Adynovate

Description

ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is formulated as a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution for intravenous injection. The product is supplied in single-use vials containing nominal (approximate) potencies of 250, 500, 1000, or 2000 international units (IU). Each vial of ADYNOVATE is labeled with the actual factor VIII activity in IU determined using one-stage clotting assay, using a reference material calibrated against a World Health Organization (WHO) International Standard for factor VIII concentrates. One IU, as defined by the WHO 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.

When reconstituted with 5 mL sterile water for injection, the final solution contains the following excipients and stabilizer in targeted amounts per vial:

ADYNOVATE contains no preservative. The specific activity of ADYNOVATE is 2700 – 8000 IU/mg protein.

ADYNOVATE is a recombinant full-length human coagulation factor VIII (2,332 amino acids with a molecular weight (MW) of 280 kDa) covalently conjugated with one or more molecules of polyethylene glycol (MW 20 kDa). [see CLINICAL PHARMACOLOGY]. The therapeutic activity of ADYNOVATE is derived from its parent drug substance, ADVATE [Antihemophilic Factor (Recombinant)], which is produced by recombinant DNA technology from the CHO cell line. ADVATE is purified from the culture medium using a series of chromatography columns. The purification process includes an immunoaffinity chromatography step in which a monoclonal antibody directed against factor VIII is employed to selectively isolate the factor VIII from the medium. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The ADVATE molecule is then covalently conjugated with the polyethylene glycol, which mainly targets lysine residues.

The cell culture, pegylation, purification process and formulation used in the manufacture of ADYNOVATE do not use additives of human or animal origins.

ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for:

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

Limitation Of Use

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

Dosage And Administration

For intravenous use after reconstitution only.

Dose

• Each vial label of ADYNOVATE states the actual factor VIII potency in international units. This may be more or less than the nominal vial potency/content. One international unit corresponds to the activity of factor VIII contained in one milliliter of normal human plasma.
• Dosage and duration of treatment depend on the severity of factor VIII deficiency, the location and extent of the bleeding, and the patient’s clinical condition. Careful monitoring of replacement therapy is necessary in cases of serious or life-threatening bleeding episodes.
• Potency assignment is determined using a one-stage clotting assay. Plasma factor VIII levels can be monitored clinically using a one-stage clotting assay.
• Calculate the dose of ADYNOVATE based on the empirical finding that one international unit of ADYNOVATE per kg body weight increases the plasma factor VIII level by 2 IU per dL of plasma. Use the following formula to estimate the expected in vivo peak increase in factor VIII level expressed as IU per dL (or % of normal) and the dose to achieve a desired in vivo peak increase in factor VIII level:

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

Dose (IU) = Body Weight (kg) × Desired factor VIII Rise (IU/dL or % of Normal) × 0.5 (IU/kg per IU/dL)

• Patients vary in their pharmacokinetic (e.g., clearance, half-life, in vivo recovery) and clinical response. Base the dose and frequency of ADYNOVATE on the individual clinical response.

On-Demand Treatment And Control Of Bleeding Episodes

A guide for dosing of ADYNOVATE for the on-demand treatment and control of bleeding episodes is provided in Table 1. Maintain plasma factor VIII activity level at or above the described plasma levels (in IU per dL or % of normal).

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

Perioperative Management

A guide for dosing ADYNOVATE during surgery (perioperative management) is provided in Table 2. Consideration should be given to maintain a factor VIII activity at or above the target range.

Table 2: Dosing for Perioperative Management

Routine Prophylaxis

Administer 40-50 IU per kg body weight 2 times per week in children and adults (12 years and older). Administer 55 IU per kg body weight 2 times per week in children (< 12 years) with a maximum of 70 IU per kg. Adjust the dose based on the patient’s clinical response.

Preparation And Reconstitution

Preparation

• Do not remove ADYNOVATE or diluent vials from the external housing.
• Examine the packaging containing ADYNOVATE to ensure no damage or peeling of the lid is evident. Do not use if the lid is not completely sealed on the blister.
• Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.

Reconstitution

Figure A

Figure B

1. Allow the ADYNOVATE package to reach room temperature before use.
2. Open the package by peeling away the lid. Remove ADYNOVATE from the package and verify that the expiration date on the label has not passed and the potency unit number is same as expected. Inspect parenteral drug products for discoloration and particulate matter. The ADYNOVATE powder should be white to off-white in color and the diluent free from foreign particles.
   Do not use if the criteria are not met.
3. Place the ADYNOVATE on a flat surface with the diluent vial on top (Figure A). The diluent vial has a blue stripe. Do not remove the blue cap until instructed in a later step.
4. With one hand holding the ADYNOVATE housing, press down firmly on the diluent vial with the other hand until the system is fully collapsed and the diluent flows down into the ADYNOVATE vial (Figure B). Do not tilt the system until the transfer is complete.
5. Verify that diluent transfer is complete. Swirl gently until the powder is completely dissolved (Figure C). Do not shake. Do not refrigerate after reconstitution.

Figure C

Administration

• Visually inspect the reconstituted ADYNOVATE solution for particulate matter and discoloration prior to administration, whenever solution and container permit. The final ADYNOVATE solution should be clear and colorless. Do not use if particulate matter or discoloration is observed.
• Administer ADYNOVATE as soon as possible, but no later than 3 hours after reconstitution.

Administration Steps

Figure D

Figure E

1. Remove the blue cap from the housing. Connect the syringe to the system (Figure D). Do not inject air into the ADYNOVATE.
2. Turn the system upside down (ADYNOVATE vial now on top). Draw the ADYNOVATE solution into the syringe by pulling the plunger back slowly (Figure E).
3. Disconnect the syringe, attach a suitable needle, and inject intravenously as instructed. If a patient is to receive more than one ADYNOVATE -BAXJECT III system or a combination of an ADYNOVATE -BAXJECT II and an ADYNOVATE -BAXJECT III system, the contents may be drawn into the same syringe.
4. Administer ADYNOVATE intravenously over a period of less than or equal to 5 minutes (maximum infusion rate 10 mL per min).

How Supplied

Dosage Forms And Strengths

ADYNOVATE is a lyophilized powder in single-use vials containing nominally (approximately) 250, 500, 750, 1000, 1500, 2000, and 3000 International Units (IU, units). The 250-1500 IU strengths come with 2 mL Sterile Water for Injection (sWFI); the 2000 and 3000 IU strengths come with 5 mL of sWFI. The actual factor VIII potency/content is labeled on each ADYNOVATE vial.

The potency assignment employs a factor VIII concentrate standard that is referenced to a WHO (World Health Organization) international standard for factor VIII concentrates and is evaluated by appropriate methodology to ensure the accuracy of the results.

ADYNOVATE in a BAXJECT III system is packaged with 2 mL or 5 mL of Sterile Water for Injection, one Terumo Microbore Infusion set (2 mL only), one full prescribing physician insert and one patient insert. Components not made with natural rubber latex.

ADYNOVATE is available in single-use vials that contain the following nominal product strengths:

Actual factor VIII activity in IU is stated on the label of each ADYNOVATE carton and housing.

Storage And Handling

• Store ADYNOVATE in powder form at 2°C to 8°C (36°F to 46°F).
• Do not freeze.
• ADYNOVATE may be stored at room temperature not to exceed 30°C (86°F) for a period of up to 3 months not to exceed the expiration date. If stored at room temperature, write the date on the carton when ADYNOVATE is removed from refrigeration.
• After storage at room temperature, do not return the product to the refrigerator.
• Do not use beyond the expiration date printed on the carton or housing.
• Store ADYNOVATE in the original box and protect it from extreme exposure to light.

Manufactured by: Baxalta US Inc. Lexington, MA 02421 USA. Revised: May 2018

The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea.

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 practice.

The safety of ADYNOVATE was evaluated in 237 previously treated patients (PTPs) and 6 previously untreated patients (PUPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 3 completed multi-center, prospective, open-label clinical studies and 4 ongoing clinical studies. The median duration of participation per subject was 401 (min-max: 3-1034) days and the median number of exposure days to ADYNOVATE per subject was 111 (min-max: 1-322).

Table 3: Adverse Reactions Reported for ADYNOVATE

Two cases of acute pancreatitis, with no precipitating cause identified in one case, were reported in adults during an extension study of the clinical trial which evaluated 137 subjects. Administration of ADYNOVATE continued and both cases resolved.

Immunogenicity

The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials. Subjects consisted of adolescent and adult (n= 148 with ≥150 prior EDs) and pediatric PTPs [(<6 years of age with ≥50 prior EDs (n= 32), ≥6 years of age with ≥150 prior EDs (n= 57)], and pediatric PUPs (n=6). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE, the factor VIII inhibitor frequency was 0 (95% CI of 0 to 0.019). One PUP subject from an ongoing study, who received at least one infusion of ADYNOVATE, developed neutralizing antibodies to factor VIII.

Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein using validated ELISA assays. The majority of subjects (238/243) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens. Twenty-eight subjects in total showed pre-existing antibodies to factor VIII (n=3), PEG-factor VIII (n=25) and/or PEG (n=3) prior to the first exposure to ADYNOVATE. Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII (n= 6), PEG-FVIII (n= 8) at one or two consecutive study visits. Antibodies were transient and not detectable at subsequent visits. Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff. Binding antibodies that were detected prior to exposure to ADYNOVATE, that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters. There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data. No subject had pre-existing or treatment-emergent antibodies to CHO protein.

The detection of antibodies that are reactive to factor VIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading.

Drug Interactions

No Information Provided

Included as part of the “PRECAUTIONS” Section

Precautions

Hypersensitivity Reactions

Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.

Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

Monitoring Laboratory Tests

• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION].
• Monitor for the development of factor VIII inhibitors. Perform the Bethesda inhibitor 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 ADYNOVATE, use Bethesda Units (BU) to determine inhibitor levels.

Patient Counseling Information

Advise patients to:

• Read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Call their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment.
• Contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor VIII therapy because this may be a sign of inhibitor development.
• Advise patients to consult with their physicians or healthcare provider prior to travel. While traveling, advise patients to bring an adequate supply of ADYNOVATE based on their current regimen of treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of ADYNOVATE or studies to determine the effects of ADYNOVATE on genotoxicity or fertility have not been performed.

Use In Specific Populations

Pregnancy

Risk Summary

The event of hypersensitivity was a mild transient non-serious rash, occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE.

There are no data with ADYNOVATE use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with ADYNOVATE. It is unknown whether ADYNOVATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ADYNOVATE should be given to a pregnant woman only if clearly needed.

In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

Risk Summary

There is no information regarding the presence of ADYNOVATE in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADYNOVATE and any potential adverse effects on the breastfed infant from ADYNOVATE or from the underlying maternal condition.

Pediatric Use

Safety and efficacy studies have been performed in 91 previously treated, pediatric patients age 1 year to <18 years who received at least one dose of ADYNOVATE as part of routine prophylaxis, on-demand treatment of bleeding episodes, or perioperative management. Adolescent subjects age 12 to <18 (n=25) were enrolled in the adult and adolescent safety and efficacy trial, and subjects <12 years of age (n=66) were enrolled in a pediatric trial. The safety and efficacy of ADYNOVATE in routine prophylaxis and the treatment of bleeding episodes were comparable between children and adults. [see Clinical Studies]

Pharmacokinetic studies in children (<12 years) have demonstrated higher clearance, a shorter half-life and lower incremental recovery of factor VIII compared to adults. Because clearance (based on per kg body weight) has been demonstrated to be higher in children (<12 years), dose adjustment or more frequent dosing based on per kg body weight may be needed in this population. [see CLINICAL PHARMACOLOGY]

Geriatric Use

Clinical studies of ADYNOVATE did not include subjects aged 65 and over.

No Information Provided

Contraindications

ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

Mechanism Of Action

ADYNOVATE, a PEGylated form of recombinant antihemophilic factor (ADVATE), [see DESCRIPTION], temporarily replaces the missing coagulation factor VIII needed for effective hemostasis in congenital hemophilia A patients. ADYNOVATE exhibits an extended terminal half-life through pegylation of the parent molecule, ADVATE, which reduces binding to the physiological factor VIII clearance receptor (LRP1).

Pharmacodynamics

Hemophilia A is a disorder characterized by a deficiency of functional coagulation factor VIII, resulting in a prolonged, patient plasma clotting time as measured by the activated partial thromboplastin time (aPTT). Treatment with ADYNOVATE normalizes the aPTT over the effective dosing period. The administration of ADYNOVATE increases plasma levels of factor VIII and can temporarily correct the coagulation defect in hemophilia A patients.

Pharmacokinetics

The pharmacokinetics (PK) of ADYNOVATE were evaluated in a multi-center, prospective, open label clinical trial and compared with ADVATE in 26 subjects prior to initiation of prophylactic treatment with ADYNOVATE and in 22 subjects after 6 months of treatment with ADYNOVATE. A single dose of 45 IU/kg was utilized for both products. The PK parameters, as shown in Table 4, were based on plasma coagulation factor VIII activity measured by the one-stage clotting assay and are presented by age groups.

Incremental recovery was comparable between both products. The PK parameters determined after 6 months of prophylactic treatment with ADYNOVATE were consistent with the initial parameter estimates.

Pediatric Pharmacokinetics

Pharmacokinetic parameters calculated from 39 subjects <18 years of age (intent-to-treat analysis) are available for 14 children (2 to <6 years), 17 older children (6 to <12 years) and 8 adolescent subjects (12 to <18 years of age), as shown in Table 4. The mean clearance (based on body weight) of ADYNOVATE was higher and the mean half-life was lower in children <12 years of age than adults. A dose adjustment may be required in children <12 years of age.

Table 4: Pharmacokinetic Parameters (Arithmetic Mean ± SD)

Clinical Studies

Original Safety And Efficacy Clinical Trial

The safety, efficacy, and PK of ADYNOVATE were evaluated in a multicenter, open-label, prospective, non-randomized, two-arm clinical trial that compared the efficacy of a twice weekly prophylactic treatment regimen to on-demand treatment and determined hemostatic efficacy in the treatment of bleeding episodes. A total of 137 male PTPs (12 to 65 years of age) with severe hemophilia A received at least one infusion with ADYNOVATE. Twenty-five of the 137 subjects were adolescents (12 to less than 18 years of age).

Subjects received either prophylactic treatment (n = 120) with ADYNOVATE at a dose of 40-50 IU per kg twice weekly or ondemand treatment (n = 17) with ADYNOVATE at a dose of 10-60 IU per kg for a 6-month period. The mean (SD) dose per prophylaxis infusion was 44.4 (3.9) IU per kg with a median dosing interval of 3.6 days. There were 91 out of 98 (93%) subjects previously treated prophylactically prior to enrollment, who experienced a reduction in dosing frequency during routine prophylaxis in the trial, with a median reduction of 33.7% (approximately one more day between doses). One hundred eighteen of 120 (98%) prophylaxis subjects remained on the starting recommended regimen without dose adjustment, and 2 subjects increased their dose to 60 IU/kg during prophylaxis due to bleeding in target joints.

On-Demand Treatment And Control Of Bleeding Episodes

A total of 518 bleeding episodes were treated with ADYNOVATE in the per-protocol population, i.e. dosed according to the protocol specific dosing requirements. Of these, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm and 157 (n=61 subjects) occurred in the prophylaxis arm. The median dose per infusion to treat all bleeding episodes in the per-protocol population was 29 (Q1: 20.0; Q3: 39.2) IU per kg. The median dose per infusion to treat a minor, moderate, or severe/major bleeding episode in the per-protocol population was 25.5 (Q1: 16.9; Q3: 37.6) IU/kg, 30.9 (Q1: 23.0; Q3: 43.1) IU/kg, or 36.4 (Q1: 29.0; Q3: 44.5) IU/kg, respectively.

A total of 591 bleeding episodes were treated with ADYNOVATE in the treated population, which was identical to the safety analysis set of subjects assigned to routine prophylaxis or on-demand treatment with ADYNOVATE and who received at least one dose of the product. Of these, 361 bleeding episodes (n=17 subjects) occurred in the on-demand arm and 230 bleeding episodes (n=75 subjects) occurred in the routine prophylaxis arm. Efficacy in control of bleeding episodes is summarized in Table 5.

Table 5: Summary of Efficacy in Control of Bleeding (Treated Population)

Routine Prophylaxis

A total of 120 subjects (treated population) received a twice a week regimen in the prophylaxis arm, and an additional 17 subjects were treated episodically in the on-demand arm. In the treated population, the median [mean] annualized bleed rate (ABR) in the ondemand treatment arm was 41.5 [40.8] compared to 1.9 [4.7] while on a twice a week prophylaxis regimen (Table 6). In the perprotocol population, the median [mean] annualized bleed rate (ABR) in the on-demand treatment arm was 41.5 [40.8] compared to 1.9 [3.7] while on a twice a week prophylaxis regimen. Using a negative binomial model to estimate the ABR, there was a significant reduction in the ABR (p <0.0001) for subjects in the prophylaxis arm compared to the on-demand arm.

Table 6: Annualized Bleed Rate by Treatment for ≥ 12 years of age (Treated Population)

In the treated population, the median [mean] ABR for the 23 adolescent subjects age 12 to <18 years of age on routine prophylaxis was 2.1 [5.2] compared to a median [mean] ABR of 1.9 [4.6] for the 97 subjects 18 years and older. Reduction in ABR between the treatment arms was observed regardless of baseline subgroups examined, including age, presence or absence of target joints, and pretrial treatment regimen. The majority of the bleeding episodes during prophylaxis (95%) were of minor/moderate severity. Forty-five out of 120 subjects (38%) experienced no bleeding episodes and 68 out of 120 subjects (57%) experienced no joint bleeding episodes in the prophylaxis arm. Of those subjects who were compliant to regimen (per-protocol population), 40 out of 101 subjects (40%) experienced no bleeding episodes. All subjects in the on-demand arm experienced a bleeding episode, including a joint bleeding episode.

Routine Prophylaxis Clinical Trial In Pediatric Subjects (<12 Years Of Age)

The safety and efficacy of ADYNOVATE was evaluated in a total of 73 pediatric PTPs with severe hemophilia A, of which 66 subjects were dosed (32 subjects aged <6 years and 34 subjects aged 6 to <12 years) in a separate pediatric clinical trial. The prophylactic regimen was 40 to 60 IU/kg of ADYNOVATE twice a week, with a mean (SD) dose of 51.1 IU/kg (5.5). The median [mean] overall ABR was 2.0 [3.61] for the 66 subjects in the treated population and the median [mean] ABRs for spontaneous and joint bleeding episodes were both 0 [1.18 and 1.12, respectively]. Of the 66 subjects treated prophylactically, 25 (38%) experienced no bleeding episodes, 44 (67%) experienced no spontaneous bleeding episodes, and 48 (73%) experienced no joint bleeding episodes.

Of the 70 bleeding episodes observed during the pediatric trial, 82.9% were controlled with 1 infusion and 91.4% were controlled with 1 or 2 infusions. Control of bleeding was rated excellent or good in 63 out of 70 (90%) bleeding episodes. The definitions of excellent or good in the pediatric clinical trial were unchanged as compared to the previously conducted prophylaxis clinical trial in adolescent and adult subjects.

Perioperative Management Clinical Trial

Eleven major surgical procedures (3 knee replacements, 2 arthroscopic synovectomies, 1 cyst extirpation, 1 port placement, 1 gastric band placement, and 3 multiple tooth extractions including 1 radicular cyst removal) and 4 additional minor surgeries (1 synoviorthesis, 1 radiosynovectomy, 1 tooth extraction, 1 dermatological surgery) were performed in 15 subjects. The preoperative loading dose ranged from 36 IU/kg to 99 IU/kg (median: 65 IU/kg) and the total postoperative dose ranged from 177 IU/kg to 769 IU/kg (median: 305 IU/kg). The median total dose for major surgeries was 362 IU/kg (range: 237-863 IU/kg) and the median total dose for minor surgeries was 97 IU/kg (range: 73-119 IU/kg).

Perioperative hemostatic efficacy was rated as excellent (blood loss less than or equal to that expected for the same type of procedure performed in a non-hemophilic patient, and required blood components for transfusions less than or similar to that expected in nonhemophilic population) for all 15 (11 major, 4 minor) procedures. The median (QR) observed intraoperative blood loss (n=10) was 10.0 (Q1: 5.0, Q3: 50.0) mL compared to the predicted average blood loss (n=11) of 50.0 (Q1: 6.0, Q3: 150.0) mL for major surgeries.