Adynovate

Rurioctocog alfa pegol (recombinant human coagulation factor VIII).

ADYNOVATE 250IU powder and solvent for solution for injection: Each vial contains nominally 250 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
ADYNOVATE 500IU powder and solvent for solution for injection: Each vial contains nominally 500 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
ADYNOVATE 750IU powder and solvent for solution for injection: Each vial contains nominally 750 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
ADYNOVATE 1000IU powder and solvent for solution for injection: Each vial contains nominally 1000 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
ADYNOVATE 1500IU powder and solvent for solution for injection: Each vial contains nominally 1500 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
ADYNOVATE 2000IU powder and solvent for solution for injection: Each vial contains nominally 2000 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
ADYNOVATE 3000IU powder and solvent for solution for injection: Each vial contains nominally 3000 IU human coagulation factor VIII (rDNA), rurioctocog alfa pegol.
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, 750, 1000, 1500, 2000, or 3000 international units (IU). Each vial of ADYNOVATE is labeled with the nominal 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 2 mL or 5 mL sterile water for injection, the final solution contains the following excipients and stabilizers in targeted amounts per mL of reconstituted product: (See Table 1.)

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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 Pharmacology: Mechanism of Action under Actions]. 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.

Pharmacology: 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.
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 on-demand 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 2. (See Table 2.)

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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 on-demand treatment arm was 41.5 [40.8] compared to 1.9 [4.7] while on a twice a week prophylaxis regimen (Table 3). In the per-protocol 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. (See Table 3.)

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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 pre-trial 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.
An extension study in adult and pediatric patients evaluated the safety and efficacy of prophylactic treatment regimen in 216 previously treated patients with severe hemophilia A. Majority had completed the adult and adolescent study or the pediatric study. Similar efficacy was noted in this extension study.
Perioperative Management Clinical Trial: Twenty-one major surgical procedures comprised of 14 orthopedic, and 7 non-orthopedic procedures, and 5 additional minor surgeries were performed in 21 subjects. The preoperative loading dose ranged from 36 IU/kg to 99 IU/kg (median: 60 IU/kg) and the total postoperative dose ranged from 23 IU/kg to 769 IU/kg (median: 183 IU/kg). The median total dose (including all administrations from pre-surgical PK and loading doses to post-hospital follow up) was 629 IU/kg (range: 464 - 1,457 IU/kg) for major orthopedic surgeries, 489 IU/kg (range: 296 - 738 IU/kg) for major non-orthopedic surgeries.
Overall 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, for all 24 (21 major, 3 minor)] procedures with available assessments.
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. (See Table 4.)

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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.

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.

For intravenous use after reconstitution only.
Dose: Each vial label of ADYNOVATE states the nominal factor VIII potency in international units. 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)] x 2 (IU/dL per IU/kg); Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 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 5. Maintain plasma factor VIII activity level at or above the described plasma levels (in IU per dL or % of normal). (See Table 5.)

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Perioperative Management: A guide for dosing ADYNOVATE during surgery (perioperative management) is provided in Table 6. Consideration should be given to maintain a factor VIII activity at or above the target range. (See Table 6.)

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Routine Prophylaxis: Administer 40-50 IU per kg body weight twice weekly in adults and adolescents (12 years and older). Administer 55 IU per kg body weight two times per week in children (< 12 years) with a maximum of 70 IU per kg. Adjust the dose and dosing intervals based on the patient's clinical response.
Previously untreated patients: The safety and efficacy of ADYNOVATE in previously untreated patients have not yet been established. No data are available.
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: 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. 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. 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. Do not shake. Do not refrigerate after reconstitution.
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: 1. Remove the blue cap from the housing. Connect the syringe to the system. 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.
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, 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).

No symptoms of overdose with recombinant coagulation factor VIII have been reported.

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).

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 & 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.
Use in Children: 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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
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 Pharmacology: Pharmacokinetics under Actions].
Use in the Elderly: Clinical studies of ADYNOVATE did not include subjects aged 65 and over.

Pregnancy: Risk Summary: 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.
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.

The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache, diarrhea, rash, nausea, dizziness and urticaria.
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 365 previously treated patients (PTPs) and previously untreated patients (PUPs) with severe hemophilia A (factor VIII less than 1% of normal), who received at least one dose of ADYNOVATE in 6 completed multi-center, prospective, open label clinical studies and 1 ongoing clinical studies. The total number of infusions within the safety database is 74487. Table 7 lists the adverse reactions reported during clinical studies. (See Table 7.)

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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 216 subjects. Administration of ADYNOVATE continued and both cases resolved.
Immunogenicity: Clinical trial subjects were monitored for neutralizing (inhibitory) antibodies to FVIII. Of the 6 completed clinical trials in previously treated patients (PTPs), in the randomized controlled trial comparing different dosing regimens of Adynovate, one previously treated patient developed a transient low titer FVIII inhibitor at 0.6 BU while receiving more frequent dosing with Adynovate. In a continuation study with Adynovate, one patient developed a transient low titer (0.6BU) FVIII inhibitor. Repeat testing did not confirm the presence of inhibitor. Both of these subjects continued treatment without change in the dose of Adynovate.
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. Persistent treatment-emergent binding antibodies against FVIII, PEG-FVIII or PEG were not detected. Out of 365 subjects, thirty six subjects in total showed pre-existing antibodies to factor VIII (n=5), PEG-factor VIII (n=31) and/or PEG (n=6) prior to the first exposure to ADYNOVATE. Twenty four subjects who tested negative at screening developed transient antibodies against factor VIII (n= 10), PEG-FVIII (n= 16) and/or PEG (n=3) at one or two consecutive study visits. Antibodies were transient and not detectable at subsequent visits. Two 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.
From an ongoing study in previously untreated patients < 6 years with severe hemophilia A, 9 cases of FVIII inhibitor development associated with treatment with Adynovate were reported.
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.

No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported.

INCOMPATIBILITIES: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal product.

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.
Store ADYNOVATE in the original box and protect from extreme exposure to light.

Advise patients to: Read the approved patient information leaflet.
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.

Haemostatics

B02BD02 - coagulation factor VIII ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.

B