR Q1; Q3) annualized number of spontaneous bleeds during prophylactic treatment independent of time of infusion was 0 (0; 0). The median (IQR Q1; Q3) annualized number of joint bleeds during prophylactic treatment independent of time of infusion was 0 (0; 1.9) in 0 to <6 years age group and 0 (0; 2.1) in 6 to 12 years age group (see Table 14).

The majority (32/53) of bleeds that occurred within 48 hours after a previous prophylaxis infusion were trauma related. Twenty-three (45.1%) subjects reported no bleeds during the six-month prophylaxis period.

Table 14: ABR in Children 12 Years of Age or Younger

Study 3

PTPs 0 to <6 yrs


(N=26) Within 48 hrs

after prophylactic treatment


Within 48 hrs after prophylactic

treatment


All Bleeds ABR Median (IQRa Q1; Q3) 1.9 (0.0; 4.0) 2.0 (0.0; 6.0) 0.0 (0.0; 2.0) 0.9 (0.0; 5.8) Number of Subjects with Zero Bleeding Episodes (%) 10 (40%) 13 (50%) aIQR = Interquartile Range bIndependent of time of infusion


How Supplied

KOVALTRY is available as a lyophilized powder in single-use glass vials, one vial per carton. It is supplied with a sterile vial adapter with 15-micrometer filter and a prefilled diluent glass barrel syringe, which together serve as a needleless reconstitution system. The prefilled diluent syringe contains Sterile Water for Injection, USP. An administration set is also provided in the package. Available sizes:


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Nominal Strength (IU)

Diluent (mL) Kit NDC Number

Color Code

250 2.5 0026-3821-25 Blue 500 2.5 0026-3822-25 Green

1000 2.5 0026-3824-25 Red 2000 5.0 0026-3826-50 Yellow 3000 5.0 0026-3828-50 Gray

Actual Factor VIII activity in IU is stated on the label of each KOVALTRY vial.

The product vial and diluent syringe are not made with natural rubber latex.


Product as Packaged for Sale

Store KOVALTRY at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Do not freeze. Within this period, KOVALTRY may be stored for a single period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature for 12 months, or after the expiration date on the product vial, whichever is earlier.

Do not use KOVALTRY after the expiration date indicated on the vial. Protect KOVALTRY from extreme exposure to light and store the vial with the lyophilized powder in the carton prior

to use.

Product After Reconstitution


Do not use KOVALTRY if the reconstituted solution is cloudy or has particulate matter. Use the administration set provided.


Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity reactions are possible with KOVALTRY [see Warnings and Precautions (5.1)]. Warn patients of the

early signs of hypersensitivity reactions (including tightness of the chest or throat, dizziness, mild hypotension and nausea during infusion) which can progress to anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.

Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A [see Warnings and Precautions (5.2)]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to Factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

Advise patients to discard all equipment, including any unused product, in an appropriate container. Advise patients to consult with their healthcare provider prior to travel. Advise patients to bring an adequate supply of

KOVALTRY while traveling based on their current regimen of treatment.


HOME

18

FDA-Approved Patient Labeling

Patient Information

KOVALTRY (KOH-vahl-tree) Antihemophilic Factor (Recombinant)

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

Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center.

What is KOVALTRY?

KOVALTRY is a 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.

KOVALTRY is used to treat and control bleeding in adults and children with hemophilia A. Your healthcare provider may give you KOVALTRY when you have surgery. KOVALTRY can reduce the number of bleeding episodes in adults and children with hemophilia A when used regularly (prophylaxis).

KOVALTRY is not used to treat von Willebrand Disease.

Who should not use KOVALTRY?

You should not use KOVALTRY if you

are allergic to rodents (like mice and hamsters). are allergic to any ingredients in KOVALTRY.

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

Tell your healthcare provider about all of your medical conditions. Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and non-

prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies. Tell your healthcare provider if you have been told you have heart disease or are at risk for heart disease. Tell your healthcare provider if you have been told that you have inhibitors to Factor VIII (because KOVALTRY may

not work for you).

What are the possible side effects of KOVALTRY?

The common side effects of KOVALTRY are headache, fever and itchy rash.

Allergic reactions may occur with KOVALTRY. Call your healthcare provider right away and stop treatment if you get tightness of the chest or throat, dizziness, decrease in blood pressure, and nausea.

Your body can also make antibodies, called “inhibitors,” against KOVALTRY, which may stop KOVALTRY 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.

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

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

What are the KOVALTRY dosage strengths?


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KOVALTRY with 2.5 mL or 5 mL Sterile Water for Injection (SWFI) comes in five different dosage strengths labeled as International Units (IU): 250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU. The five different strengths are color-coded as follows:

Blue 250 IU with 2.5 mL SWFI

Green 500 IU with 2.5 mL SWFI

Red 1000 IU with 2.5 mL SWFI

Yellow 2000 IU with 5 mL SWFI

Gray 3000 IU with 5 mL SWFI

How do I store KOVALTRY?

Do not freeze KOVALTRY.

Store KOVALTRY at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, KOVALTRY may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage clearly on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The product then expires after storage at room temperature for 12 months, or after the expiration date on the product vial, whichever is earlier. Store vials in their original carton and protect them from extreme exposure to light.


Throw away any unused KOVALTRY after the expiration date.

Do not use reconstituted KOVALTRY if it is not clear.

What else should I know about KOVALTRY and hemophilia A?

Finding veins for injections may be difficult in young children. When frequent injections are required, your healthcare provider may propose to have a device surgically placed under the skin to facilitate access to the bloodstream. These devices may result in infections.

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

This leaflet summarizes the most important information about KOVALTRY. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about KOVALTRY that was written for healthcare professionals.


20

Instructions for Use

KOVALTRY (KOH-vahl-tree) Antihemophilic Factor (Recombinant)


You should always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using KOVALTRY. 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 KOVALTRY.

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

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

Talk to your healthcare provider before traveling. You should plan to bring enough KOVALTRY for your treatment during this time.

See the step-by-step instructions below for reconstituting KOVALTRY with vial adapter. Follow the specific infusion instruction leaflet included with the infusion set provided.

Carefully handle KOVALTRY. Dispose of all materials, including any leftover reconstituted KOVALTRY product, in an appropriate container.

Reconstitution

Always work on a clean surface and wash your hands before performing the following procedure. Use only the components for reconstitution and administration that are provided with each package of KOVALTRY. If a package is opened or damaged, do not use this component. If these components cannot be used, please contact your healthcare provider.

Prepare a clean flat surface and gather all the materials needed for the infusion.

1. Warm the unopened diluent syringe and the concentrate vial to a temperature not to exceed 37°C or 99°F.

2. Remove protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper.

3. Place product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.


21









12. Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the administration set provided and inject intravenously (K). NOTE: follow instructions for infusion set provided.


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Pooling

If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. To combine the content of the vials, use a larger plastic syringe (not provided) to pool the solution into the syringe and administer as usual.

Rate of Administration

The entire dose of KOVALTRY can usually be infused within 1 to 15 minutes. Your healthcare provider will determine the rate of administration that is best for you.

Resources at Bayer available to the patient:

For Adverse Reaction Reporting, contact Bayer Medical Communications 1-888-84-BAYER (1-888-842-2937)

To receive more product information, contact KOVALTRY Customer Service 1-888-606-3780

Bayer Reimbursement HELPline 1-800-288-8374

For more information, visit www.KOVALTRY-us.com

Bayer HealthCare LLC Whippany, NJ 07981 USA

U.S. License No. 8


1

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KOGENATE FS safely and effectively. See full prescribing information for KOGENATE FS. KOGENATE FS (Antihemophilic Factor [Recombinant], Formulated with Sucrose) For Intravenous Use, Lyophilized Powder for Reconstitution with Vial Adapter Initial U.S. Approval: 1993 --------------------------- INDICATIONS AND USAGE -------------------------- Kogenate FS is an Antihemophilic Factor (Recombinant) indicated for: On-demand treatment and control of bleeding episodes in adults and

children with hemophilia A. Perioperative management of bleeding in adults and children with

hemophilia A. Routine prophylaxis to reduce the frequency of bleeding episodes in

children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage.

Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A.

Kogenate FS is not indicated for the treatment of von Willebrand disease. ---------------------- DOSAGE AND ADMINISTRATION ---------------------- For intravenous use only. Each vial of Kogenate FS contains the labeled amount of recombinant

factor VIII in international units (IU, unit). Control of bleeding episodes and perioperative management (2.1): Dose (units) = body weight (kg) x desired factor VIII rise (IU/dL or %

of normal) x 0.5 (IU/kg per IU/dL). Titrate doses to patient’s clinical response. Determine treatment frequency based on type of bleeding episode. For routine prophylaxis in adults: 25 units per kg three times a week (2.1).

For routine prophylaxis in children: 25 units per kg every other day (2.1).

--------------------- DOSAGE FORMS AND STRENGTHS -------------------- Available as lyophilized powder in single use vials containing nominally 250, 500, 1000, 2000, and 3000 IU (3). Kogenate FS is provided with a sterile vial

adapter with 15-micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

------------------------------ CONTRAINDICATIONS ----------------------------- Do not use in patients who have life-threatening hypersensitivity reactions, including anaphylaxis to mouse or hamster protein or other constituents of the product (4).

----------------------- WARNINGS AND PRECAUTIONS ---------------------- Hypersensitivity reactions, including anaphylaxis, are possible. Should

symptoms occur, discontinue treatment with Kogenate FS and administer appropriate treatment (5.1).

Development of activity-neutralizing antibodies can occur in patients receiving factor VIII-containing products, including Kogenate FS. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration (5.2).

When clotting is normalized by treatment with factor VIII, development of cardiovascular risk factors may be the same as the risk for non-hemophilic patients (5.3).

Monitor plasma factor VIII levels during infusions when indicated (5.4).

------------------------------ ADVERSE REACTIONS ----------------------------- The most common adverse reactions (≥4%) in clinical trials are inhibitor formation (neutralizing antibodies) in previously untreated and minimally treated patients (PUPs and MTPs), skin-associated hypersensitivity reactions (e.g., rash, pruritus, urticaria), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) associated infections.


----------------------- USE IN SPECIFIC POPULATIONS ---------------------- Pregnancy: No human or animal data. Use only if clearly needed (8.1). Pediatric Use: Higher factor VIII clearance may occur in children (4.4–

16 years). Dose adjustment may be needed (8.4).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 5/2016

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION


3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions 5.2 Neutralizing Antibodies 5.3 Cardiovascular Risk Factors 5.4 Monitoring Laboratory Tests

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use

11 DESCRIPTION 12 CLINICAL PHARMACOLOGY


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION


Kogenate® FS is a recombinant antihemophilic factor indicated for:

On-demand treatment and control of bleeding episodes in adults and children with hemophilia A. Perioperative management of bleeding in adults and children with hemophilia A.

HOME Kogenate® FS Prescribing Information

2

Routine prophylaxis to reduce the frequency of bleeding episodes in children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage.

Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A.

Kogenate FS is not indicated for the treatment of von Willebrand disease.


For intravenous use after reconstitution only.

2.1 Dose Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of

bleeding, and the patient’s clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.

Each vial of Kogenate FS has the recombinant factor VIII (rFVIII) potency in international units (IU, unit) stated on

the label. One IU (unit), as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas:

Dosage (units) = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

or

IU/dL (or % normal) = Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg]

Titrate dose to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Kogenate FS.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that appropriate laboratory tests, including serial factor VIII activity assays, are performed [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

On-Demand Treatment and Control of Bleeding Episodes

A guide for dosing Kogenate FS for on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.


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Table 1 Dosing for On-Demand Treatment and Control of Bleeding Episodes

Type of Bleeding Episodes


normal)

Dose (IU/kg)

Frequency of Doses (hours)

Duration of Therapy (days)

Minor Early hemarthrosis, minor muscle or oral bleeds.

20 – 40 10 – 20 Repeat dose if there is evidence of further bleeding.

Until bleeding is resolved

Moderate Bleeding into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma.

30 – 60 15 – 30 12 – 24 Until bleeding is resolved

Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath. Fractures. Head trauma.

80 – 100 Initial: 40 – 50 Repeat: 20 – 25

8 – 12 Until bleeding is resolved

Perioperative Management of Bleeding

A guide for dosing Kogenate FS during surgery (perioperative management of bleeding) is provided in Table 2. The goal of treatment is to maintain a plasma factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2.

Table 2 Dosing for Perioperative Management of Bleeding

Type of Surgery


normal)

Dose (IU/kg)

Frequency of Doses (hours)

Duration of Therapy (days)

Minor Including tooth extraction

30 – 60 15 – 30 12 – 24

Until bleeding is resolved.

Major Examples include tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma.

100 50 Pre-operatively to achieve 100% activity.

6 – 12 to keep FVIII activity in desired range

Until healing is complete.


4

Routine Prophylaxis in Adults

The recommended dose for routine prophylaxis is 25 units per kg of body weight three times per week.

Routine Prophylaxis in Children

The recommended dose for routine prophylaxis is 25 units per kg of body weight every other day.5

2.2 Preparation and Reconstitution Kogenate FS is administered by intravenous injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.

Reconstitute and administer Kogenate FS with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

Product reconstitution, administration, and handling of the administration set and needles must be done with caution because percutaneous puncture with a needle contaminated with blood can transmit infectious viruses, including HIV (AIDS) and hepatitis. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Kogenate FS product, in an appropriate container. Obtain immediate medical attention if injury occurs.

For any questions about the handling, reconstitution and administration of Kogenate FS, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).

For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling.

The procedures below are provided as general guidelines for the reconstitution of Kogenate FS provided with a sterile vial adapter with 15-micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures.

Reconstitute Kogenate FS with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

Filter the reconstituted product prior to administration to remove potential particulate matter in the solution. Filtering can be achieved by using the vial adapter.

Vacuum Transfer and Reconstitution

1. Prepare the product under aseptic conditions. 2. Warm both unopened vial and syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F). 3. Remove protective cap from the vial (A). Aseptically cleanse the rubber stopper with alcohol, being careful not to

handle the rubber stopper. 4. Place product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not

remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.


6. Now remove and discard the adapter housing (D). 7. Attach the prefilled syringe to the threaded vial adapter by turning clockwise (E). 8. Grasp the plunger rod by the top plate and remove from carton. Avoid touching the sides and threads of the

plunger rod. Immediately attach the plunger rod by turning it firmly clockwise into the threaded syringe rubber stopper (F).

9. Inject the diluent by slowly pushing down on the plunger rod (G).


5

10. Swirl vial gently until all material is dissolved (H). Do not shake vial. Be sure that the powder is completely dissolved. Do not use solutions containing visible particles or that are cloudy.

11. Withdraw solution into the syringe by holding the vial on end above the vial adapter and syringe (I) then draw the plunger rod out slowly and smoothly. Ensure that the entire content of the vial is drawn into the syringe.

12. With the plunger rod in place, remove the syringe from the vial adapter (the latter should remain attached to the vial). Attach the syringe to the administration set provided and inject intravenously (J).

13. If the same patient is to receive more than one bottle, reconstitute each bottle with the diluent syringe provided then combine solutions in a larger syringe (not provided) and administer as usual.

2.3 Administration For intravenous use after reconstitution only.

Inspect Kogenate FS visually for particulate matter and discoloration prior to administration, wherever solution and container permit. Do not use Kogenate FS if you notice any particulates or turbidity in the solution.

Store the reconstituted Kogenate FS at room temperature prior to administration, but administer it within 3 hours.

Administer Kogenate FS using the administration set provided over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient. Determine the pulse rate before and during administration of Kogenate FS. If there is a significant increase in pulse rate, reduce the rate of administration or temporarily halt the infusion allowing the symptoms to disappear promptly.


Kogenate FS is available as a lyophilized powder in single use glass vials containing nominally 250, 500, 1000, 2000, and 3000 International Units (IU, unit).

Each vial of Kogenate FS is labeled with the recombinant antihemophilic factor activity expressed in International Units per vial. This potency assignment employs a factor VIII concentrate standard that is referenced to a WHO International Standard for factor VIII concentrates, and is evaluated by appropriate methodology to ensure accuracy of the results.

4 CONTRAINDICATIONS

Kogenate FS is contraindicated in patients who have life-threatening hypersensitivity reactions, including anaphylaxis to mouse or hamster protein or other constituents of the product (sucrose, glycine, histidine, sodium, calcium chloride, polysorbate 80, imidazole, tri-n-butyl phosphate, and copper).


6


5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis have been reported with Kogenate FS. Reported symptoms included facial swelling, flushing, hives, decrease in blood pressure, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, and vomiting.

Kogenate FS contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins [see Description (11)]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment.

5.2 Neutralizing Antibodies Neutralizing antibodies (inhibitors) have been reported following administration of Kogenate FS, predominantly in previously untreated patients (PUPs) [see Adverse Reactions (6)]. Carefully monitor patients for the development of factor VIII inhibitors, using appropriate clinical observations and laboratory tests.6 If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration [see Warnings and Precautions (5.4)].

5.3 Cardiovascular Risk Factors Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII.

5.4 Monitoring Laboratory Tests Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels

have been achieved and maintained, when clinically indicated [see Dosage and Administration (2)]. Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present. If

expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Kogenate FS, use Bethesda Units (BU) to titer inhibitors. ◦ If the inhibitor is less than 10 BU per mL, the administration of additional Kogenate FS concentrate may

neutralize the inhibitor and may permit an appropriate hemostatic response. o If inhibitor titers are above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise

following Kogenate FS infusion as a result of an anamnestic response to factor VIII. The on-demand treatment and control of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

6 ADVERSE REACTIONS

Serious adverse reactions seen with Kogenate FS are systemic hypersensitivity reactions, including bronchospastic reactions and/or hypotension and anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

The most common adverse reactions (≥ 4%) observed in clinical trials were inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., rash, pruritus), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) associated infections.


7

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

Previously Treated Patients (PTPs)

During the open-label clinical studies conducted in 73 PTPs, there were 24 adverse reactions reported in the course of 24,936 infusions.

Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

Table 3 Adverse Reactions (AR) in Previously Treated Patients with Frequency of ≥ 4% (Age Range 12–59 years)

MedDRA Primary SOC Preferred Term N = 73 AR (%)

Skin and Subcutaneous Tissue Disorders

Rash, pruritus 6 (8.2%)

General Disorders and Administration Site Conditions

Infusion site reactions 3 (4.1%)

SOC = System Organ Class

Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)

In clinical studies with pediatric PUPs and MTPs, there were 29 adverse reactions reported in the course of 9,389 infusions.

Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

Table 4 Adverse Reactions (AR) in Previously Untreated Patients and Minimally Treated Patients with Frequency of ≥ 4% (Age Range 2–27 months)

MedDRA Primary SOC Preferred Term N = 61 AR (%)

Skin and Subcutaneous Tissue Disorders

Rash, pruritus, urticaria

10 (16%)

Blood and Lymphatic System Disorders

Factor VIII inhibition (neutralizing antibodies)

9 (15%)†

General Disorders and Administration Site Conditions

Infusion site reactions 4 (7%)

SOC = System Organ Class † Denominator for de novo inhibitors is N = 60, since one patient had a pre-existing inhibitor.

Minimally Treated Patients (MTPs) in the Joint Outcome Study

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration.


8

Table 5 Adverse Reactions in Minimally Treated Patients in the Joint Outcome Study (Age Range 0–6 years)

MedDRA Primary SOC Preferred Term Prophylaxis Arm N = 32

AR (%)

Enhanced Episodic Arm N = 33

AR (%) Surgical and Medical Procedures

Central venous catheterization, Catheter removal

19 (59%) 18 (55%)‡

Infections and Infestations Central line infection 6 (19%) 6 (18%) General Disorders and Administration Site Conditions

Pyrexia 1 (3%) 4 (12%)

SOC = System Organ Class ‡ Three patients from the enhanced episodic arm had catheter removal.

Immunogenicity

In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor. In the other 72 patients, followed over 4 years, no de novo inhibitors were observed.

In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 (> 5 BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).

In the Joint Outcome Study with Kogenate FS,5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (> 5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).

Inhibitor data in PUPs have been collected in several postmarketing registries [see Postmarketing Experience (6.2)].

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kogenate FS with the incidence of antibodies to other products may be misleading.

6.2 Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reaction has been identified during post approval use of Kogenate FS:

Sensory System – Dysgeusia

Immunogenicity – Postmarketing Registries

Data from the Research of Determinants of Inhibitor Development (RODIN) study7, French National Registry (FranceCoag)8 and United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO)9 registry reported an inhibitor development rate in PUPs for Kogenate FS of 38%, 50% and 35%, respectively, which is comparable to previously-reported inhibitor rates10 for FVIII products. These registry studies show a trend towards an increased risk of inhibitor development in PUPs, as compared to the reference rFVIII product. A survey of Canadian hemophilia centers11 (2005 to 2012) and available data from the European Haemophilia Safety Surveillance (EUHASS) 12 registry from 2009


9

to 2013, reported an inhibitor development rate in PUPs for Kogenate FS of 42% and 31%, respectively, with no statistically significant differences observed across FVIII products.


8.1 Pregnancy Pregnancy Category C.

Animal reproduction studies have not been conducted with Kogenate FS. It is also not known whether Kogenate FS can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Kogenate FS should be given to a pregnant woman only if clearly needed.

8.2 Labor and Delivery There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Kogenate FS should be used only if clinically needed.

8.3 Nursing Mothers It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Kogenate FS is administered to a nursing woman.

8.4 Pediatric Use Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children, in comparison to adults, present higher factor VIII clearance values and, thus, lower half-life and recovery of factor VIII. This may be due to differences in body composition.13 Account for this difference in clearance when dosing or following factor VIII levels in the pediatric population [see Clinical Pharmacology (12.3)].

Routine prophylactic treatment in children ages 0–2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5–16 years for children who have no existing joint damage [see Clinical Studies (14)].

8.5 Geriatric Use Clinical studies with Kogenate FS did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.

11 DESCRIPTION

Kogenate FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced.14 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Kogenate FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Kogenate FS.

The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances.


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Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.15-19 Several of the individual production and raw material preparation steps in the Kogenate FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. These TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10).

Kogenate FS is formulated with the following as stabilizers (see Table 6) in the final container and is then lyophilized. The final product does not contain any preservative. It is a sterile, nonpyrogenic, powder preparation for intravenous injection. Intravenous administration of sucrose contained in Kogenate FS will not affect blood glucose levels.

Table 6 Stabilizers Contained in Kogenate FS Final Container

Stabilizer 250 IU, 500 IU, 1000 IU Nominal Vial Sizes

2000 IU, 3000 IU Nominal Vial Sizes

Sucrose 0.9–1.3% 0.9–1.2% Glycine 21–25 mg/mL 20–24 mg/mL Histidine 18–23 mmol/L 17–22 mmol/L

Table 7 lists the inactive ingredients/excipients also contained in the final product.

Table 7 Inactive Ingredients/Excipients

Inactive Ingredient/Excipient 250 IU, 500 IU, 1000 IU 2000 IU, 3000 IU Sodium 27–36 mEq/L 26–34 mEq/L Calcium 2.0–3.0 mmol/L 1.9–2.9 mmol/L Chloride 32–40 mEq/L 31–38 mEq/L Polysorbate 80 64–96 µg/mL 64–96 µg/mL Sucrose 28 mg/vial 52 mg/vial Imidazole, tri-n-butyl phosphate, and copper

Trace amounts Trace amounts


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

12.2 Pharmacodynamics The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of 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.

12.3 Pharmacokinetics The pharmacokinetic properties of Kogenate FS were investigated in two separate studies in adult and pediatric previously treated patients (PTPs).

Pharmacokinetic studies with Kogenate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A. The pharmacokinetic parameters for Kogenate FS were measured in a randomized, crossover clinical trial with the predecessor KOGENATE product using a single dose administration of 50 IU per 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 8).


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Table 8 Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE

Parameter Kogenate FS KOGENATE Initial PK

(Mean±SD) PK at week 24

(Mean±SD)Reference

(Mean±SD) AUC (IU•h/dL) 1588.05 ± 344.32 1487.08 ± 381.73 1879.02 ± 412.32 Cmax (IU/dL) 114.95 ± 20.19 109.42 ± 20.09 127.40 ± 33.21 Half-life (hr) 13.74 ± 1.82 14.60 ± 4.38 14.07 ± 2.62 In Vivo Recovery (IU/dL / IU/kg)

2.20 ± 0.34 2.11 ± 0.37 2.43 ± 0.60

The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4–18.1 years of age, average age 12).13 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. The pharmacokinetic parameters are depicted in Table 9.

Table 9 Pharmacokinetic Parameters for Kogenate FS in Children

Parameter Mean (range) AUC (IU•h/dL) 1320.0 Clearance (mL/h•kg) 4.1 Half-life (hr) 10.7 (7.8–15.3) In Vivo Recovery (IU/dL / IU/kg) 1.9 (1.25–2.76)


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted with Kogenate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. By inference, the predecessor KOGENATE product and Kogenate FS would be expected to have equivalent mutagenic and carcinogenic potential.

The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

13.2 Animal Toxicology and/or Pharmacology Preclinical studies evaluating Kogenate FS in hemophilia A with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of hemostasis. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Kogenate FS in laboratory animals.

Kogenate FS has been shown to be comparable to the predecessor KOGENATE product with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology.

14 CLINICAL STUDIES

Previously Treated Patients (PTPs) Clinical Studies

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.


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A total of 5,684 bleeding episodes were treated during the studies; 92.7% of the bleeds were treated with one (79.7%) or two (13.0%) infusions. Patients could be treated with on-demand or prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2–3 infusions per week).

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. Efficacy was measured by the attending surgeon based on a comparison of estimated blood loss from experience with non-hemophilic patients undergoing similar procedures. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories: “excellent (blood loss less than expected),” “good (blood loss as expected),” “moderate (blood loss more than expected),” or “none (uncontrolled bleeding).” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases.

Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) Clinical Study

Kogenate FS has been used in the treatment of bleeding episodes in pediatric PUPs and 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; the bleeds were treated with one (73%) or two (15%) infusions.

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 attending surgeon measured efficacy and assigned a rating to the hemostatic outcome according to 4 categories as described above for PTPs. Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases.

Adult Prophylaxis for Bleeding Frequency Reduction

A 3-year, multicenter, open-label, parallel-group, prospective, randomized, controlled clinical study of the effect of routine prophylaxis with Kogenate FS versus on-demand use on bleeding frequency in adults and adolescents included 84 PTPs with severe Hemophilia A (FVIII level < 1 IU/dL), age 15 to 50 years. Patients were matched at baseline on demographic and disease characteristics. The median number of bleeds in the year before enrollment was 18.

Patients were randomized 1:1 to prophylaxis (25 units per kg three times a week) or on-demand use of Kogenate FS. Escalation of the prophylaxis dose by 5 units per kg/infusion after years 1 and 2, up to a maximum of 35 units per kg/infusion, was allowed.

Bleeding frequency was analyzed in the intent-to-treat population after a median follow-up period of 1.4 years. Patients who received prophylaxis experienced statistically significantly fewer bleeds (p<0.0001) compared to patients treated on-demand regardless of baseline subgroups examined including age, bleeding history, and presence or absence of target joints. The ratio of the mean bleeding frequency was 15.2 (95% CI: 8.5, 27.2; p<0.0001) for on-demand versus prophylaxis, indicating that patients who received on-demand treatment experienced on average 15.2 times as many bleeds compared to patients treated with prophylaxis. The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate (bleeds/subject/year) in the on-demand group was 33 versus zero in the prophylaxis group. Most of the bleeding occurred in joints: the median joint bleed rate (joint bleeds/subject/year) was 24 in the on-demand group versus zero in the prophylaxis group. The mean annualized joint bleed rate was 29 in the on-demand group versus 2 in the prophylaxis group.

Twenty-two of 42 (52%) prophylaxis subjects experienced no bleeding, and 12 of 42 (29%) prophylaxis subjects experienced only 1–2 bleeds during the follow-up period.

Among prophylaxis patients the mean number of infusions/week was 2.8, and the median dose per prophylaxis infusion was 26 units per kg.


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Pediatric Prophylaxis for 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 per kg every other day (primary prophylaxis; n = 32) or at least 3 doses totaling a minimum of 80 IU per 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 10 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.,20 and X-rays were scored using the method of Pettersson et al.21 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 10 Subjects with Joint Damage (Subjects with Available Baseline and Endpoint Data)

Endpoint Assessment

Prophylaxis Episodic Therapy p-value Incidence (%) Relative Risk

(95% CI) Incidence (%) Relative Risk

(95% CI) MRI 2/27 (7%) 0.17 (0.04, 0.67) 13/29 (45%) 6.05 (1.50, 24.38) 0.002 Radiography 1/28 (4%) 0.19 (0.02, 1.55) 5/27 (19%) 5.19 (0.65, 41.54) 0.101 MRI or Radiography

2/30 (7%) 0.16 (0.04, 0.65) 13/31 (42%) 6.29 (1.55, 25.55) 0.002

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.

15 REFERENCES

1. White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, for the Factor VIII and Factor IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definitions in hemophilia. Thromb Haemost 85:560-75, 2001.

2. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. N Engl J Med 275(9):471–5, 1966.


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3. Schwartz RS, Abildgaard CF, Aledort LM, et al: Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. Recombinant Factor VIII Study Group. N Engl J Med 323(26):1800-5, 1990.

4. White GC 2nd, Courter S, Bray GL, et al: A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. The Recombinate Previously Treated Patient Study Group. Thromb Haemost 77(4):660-667, 1997.

5. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357(6):535-44.

6. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors. Ann NY Acad Sci 614:97-105, 1991. 7. Gouw SC, van den Berg HM, et al: Intensity of factor VIII treatment and inhibitor development in children with

severe hemophilia A: the RODIN study. Blood 121(20): 4046-4055, 2013. 8. Calvez T, Chambost H, et al: Recombinant factor VIII products and inhibitor development in previously untreated

boys with severe hemophilia A. Blood 124(23): 3398-3408, 2014. 9. Collins PW, Palmer BP, et al: Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated

UK children with severe hemophilia A, 2000-2011. Blood 124(23): 3389-3397, 2014. 10. Franchini M, Coppola A, et al: Systematic Review of the Role of FVIII Concentrates in Inhibitor Development in

Previously Untreated Patients with Severe Hemophilia A: A 2013 Update. Semin Throm Hemost (39): 752-766, 2013.

11. Vezina C, Carcao M, et al: Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010. Haemophilia 20(6): 771-776, 2014.

12. Fisher K, Lassila, R, et al. Inhibitor development in haemophilia according to concentrate: Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 113.4, 2015.

13. Barnes C, Lillicrap D, Pazmino-Canizares J, et al: Pharmacokinetics of recombinant factor VIII (Kogenate-FS®) in children and causes of inter-patient pharmacokinetic variability. Haemophilia 12 (Suppl. 4): 40-49, 2006.

14. Lawn RM, Vehar GA: The molecular genetics of hemophilia. Sci Am 254(3):48–54, 1986. 15. Stenland CJ, et al: Partitioning of human and sheep forms of the pathogenic prion protein during the purification of

therapeutic proteins from human plasma. Transfusion 42(11):1497-500, 2002. 16. Lee DC, Miller JL, Petteway SR: Pathogen safety of manufacturing processes for biological products: special

emphasis on KOGENATE® Bayer. Haemophilia 8(Suppl. 2):6-9, 2002. 17. Lee DC, Stenland CJ, Miller JL, et al: A direct relationship between the partitioning of the pathogenic prion protein

and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 41(4):449-55, 2001.

18. Cai K, Miller JL, Stenland CJ, et al: Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 1597(1):28-35, 2002.

19. Trejo SR, Hotta JA, Lebing W, et al: Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 84(3):176-87, 2003.

20. 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.

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


How Supplied

Kogenate FS with vial adapter, with 15-micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system, is supplied in the following single use glass vial sizes. A prefilled diluent syringe containing Sterile Water for Injection, USP, a sterile vial adapter for reconstitution, and an administration set are also provided.


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Kit NDC Number Approximate FVIII Activity (IU) Diluent (mL)

0026-3782-25 250 2.5

0026-3783-35 500 2.5

0026-3785-55 1000 2.5

0026-3786-65 2000 5.0

0026-3787-75 3000 5.0

Actual factor VIII activity in IU is stated on the label of each Kogenate FS Vial. Use the actual potency as indicated on the vial label to calculate the dose.


The product vial and diluent syringe are not made with natural rubber latex.

Product as Packaged for Sale

Store Kogenate FS at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Kogenate FS may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature, or after the expiration date on the product vial, whichever is earlier.

Do not use Kogenate FS after the expiration date indicated on the vial. Do not freeze. Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use.

Product After Reconstitution

After reconstitution, store the Kogenate FS solution at room temperature and administer within 3 hours. Use the administration set provided.


Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Advise patients to report any adverse reactions or problems following Kogenate FS administration to their physician

or healthcare provider. Allergic-type hypersensitivity reactions have been reported with Kogenate FS. Warn patients of the early signs of

hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.

Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

Advise patients to consult with their healthcare provider prior to travel. While traveling advise patients to bring an adequate supply of Kogenate FS based on their current regimen of treatment.


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FDA-Approved Patient Labeling

Patient Information

Kogenate FS (kō-jen-ate)

Antihemophilic Factor (Recombinant)

Formulated with Sucrose

This leaflet summarizes important information about Kogenate FS with vial adapter. 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 Kogenate FS. If you have any questions after reading this, ask your healthcare provider.


What is Kogenate FS?

Kogenate FS is a 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.

Kogenate FS is used to treat and control bleeding in adults and children with hemophilia A. Your healthcare provider may give you Kogenate FS when you have surgery. Kogenate FS can reduce the number of bleeding episodes when used regularly (prophylaxis). Kogenate FS can reduce the risk of joint damage in children.

Kogenate FS is not used to treat von Willebrand Disease.

Who should not use Kogenate FS?

You should not use Kogenate FS if you

are allergic to rodents (like mice and hamsters). are allergic to any ingredients in Kogenate FS.

Tell your healthcare provider if you are pregnant or breast-feeding because Kogenate FS may not be right for you.

What should I tell my healthcare provider before I use Kogenate FS?

Tell your healthcare provider about all of your medical conditions.

Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies.

Tell your healthcare provider if you have been told you have heart disease or are at risk for heart disease.

Tell your healthcare provider if you have been told that you have inhibitors to factor VIII (because Kogenate FS may not work for you).

What are the possible side effects of Kogenate FS?

You could have an allergic reaction to Kogenate FS. Call your healthcare provider right away and stop treatment if you get


17

rash or hives itching tightness of the chest or throat difficulty breathing light-headed, dizziness nausea decrease in blood pressure

Your body can also make antibodies, called “inhibitors,” against Kogenate FS, which may stop Kogenate FS 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.

Other common side effects of Kogenate FS are

Local injection site reactions (pain, swelling, irritation at infusion site) Infections from implanted injection device

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

Finding veins for injections may be difficult in young children. When frequent injections are required your child's healthcare provider may propose to have a device surgically placed under the skin to facilitate access to the bloodstream. These devices may result in infections.

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

How do I store Kogenate FS?

Do not freeze Kogenate FS.

Store Kogenate FS at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Kogenate FS may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage clearly on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The product then expires after storage at room temperature, or after the expiration date on the product vial, whichever is earlier. Store vials in their original carton and protect them from extreme exposure to light.

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

Throw away any unused Kogenate FS after the expiration date.

Do not use reconstituted Kogenate FS if it is not clear to slightly cloudy and colorless.

What else should I know about Kogenate FS and hemophilia A?

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

This leaflet summarizes the most important information about Kogenate FS. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Kogenate FS that was written for healthcare professionals.


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Instructions for use

How should I take Kogenate FS?


See the step-by-step instructions for reconstituting Kogenate FS at the end of this leaflet and the specific infusion instruction leaflet provided.

You should always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using Kogenate FS. 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 Kogenate FS.

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

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

Talk to your healthcare provider before traveling. You should plan to bring enough Kogenate FS for your treatment during this time.

Carefully handle Kogenate FS. Dispose of all materials, including any leftover reconstituted Kogenate FS product, in an appropriate container.

Reconstitution and use of Kogenate FS

Always work on a clean surface and wash your hands before performing the following procedure. Use only the components for reconstitution and administration that are provided with each package of Kogenate FS. If a package is opened or damaged, do not use this component. If these components cannot be used, please contact your healthcare provider. If you have any questions about Kogenate FS contact Bayer at 1-888-84-BAYER (1-888-842-2937).

1. Warm the unopened diluent and the concentrate to a temperature not to exceed 37°C or 99°F.

2. Remove protective cap from the vial (A). Aseptically cleanse the rubber stopper with alcohol, being careful not to handle the rubber stopper.

3. Place product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.



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5. Now remove and discard the adapter housing (D).

6. Attach the prefilled syringe to the threaded vial adapter by turning clockwise (E).

7. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Immediately attach the plunger rod by turning it firmly clockwise into the threaded syringe rubber stopper (F).

8. Inject the diluent by slowly pushing down on the plunger rod (G).

9. Swirl vial gently until all material is dissolved (H). Do not shake vial. Be sure that the powder is completely dissolved. Do not use solutions containing visible particles or that are cloudy.

10. Withdraw solution into the syringe by holding the vial on end above the vial adapter and syringe (I) then draw the plunger rod out slowly and smoothly. Ensure that the entire content of the vial is drawn into the syringe.

11. With the plunger rod in place, remove the syringe from the vial adapter (the latter should remain attached to the vial). Attach the syringe to the administration set provided and inject intravenously (J). NOTE: follow instructions for infusion set provided.


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12. If the same patient is to receive more than one bottle, reconstitute each bottle with the diluent syringe provided then combine solutions in a larger syringe (not provided) and administer as usual.

Rate of administration

The entire dose of Kogenate FS can usually be infused within 1 to 15 minutes. However, your healthcare provider will determine the rate of administration that is best for you.

Resources at Bayer available to the patient:

For Adverse Reaction Reporting contact:

Bayer Medical Communications 1-888-84-BAYER (1-888-842-2937)

Contact Bayer to receive more product information:

Kogenate FS Customer Service 1-888-606-3780

Bayer Reimbursement HELPline 1-800-288-8374

For more information, visit www.kogenatefs.com

Bayer HealthCare LLC Whippany, NJ 07981 USA

U.S. License No. 8

(License Holder: Bayer Corporation)

http://www.kogenatefs.com/


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