Kogenate FS

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 with the administration set provided with the product as it incorporates an in-line filter. In situations where the administration set provided cannot be used (e.g. when infusing into a peripheral or central line), use a separate filter compatible with Kogenate FS.
•   NOTE: Do not use the administration set provided with the product to draw blood because it contains an in-line filter. When blood must be withdrawn prior to an infusion, use an administration set without a filter, then infuse Kogenate FS through an injection filter. For any questions about compatible separate filters, contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).

• •Administer Kogenate FS 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.

3 DOSAGE FORMS AND STRENGTHS

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 IU 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, sucrose, imidazole, tri-n-butyl phosphate, and copper).

5 WARNINGS AND PRECAUTIONS

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. 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 (5.3)].

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.

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 treatment or prevention 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.

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.

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.

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.

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.

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).

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

The following adverse reaction has been identified during post approval use of Kogenate FS. 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.

Sensory System – Dysgeusia

Additionally, available registries have reported inhibitor rates for PUPs with severe hemophilia A in the range of 28% to 38% for factor VIII products.

8 USE IN SPECIFIC POPULATIONS

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.⁷ 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.⁸ 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.

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.^9-13 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 7 lists the inactive ingredients/excipients also contained in the final product.

12 CLINICAL PHARMACOLOGY

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).

The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4–18.1 years of age, average age 12).⁷ The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. The pharmacokinetic parameters are depicted in Table 9.

13 NONCLINICAL TOXICOLOGY

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. 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

An ongoing, 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.

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.,¹⁴ and X-rays were scored using the method of Pettersson et al.¹⁵ 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.

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

• •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.
• •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.
• •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.
• •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.
• •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.
• •Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors. Ann NY Acad Sci 614:97-105, 1991.
• •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.
• •Lawn RM, Vehar GA: The molecular genetics of hemophilia. Sci Am 254(3):48–54, 1986.
• •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.
• •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.
• •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.
• •Cai K, Miller JL, Stenland CJ, et al: Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 1597(1):28-35, 2002.
• •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.
• •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.
• •Pettersson H, Ahlberg A, Nilsson IM: A radiologic classification of hemophilia arthropathy. Clin Orthop Relat Res 149:153-159, 1980.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Kogenate FS Antihemophilic Factor (Recombinant) with BIO-SET^®, a needleless self-contained system, is supplied in the following single use glass vial sizes. A prefilled diluent syringe containing Sterile Water for Injection, USP, an administration set, two alcohol swabs, one bandage, and one cotton pad are also provided.

Actual factor VIII activity in IU is stated on the label of each Kogenate FS Vial.

Storage and Handling

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.

17 PATIENT COUNSELING INFORMATION

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.

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 BIO-SET, a needleless self-contained reconstitution system. 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.

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

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 prevent or 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

• •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.

Instructions for use

How should I take Kogenate FS?

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

See the step-by-step instructions for reconstituting Kogenate FS with BIO-SET 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. Prepare

A. Open

The easiest way to remove the cap from the vials is to move the top from side-to-side while pulling upward at the same time. This breaks the small plastic tabs that connect the cap to the top of the vial.