Helixate Fs Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

HELIXATE^® FS is a sterile, stable, purified, nonpyrogenic, dried product, which has been manufactured by recombinant DNA technology.

INDICATIONS AND CLINICAL USE

HELIXATE FS (Antihemophilic Factor [Recombinant]) is indicated for the treatment of classical hemophilia (hemophilia A), in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII (FVIII). HELIXATE FS provides a means of temporarily replacing the missing clotting factor in order to correct or prevent bleeding episodes, or in order to perform emergency or elective surgery in persons with hemophilia.

When used as a regular prophylactic treatment, HELIXATE FS is indicated:

• to prevent the occurrence of spontaneous hemorrhagic episodes and to prevent joint damage in children with no pre-existing joint damage (see Product Monograph Part II: CLINICAL TRIALS – Pediatric Prophylaxis).
• to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A (see Product Monograph Part II: CLINICAL TRIALS – Adult Prophylaxis).

Because HELIXATE FS showed comparable biological activity to other FVIII preparations, it should be used in the same manner as HELIXATE (Antihemophilic Factor [Recombinant]). This includes treatment of bleeding in certain patients with inhibitors to FVIII. In clinical studies of HELIXATE, some patients who developed inhibitors on study continued to manifest a clinical response when inhibitor titers were less than 10 Bethesda Units (B.U.) per mL. When an inhibitor is present, the dosage requirement for FVIII is variable. The dosage can be determined only by clinical response and by monitoring of circulating FVIII levels after treatment (see DOSAGE AND ADMINISTRATION).

HELIXATE FS does not contain von Willebrand Factor and therefore, is not indicated for the treatment of von Willebrand disease.

Geriatrics (>65 years of age)

Clinical studies with HELIXATE FS did not include sufficient numbers of patients aged 65 and over to be able to determine whether they respond differently from younger patients. However, clinical experience with HELIXATE and other FVIII products has not identified differences between the elderly and younger patients. As with any patient receiving HELIXATE FS, dose selection for an elderly patient should be individualized.

Pediatrics (<18 years of age)

HELIXATE FS is appropriate for use in pediatric patients. Safety and efficacy studies have been performed in two studies (n=60) in less than 4 year old previously untreated and minimally treated pediatric patients.

CONTRAINDICATIONS

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section.
• Known hypersensitivity to mouse or hamster protein.

WARNINGS AND PRECAUTIONS

General

HELIXATE FS (Antihemophilic Factor [Recombinant]) is intended for the treatment of bleeding disorders arising from a deficiency in FVIII. This deficiency should be proven prior to administering HELIXATE FS.

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

Persons with hemophilia who have 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 FVIII.

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

Carcinogenesis and Mutagenesis

See Product Monograph PART II: TOXICOLOGY – Carcinogenicity/Mutagenesis Product Monograph for details.

Immune

The development of circulating neutralizing antibodies to FVIII may occur during the treatment of patients with hemophilia A. Inhibitor formation is especially common in young children with severe hemophilia during their first years of treatment or in patients of any age who have received little previous treatment with FVIII. Nonetheless, inhibitor formation may occur at any time in the treatment of a patient with hemophilia A. Patients treated with any rFVIII preparation, including rFVIII-FS, should be carefully monitored for the development of antibodies to rFVIII by appropriate clinical observation and laboratory tests, according to the recommendation of the patient’s hemophilia treatment center. In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent thrombophlebitis at the infusion site, as with any other long-term intravenous infusions.

Among patients treated with antihemophilic factor products, cases of hypotension, urticaria, and chest tightness in association with hypersensitivity reactions have been reported in the literature. Very rare cases of allergic and anaphylactic reactions have been reported with the predecessor product HELIXATE (Antihemophilic Factor [Recombinant]), particularly in very young patients or patients who have previously reacted to other FVIII products (see ADVERSE REACTIONS – Postmarket Adverse Drug Reactions). Serious anaphylactic reactions require immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.

In clinical studies, HELIXATE FS has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients ([MTPs], defined as having equal to or less than 4 exposure days). Bleeding episodes were treated effectively with 1 or 2 infusions of rFVIII-FS. Overall, 9 out of 60 (15%) patients developed inhibitors. This included 5 out of 37 (14%) PUPs and 4 out of 23 (17%) MTPs patients treated with HELIXATE FS, overall 6 out of 60 (10%) with a titer above 10 BU and 3 out of 60 (5%) with a titer below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range: 3-18 days). (1, 2)

The median number of exposure days in the clinical studies was 114 (range: 4–478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in poststudy follow-up and 1 of them developed a low titer inhibitor. The fifth patient was lost to follow-up.

Formation of Antibodies to Mouse and Hamster Protein

Assays to detect seroconversion to mouse and hamster protein were conducted on all patients in clinical studies. None of the patients developed specific antibodies to these proteins following study enrollment and no animal protein associated serious allergic reactions have been observed with rFVIII-FS infusions. Although no such reactions were observed, patients should be made aware of the possibility of a hypersensitivity reaction to mouse and/or hamster protein and alerted to the early signs of such a reaction (eg, hives, localized or generalized urticaria, wheezing, and hypotension). Patients should be advised to discontinue use of the product and contact their physician if such symptoms occur.

Special Populations

Pregnant Women

Animal reproduction studies have not been conducted with HELIXATE FS. It is also not known whether HELIXATE FS can cause fetal harm when administered to a pregnant woman or whether it affects reproduction capacity. HELIXATE FS should not be used during pregnancy unless the benefits clearly outweigh any potential risks. As the disease almost exclusively affects males, no females have been included in clinical studies.

Nursing Women

HELIXATE FS should not be used during lactation unless the benefits clearly outweigh any potential risks.

Geriatrics (>65 years of age)

Clinical studies with HELIXATE FS did not include sufficient numbers of patients aged 65 and over to be able to determine whether they respond differently from younger patients. However, clinical experience with HELIXATE and other FVIII products has not identified differences between the elderly and younger patients. As with any patient receiving HELIXATE FS, dose selection for an elderly patient should be individualized.

Pediatrics (<18 years of age)

HELIXATE FS is appropriate for use in pediatric patients. Safety and efficacy studies have been performed in two studies (n=60) in less than 4 year old previously untreated and minimally treated pediatric patients. According to a published study (3), children in comparison to adults present higher FVIII clearance values and thus lower recovery of FVIII, which may be explained by differences in pharmacokinetics. This information should be taken into account when dosing or following FVIII levels in such a population (see DOSAGE AND ADMINISTRATION - Dosing Considerations and Product Monograph Part II: CLINICAL TRIALS).

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Monitoring and Laboratory Tests

The clinical effect of HELIXATE FS is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more HELIXATE FS than would be estimated in order to attain satisfactory clinical results. If the calculated dose fails to attain the expected FVIII levels or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests. When an inhibitor is present, the dosage requirement for rFVIII-FS is extremely variable and the dosage can be determined only by the clinical response.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

During the clinical studies conducted in previously treated patients, 451 adverse events were reported in the course of 24,936 infusions (1.8%). Only 24 events in 13 patients were considered to be at least remotely drug-related to rFVIII-FS administration (0.1%, relative to the number of infusions). In clinical studies with 73 PTPs, one patient had a pre-existing inhibitor. In the other 72 patients, followed over four years, no de novo inhibitors were observed.

In clinical studies with previously untreated patients (PUPs) and minimally treated (MTPs) pediatric patients, 726 adverse events were reported in the course of 9,389 infusions (7.7%) These included the expected complication of inhibitor development in 9 patients (see WARNINGS AND PRECAUTIONS – Immune).

Postmarket Adverse Drug Reactions

The following adverse reactions have been identified during postapproval use of HELIXATE FS. Because these 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.

Among patients treated with HELIXATE FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, and vomiting) have been reported, particularly in very young patients or patients who had previously reacted to other FVIII concentrates.

In extensive postregistration studies with HELIXATE FS involving more than 1000 patients, the following was observed: Less than 0.2% of PTPs developed de novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de novo inhibitors.

Available registries have reported inhibitor rates for PUPs with severe hemophilia A in the range of 28 to 38% for FVIII products.

DRUG INTERACTIONS

Drug-Drug Interactions

HELIXATE FS is a recombinant version of FVIII, a physiological human protein. Besides the known interactions of FVIII with other coagulation proteins, no other interactions with other drugs have been established.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal preparations have not been established.

Drug-Laboratory Interactions

There are no known laboratory interactions.

Drug-Lifestyle Interactions

No effects on the ability to drive or to use machines have been observed.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Each bottle of HELIXATE FS (Antihemophilic Factor [Recombinant]) has the rFVIII-FS potency in international units stated on the label based on the one-stage assay methodology. The reconstituted product must be administered intravenously by direct syringe injection. The product must be administered within 3 hours after reconstitution. It is recommended to use the microbore tubing administration set provided to minimize losses of product due to adsorption and volume retention. HELIXATE FS should not be mixed with other medicinal products or infusion solutions.

According to a published study (3), children in comparison to adults present higher FVIII clearance values and thus lower recovery of FVIII which may be explained by differences in pharmacokinetics. This information should be taken into account when dosing or following FVIII levels in such a population.

Recommended Dose and Dosage Adjustment

The dosages described below are presented as general guidance. It should be emphasized that the dosage of HELIXATE FS required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors and the FVIII level desired. It is often critical to follow the course of therapy with FVIII level assays.

The clinical effect of HELIXATE FS is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more HELIXATE FS than would be estimated in order to attain satisfactory clinical results.

It has been shown in a clinical study performed in 14 adults with severe hemophilia A (≤1% FVIII:C) undergoing a major surgery that HELIXATE FS can be used for continuous infusion in surgeries (pre- and postoperative). In this study, heparin was used to prevent thrombophlebitis at the infusion site, as with any other long-term intravenous infusions. For the calculation of the initial infusion rate, clearance can be obtained by performing a presurgery decay curve, or by starting from an average population value (3.0-3.5 mL/h/kg) and then adjusting accordingly.

Infusion rate (in IU/kg/h) = Clearance (in mL/h/kg) x desired factor VIII level (in IU/mL)

Continuous infusion, clinical, and in vitro stability has been demonstrated using ambulatory pumps with a polyvinyl chloride (PVC) reservoir. HELIXATE FS contains low levels of polysorbate-80 as an excipient, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from PVC materials. This should be considered for a continuous infusion administration (see Reconstitution: For Continuous Infusion).

If the calculated dose fails to attain the expected FVIII levels or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests. When an inhibitor is present, the dosage requirement for rFVIII-FS is extremely variable and the dosage can be determined only by the clinical response.

Some patients with low titer inhibitors (<10 B.U.) can be successfully treated with rFVIII-FS without a resultant anamnestic rise in inhibitor titer. Factor VIII levels and clinical response to treatment must be assessed to ensure adequate response. Use of alternative treatment products, such as Factor IX Complex products, Antihemophilic Factor (Porcine), recombinant Factor VIIa, or Activated Procoagulant Protein may be necessary for patients with anamnestic responses to FVIII treatment and/or high titer inhibitors.

Calculation of Dosage

The in vivo percent increase in FVIII level can be estimated by multiplying the dose of rFVIII-FS per kilogram of body weight (IU/kg) by 2%. This method of calculation is based on clinical findings by Abildgaard et al. (4) and is illustrated in the following examples.

Equation 1 – Calculation of HELIXATE FS Dosage (Expected % FVIII Increase)
	(kg)t body weigh 2%/IU/kg ed administer units # increase FVIII % Expected
	40% kg 70 2%/IU/kg IU 1400 : adult kg 70 afor Example

Equation 2 – Calculation of HELIXATE FS Dosage (Dosage Required)
	2%/IU/kg increase FVIII % desired (kg)t body weigh (IU) required Dosage
	required IU 750 2%/IU/kg 100% kg 15 : child kg 15 afor Example

The dosage necessary to achieve hemostasis depends upon the type and severity of the bleeding episode, according to the following general guidelines.

Prophylaxis

FVIII products may also be administered on a regular schedule for prophylaxis of bleeding, as reported by Nilsson et al. (5, 6) In children, the recommended dose for a regular prophylaxis schedule is 25 IU/kg of body weight every other day. (7) In adults, the recommended dose for routine prophylaxis is 25 IU/kg of body weight three times per week.

Immune Tolerance

FVIII products have been administered to patients on a high dose schedule in order to induce immune tolerance to FVIII, which resulted in disappearance of the inhibitor activity. There is currently no consensus among treaters to the optimal treatment schedule.

Administration

For details on precautions associated with administration, see WARNINGS AND PRECAUTIONS – General.

Rate of Administration

Data from clinical trials, including patients between 0-68 years old, shows that the entire dose is administered in a median of 5 minutes. The rate of administration, however, should be adapted to the response of each patient.

HELIXATE FS can be infused by continuous infusion. The infusion rate should be calculated based on the clearance and the desired FVIII level. In a clinical study performed in 14 adults with severe hemophilia A (≤1% FVIII:C) who underwent a major surgery, the range of infusion rates for HELIXATE FS was 0.2 to 3.6 mL/h. Example: For a 75 kg patient with a clearance of 3 mL/h/kg, the initial infusion rate would be 3 IU/h/kg to achieve a FVIII level of 100%. For calculation of mL/h, multiply infusion rate in IU/h/kg by kg bw/concentration of solution (IU/mL).

Higher infusion rates may be required in conditions with accelerated clearance during major bleeds and extensive tissue damage during surgical interventions. Subsequent infusion rates should be calculated based on the actual FVIII levels and recalculated clearance for each day post surgery based on the equation: clearance = infusion rate/actual FVIII level.

Reconstitution

Parenteral Products

HELIXATE FS powder should only be reconstituted with the supplied diluent (2.5 or 5.0 mL Sterile Water for Injection) using the supplied sterile transfer device. Reconstitution and dilution should be performed in accordance with good practices rules, particularly with attention to asepsis.

If any component of the package is opened or damaged, do not use this component. Inspect visually for particulate matter and discoloration prior to administration. Do not use HELIXATE FS if you notice any particulates or turbidity in the solution. The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the Mix2vial adapter. After reconstitution, the product is to be used within 3 hours.

Always work on a clean surface and wash your hands before performing the following procedures.

1. 1. Warm the unopened diluent and the product to room temperature (no more than 37°C).
2. 2. Place the product vial, diluent vial and Mix2Vial™ on a flat surface.
3. 3. Ensure product and diluent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.
4. 4. Open the Mix2Vial package by peeling away the lid (Fig. 1). Leave the Mix2Vial in the clear package. Place the diluent vial on an even surface and hold the vial tight. Grip the Mix2Vial together with the package and snap the blue end onto the diluent stopper (Fig. 2).
5. 5. Carefully remove the clear package from the Mix2Vial set. Make sure that you only pull up the package and not the Mix2Vial set (Fig. 3).
6. 6. With the product vial firmly on a surface, invert the diluent vial with the set attached and snap the transparent adapter onto the product vial stopper (Fig. 4). The diluent will automatically transfer into the product vial.
7. 7. With the diluent and product vial still attached, gently swirl the product vial to ensure the product is fully dissolved (Fig. 5). Do not shake vial.
8. 8. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the blue diluent-side of the Mix2Vial set and unscrew the set into two pieces (Fig. 6).
9. 9. Draw air into an empty, sterile syringe. While the product vial is upright, screw the syringe to the Mix2Vial set. Inject air into the product vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly (Fig. 7).
10. 10. Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial set (Fig. 8).

For Bolus Injection

1. 11. Attach the syringe to the administration set made of microbore tubing provided with HELIXATE FS. Use of administration sets without microbore tubing may result in a larger retention of the solution within the administration set.
2. 12. If the same patient is to receive more than one bottle, the contents of two bottles may be drawn into the same syringe through a separate unused Mix2Vial set before attaching the vein needle.
3. 13. Inspect visually for particulate matter and discoloration prior to administration.

Figure 1 – Reconstitution Procedure
Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8

For Continuous Infusion

Reconstitute HELIXATE FS according to Steps 1-10 above. Continuous infusion of HELIXATE FS must employ an infusion pump that can provide continuous delivery, deal with low volumes and low infusion speeds. Technical instructions of the pump manufacturer, including the devices to be used, should be followed. The reservoir of the pump should be filled under aseptic conditions and the reservoir and tubing should be changed at least every 24 hours. During in vitro studies, reconstituted product for continuous infusion was shown to be stable for 24 hours at temperatures up to 30°C in polyvinyl chloride (PVC) bags. This should be kept in mind if the continuous infusion is not intended to be started immediately after reconstitution. In a clinical study performed in 14 adults with severe hemophilia A (≤1%FVIII:C) undergoing a major surgery, a minute amount of heparin was added to the infusion solution (final concentration of 5 U/mL) in order to prevent local thrombophlebitis at the site of the infusion. Refer to Table 6 for infusion rates.

Note: HELIXATE FS reconstituted with 2.5 mL or 5.0 mL Sterile Water for Injection should not be further diluted

OVERDOSAGE

No symptoms of overdose have been reported.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

See INDICATIONS AND CLINICAL USE.

Pharmacodynamics

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

Pharmacokinetics

Initial pharmacokinetic studies were conducted in 35 patients, with severe hemophilia A. (8)

Absorption

Not applicable. HELIXATE FS is administered directly into the blood stream by IV injection.

Distribution

No specific distribution studies have been performed, however after administration of HELIXATE FS (Antihemophilic Factor [Recombinant]), peak factor VIII activity decreases by a two-phase exponential decay. This is similar to that of plasma-derived factor VIII. HELIXATE FS binds to its natural protein carrier vWF and is mostly confined into the vascular space.

Metabolism

HELIXATE FS is metabolized as it produces its biological activity during the activation of the coagulation cascade.

Excretion

After administration of HELIXATE FS (Antihemophilic Factor [Recombinant]), peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approximately 13 hours. The half-life data for rFVIII-FS were unchanged after 24 weeks of exclusive treatment, indicating continued efficacy and no evidence of FVIII inhibition.

Duration of Effect

The duration of effect is variable and dependent on the individual patient, the severity of the bleed and the clinical situation.

STORAGE AND STABILITY

HELIXATE FS (Antihemophilic Factor [Recombinant]) should be stored under refrigeration (2°C-8°C). Storage of lyophilized powder at room temperature (up to 25°C) for 12 months, such as in home storage situations, may be done. If the product is stored outside the refrigerator, please add the date removed from refrigeration and note a new expiry date on the carton and vial. The new expiry date should be 3 months from the date product is removed from the refrigerator, or the previously stamped expiry date, whichever is shorter. Once product is removed from refrigeration, it cannot be returned to the refrigerator. Freezing must be avoided. Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use.

After reconstitution, the product should be used immediately (within 3 hours) for direct syringe injection. For continuous infusion, stability has been demonstrated for 24 hours at 30°C in polyvinyl chloride (PVC) bags.

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

HELIXATE FS (Antihemophilic Factor [Recombinant]) is supplied in the following single use bottles. A suitable volume of Sterile Water for Injection, USP, a Mix2Vial^™ filter transfer set, and an administration set equipped with microbore tubing are provided. The actual potency is printed on the label and the carton.

Each vial of HELIXATE FS contains the labelled amount of rFVIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation FVIII, human, is approximately equal to the level of FVIII activity found in 1 mL of fresh pooled human plasma. The final product, when reconstituted as directed, contains the following ingredients.

The product contains no preservative. HELIXATE FS must be administered by the intravenous route.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Product Characteristics

HELIXATE FS is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII (FVIII) gene has been introduced. The BHK cell culture medium, which is used during manufacturing contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. No human or animal proteins, such as albumin, are added during the purification and formulation processes of HELIXATE FS.

HELIXATE FS is a highly purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit.

Studies to further elucidate the carbohydrate structure of rFVIII, indicated that both pdFVIII and rFVIII contain mainly high mannose type and complex-type sugar chains.

Viral Inactivation

The purification process includes an effective 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 FVIII (rFVIII) and remove contaminating substances.

Prion Inactivation

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 variant Creutzfeldt-Jakob Disease (vCJD) and Creutzfeldt-Jakob Disease (CJD) agents. Several of the individual production and raw material preparation steps in the HELIXATE FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps included the Fraction II+III separation step for Human Plasma Protein Solution (6.0 log₁₀) and an anion exchange chromatography step for the HELIXATE FS process (3.6 log₁₀). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

CLINICAL TRIALS

Previously Treated Patients

Study demographics and trial design

A total of 73 patients with severe hemophilia A, age 12-59, who had been previously treated with other recombinant/plasma-derived FVIII products were treated up to 54 months in studies with rFVIII-FS in Europe and North America. A total of 24,924 infusions (or 45 million units) of rFVIII-FS were administered during the studies. A total of 5,684 bleeding episodes were treated during the studies. The majority of bleeding episodes (92.7%) were treated successfully with one or two infusions, with a median dosage of approximately 32.5 and 29.6 IU/kg per treatment infusion, in Europe and North America, respectively. Prophylactic treatment accounted for 76% of infusions administered during the studies. Thirty patients have received rFVIII-FS for 41 surgical procedures (16 minor and 25 major). Hemostasis was satisfactory in all cases. One out of the 73 PTPs started the study with a pre-existing inhibitor. Excluding this patient, zero patients developed inhibitors. (1, 8, 9)

For additional details, see Product Monograph Part I: ACTION AND CLINICAL PHARMACOLOGY.

Study Results

These two studies showed that HELIXATE FS demonstrates comparable efficacy to HELIXATE. Treatment with HELIXATE FS was associated with an excellent efficacy profile when used in the treatment of patients with hemophilia A.

Previously Untreated and Minimally Treated Patients

In completed clinical studies, HELIXATE FS has been used in the treatment of bleeding episodes in previously untreated patients (PUPs) and minimally treated pediatric patients (MTPs). In completed studies, 37 PUPs and 24 MTPs have been treated with 9,419 infusions of HELIXATE FS corresponding to a total of 7.5 million IU for a follow-up duration up to 3.1 years and a median of 115 exposure days. A total of 1047 bleeding episodes were treated effectively with one or two infusions of rFVIII-FS in 88.1% of cases. A total of 29 surgical procedures were performed in 23 patients. Hemostasis was satisfactory in all cases. One out of the 61 PUPs/MTPs started the study with a pre-existing inhibitor. Excluding this patient, 9 out of 60 (15%) patients developed inhibitors after a median number of 7 exposure days (range of 2-16 exposure days). (1, 2)

Pediatric Prophylaxis

Sixty-five young boys less than 30 months of age with severe hemophilia A (factor VIII level ≤ 2 IU/dL) and normal joints, as well as a history of less than 3 hemorrhages in the same joints, were observed for 5 years in a multicenter, open-label, prospective, randomized, controlled clinical study. (7) Patients received either 25 IU/kg every other day (prophylaxis; n=32) or at least 3 doses totaling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n=33). Endpoints were joint damage evaluated by magnetic resonance imaging (MRI) and/or radiography, as well as the frequency of bleeding episodes (joint bleeds and other bleeds). Joint damage detected by MRI or x-ray in the ankles, knees, and elbows (ie, 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 higher risk of experiencing 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 (P<0.001). Three subjects (9%) receiving episodic treatment experienced recurrent life-threatening hemorrhages versus no subjects receiving prophylactic treatment (P=0.238). Three patients in the prophylaxis group developed high-titer inhibitors compared to none in the enhanced episodic group. While many of the detected inhibitors were low titer and transient, the overall incidence of inhibitor development in PUPs and MTPs was 13% across both study groups, which is comparable to a demonstrated incidence of 15% in a previous randomized controlled trial. (1)

Adult Prophylaxis

A 3-year, multicenter, open-label, parallel-group, prospective, randomized, controlled clinical study of the effect of regular prophylaxis with HELIXATE FS versus on-demand use on bleeding frequency and joint outcomes was performed in adults and adolescents with severe hemophilia A (FVIII level < 1 IU/dL). (10)

Eighty-four PTPs, aged 15 to 50 years (mean: 30.6 years), were randomized 1:1 to either a standard prophylaxis regimen (25 IU/kg three times a week) or on-demand use of HELIXATE FS. Escalation of the prophylaxis dose by 5 IU/kg/infusion after Years 1 and 2, up to a maximum of 35 IU/kg/infusion, was allowed. Baseline characteristics (eg, demographics, disease state) were similar between the two treatment groups. The median number of bleeds in the year before enrollment for all 84 patients was 18.

The primary endpoint, bleeding frequency, was analyzed in the intent-to-treat population after a median follow-up period of about 1.7 years. Prophylactic treatment led to a statistically significant and clinically meaningful decrease in bleeds (P < 0.0001), as well as in a number of other bleeding endpoints (see Table 10) compared to on-demand treatment. The median annual bleed rate (bleeds/subject/year) in the on-demand group was 28 versus zero in the prophylaxis group. All of the 42 patients in the on-demand group had at least one bleeding event, and only 21 of the 42 patients in the prophylaxis group had a bleeding event. For these patients who had at least one bleeding event, the median time to first bleed was 3.3 days in the on-demand group and 87.9 days in the prophylaxis group.

Twenty-two patients from the prophylaxis group (52%) and one patient from the on-demand group (2%) did not experience a bleeding event (defined as spontaneous or traumatic bleed), and 12 prophylaxis patients (29%) and 1 on-demand patient (2%) experienced only 1-2 bleeds.

There was a 94% reduction in the mean annual bleed rate: 30.52 bleeds/patient/year in the on-demand group versus 1.98 bleeds/patient/year in the prophylaxis group. Those patients who received prophylaxis experienced 16.1 times fewer bleeds compared to patients treated on-demand. There was a 93% reduction in the mean annual joint bleed rate: 24.15 bleeds/patient/year in the on-demand group versus 1.69 bleeds/patient/year in the prophylaxis group.

Prophylactic compared to on-demand treatment with HELIXATE FS resulted in large reductions in bleeding regardless of baseline characteristic examined including age, bleeding history, and presence or absence of target joints (see Table 11). In particular, the median annual bleed rate among on-demand patients >30 years of age was 25, compared to 0 among prophylaxis patients in the same age group.

The most common self-rating of bleed severity among prophylaxis patients was mild (44%), compared to moderate (58%) for on-demand patients (Table 12).

Bleeding episodes were treated effectively with 1 or 2 infusions of HELIXATE FS. Among prophylaxis patients, this level of hemostasis was achieved with a moderate exposure to HELIXATE FS: the mean number of infusions/week was 2.4, and the median dose per prophylaxis infusion was 27 IU/kg.

No inhibitors were detected in this study. The adverse event profile was consistent with previous studies.

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacologic activity of rFVIII-FS has been demonstrated in vitro in both clotting and factor Xa assays. Binding to von Willebrand Factor has also been demonstrated. The genetic, biochemical and clinical demonstration of FVIII deficiency in a colony of miniature Schnauzer dogs has been reported. As well, the efficacy of rFVIII in this animal model has been proven.

In a study of rFVIII-FS, two dogs previously untreated with FVIII were administered rFVIII-FS and two dogs previously treated with FVIII were administered rFVIII. Each preparation was infused at approximately 400 IU/kg. Animals treated with rFVIII-FS displayed a correction of bleeding time, as well as normalization of biochemical parameters of bleeding. FVIII recovery, as determined by immunoreactivity, appeared similar in all treated animals.

Animals in the safety pharmacology studies received doses of 300 IU/kg, representing a significant margin of safety when compared to the intended therapeutic dosage (25 IU/kg). The most significant effect noted was a transient increase in arterial pressure in rats, related to the relative amount of glycine in the 250 IU compared to the 500 and 1000 IU fill sizes. This is a species-specific effect observed with other proteins that use glycine as an excipient and does not present a risk to the human population.

A common test-article related finding in rabbits was a decrease in the aPTT, a measure of the activated clotting time of blood. This was not unexpected in that FVIII is required for activity. Since all animals received the same dose of material (300 IU/kg), no conclusions with regard to dose/response relationship between the aPTT and test article can be made.

In conclusion, there does not appear to be any untoward effects of rFVIII-FS on the organ systems evaluated.

In five separate infusion studies in rabbits, rFVIII-FS displayed similar pharmacokinetics to that of rFVIII. The molecule behaved similarly from experiment to experiment. There was interstudy variance with the area under the curve and clearance in one study, displaying slightly lower and higher values, respectively, versus all other studies. This is most likely the result of metabolic differences in the rabbits used in each study. Overall, the degree of homology between studies is quite remarkable.

Human Pharmacology

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

Absorption and Bioavailability

HELIXATE FS is administered by IV injection and the whole dose is available in the bloodstream. The recovery data for rFVIII-FS were unchanged after 24 weeks of exclusive treatment, indicating continued efficacy and no evidence of FVIII inhibition. The mean FVIII recovery measured 10 minutes following a dose of rFVIII-FS in 37 patients after 24 weeks of treatment with rFVIII-FS was 2%/IU/kg, which was unchanged from FVIII recovery determined at baseline and at Weeks 4 and 12.

Pharmacokinetics

Initial pharmacokinetic studies were conducted in 35 patients, with severe hemophilia A.

Distribution

No specific distribution studies have been performed, however after administration of HELIXATE FS (Antihemophilic Factor [Recombinant]), peak factor VIII activity decreases by a two-phase exponential decay. This is similar to that of plasma-derived factor VIII. HELIXATE FS binds to its natural protein carrier vWF and is mostly confined into the vascular space.

Metabolism

No specific metabolism studies have been performed. HELIXATE FS as regular FVIII is metabolized as it produces its biological activity during the activation of the coagulation cascade.

Excretion

After administration of HELIXATE FS (Antihemophilic Factor [Recombinant]), peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approximately 13 hours. The half-life data for rFVIII-FS were unchanged after 24 weeks of exclusive treatment, indicating continued efficacy and no evidence of FVIII inhibition.

Mean baseline clearance for 14 adult patients undergoing major surgeries with continuous infusion is 188 mL/h corresponding to 3.0 mL/h/kg (range 1.6-4.6 mL/h/kg).

TOXICOLOGY

Acute Toxicity

The acute intravenous toxicity of rFVIII-FS was determined in mice, rats, and rabbits. The intravenous LD₅₀’s are >50, >33 and >10 mL/kg, respectively. Only rats failed to tolerate the planned dose (135 mL/kg) and this was most likely due to a species related sensitivity to the excipient, glycine. Nevertheless, with the high doses tolerated, a wide margin of safety has been shown with the doses administered in these three species.

Gal α 1-3Gal Structure in rFVIII

Studies to further elucidate the carbohydrate structure of rFVIII, indicated that both pdFVIII and rFVIII contain mainly high mannose type and complex-type sugar chains. While some overall quantitative configuration differences were observed, these were not regarded as significant: however, these investigations did reveal the presence of a unique terminal sugar structure in a minority of the rFVIII molecules, a galactose α 1-3 galactosyl (gal α 1-3 gal) group.

Biological Significance of Gal α-3

Literature reports indicate the potential for interaction of naturally occurring anti-α gal antibody with rFVIII bearing this structure. This may result in altered pharmacokinetics, reduced clinical efficacy or acute intolerance to rFVIII containing this structure. A series of preclinical experiments were conducted to address these issues.

Baboons were infused with either plasma-derived FVIII or an experimental batch of rFVIII with α gal content in the range of 5M/M FVIII (ie, approximately 10-fold greater than the amount in clinical lots of rFVIII). All preparations were labelled with radioactive iodine to facilitate monitoring. The results of these studies indicated little if any difference between the two preparations, suggesting that in this model the presence of this carbohydrate structure was of minimal (if any) biological significance. No anomalous tissue distribution or excretion of the α gal-containing rFVIII was observed.

In an effort to assess actual recovery effects of this structure, baboons were infused with large doses (300 IU/kg) of the preparations or a clinical lot of rFVIII and actual FVIII:C levels monitored over a 60 minute interval; no significant consistent difference in increment in FVIII:C titers was observed. Importantly, despite the 10-fold greater content of α gal residue in the experimental lot and the demonstration of substantial anti-α antibody titers in all animals, no acute intolerance (ie, anaphylaxis) was observed in these studies nor were any physiological or biochemical anomalies recorded over several weeks of observation. It can be concluded from these studies that the presence of this structure in rFVIII does not appear to confer any acute tolerance problems.

In conclusion, no apparent clinically or biologically significant consequence to the presence of the gal α 1-3 gal carbohydrate structure in rFVIII has been demonstrated despite evidence of circulating antibody capable of recognizing this residue in appropriate animal species. While in vitro systems clearly indicate anti-α gal antibody found in humans can bind to rFVIII bearing these structures, extrapolation to in vivo effects does not appear possible. This may be due to the relatively low concentration of this structure in clinical lots of rFVIII, the association of FVIII with von Willebrand Factor in circulation or other as yet unexplored reasons. Results from our studies have permitted a conclusion that this carbohydrate structure confers little if any significant consequence to the biological fate of rFVIII.

Repeated Dose Toxicity

Repeated administration studies were performed in two species: rabbits and dogs. The animals were administered 305 IU/kg of rFVIII-FS intravenously on five successive days to assess the effects of repeated administration. One group of animals was sacrificed on the day following the fifth infusion (Day 6), another was sacrificed four weeks (Day 33) after the series of infusions in order to assess delayed effects.

No adverse effects were seen in rabbits with regard to weight gain, hematology, blood chemistry or necropsy. Five of the 24 rabbits showed an antibody titer prior to dosing or on Day 6 following administration of rFVIII-FS or the excipient control substance. Four of the 6 rabbits in the rFVIII-FS Day 33 group mounted an antibody titer to rFVIII-FS by Day 33. There were no apparent adverse effects in those rabbits that developed a titer. Histopathology evaluation did not reveal any treatment-related changes and no immune-mediated pathology was seen.

No adverse effects were seen in dogs with regard to urinalysis, necropsy, or histopathology. Statistically significant changes in hematology and blood chemistry (both between and within groups) were observed; however, these changes were slight and not considered to be of clinical significance. Antibodies were not detected at Day 6. Three of the 4 dogs administered rFVIII-FS, as well as one dog inadvertently administered rFVIII-FS on the third day of infusion, developed an antibody titer at Day 33. No adverse effects were seen in dogs that developed an antibody titer.

Results of the acute and repeated dose studies indicate a low order of toxicity for rFVIII-FS, except for apparent immunological responses to the heterologous protein. The antibody response is not expected in the clinic. With the expected clinical dose of 25 IU/kg, a wide margin of safety of rFVIII-FS has been demonstrated in laboratory animals.

Neoantigenicity

Theoretically, the process of protein purification has the potential to induce changes in the molecule that may induce an immune response when administered. In preclinical models, many therapeutic proteins have been shown to induce an antibody response with repeated administration. In order to determine if the solvent/detergent purification process induces physical or conformation changes that produce new epitopes on the rFVIII model, four neoantigenicity studies using alternate protein: excipient ratios of rFVIII-FS and “high aggregate” lots, were performed that make use of the naturally occurring immune response to foreign proteins. The methodology involved hyperimmunization of rabbits with rFVIII-FS. Serum containing antibodies to the rFVIII-FS was tested for unique epitopes compared to rFVIII. In each study, all antibodies cross-reacted with both rFVIII and rFVIII-FS.

Carcinogenicity/Mutagenesis

In vitro evaluation of the mutagenic potential of rFVIII did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation of rFVIII in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that rFVIII does 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.

REFERENCES

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