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 Helixate 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) × desired factor VIII rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)

or

IU/dL (or % normal) = Total Dose (IU)/body weight (kg) × 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 Helixate 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)].

2.2 Preparation and Reconstitution

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

Reconstitute and administer Helixate 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 Helixate FS product, in an appropriate container. Obtain immediate medical attention if injury occurs.

For any questions about the handling, reconstitution and administration of Helixate FS, contact CSL Behring Medical Affairs at 1-800-504-5434.

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 Helixate FS.

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

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

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Filter the reconstituted product prior to administration to remove potential particulate matter in the solution. Filtering can be achieved by using the Mix2Vial® vial adapter.

Vacuum Transfer and Reconstitution

1.	Prepare the product under aseptic conditions.
2.	Warm the unopened diluent and the concentrate to a temperature not to exceed 37°C or 99°F.
3.	Place the product vial, diluent vial and Mix2Vial on a flat surface.
4.	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.
5.	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).
6.	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).
7.	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.
8.	With the diluent and product vial still attached, gently swirl the product vial to ensure the powder is fully dissolved (Fig. 5). Do not shake vial.
9.	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)
10.	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).
11.	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). Attach the syringe to an administration set made with microbore tubing. Use of other administration sets without microbore tubing may result in a larger retention of the solution within the administration set.
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.

2.3 Administration

For intravenous use after reconstitution only.

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Inspect Helixate FS visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Turbid or discolored solution should be discarded.

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

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Administer Helixate 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 Helixate 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.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis have been reported with Helixate 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.

Helixate 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 Helixate FS if symptoms occur and seek immediate emergency treatment.

5.2 Neutralizing Antibodies

Neutralizing antibodies (inhibitors) have been reported following administration of Helixate 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

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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)].

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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 Helixate FS, use Bethesda Units (BU) to titer inhibitors.

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If the inhibitor is less than 10 BU per mL, the administration of additional Helixate FS concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

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If inhibitor titers are above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following Helixate 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.

6.1 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.

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

8.1 Pregnancy

8.2 Labor and Delivery

There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Helixate 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 Helixate 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 Helixate FS did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.

12.1 Mechanism of Action

Helixate 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 Helixate FS normalizes the aPTT over the effective dosing period.

12.3 Pharmacokinetics

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

Pharmacokinetic studies with Helixate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A. The pharmacokinetic parameters for Helixate FS were measured in a randomized, crossover clinical trial with the predecessor HELIXATE product using a single dose administration of 50 IU per kg. After 24 weeks, the same dose of Helixate FS was administered to the same patients. The recovery and half-life data for Helixate 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 Helixate 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with Helixate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. By inference, the predecessor product HELIXATE and Helixate 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 Helixate 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 Helixate FS in laboratory animals.

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

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 Helixate 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 Helixate 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

Helixate 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 Helixate 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 Helixate 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 Helixate 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.,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.

How Supplied

Helixate FS is available as a kit in the following single-use glass vial sizes. A suitable volume of Sterile Water for Injection, USP and Mix2Vial® filter transfer device are provided in the kit.

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

Storage and Handling

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