Coagadex

Description of Coagadex

COAGADEX is a plasma-derived, sterile, purified concentrate of human coagulation Factor X that contains sucrose as a stabilizer. It is formulated as a lyophilized powder for solution for intravenous administration. When reconstituted with Sterile Water for Injection, COAGADEX contains nominally (approximately) 100 IU/mL of coagulation Factor X and the following inactive ingredients: chloride, phosphate, citrate, sucrose and sodium. Each vial of COAGADEX is labeled with the actual Factor X activity/content expressed in IU per vial. Factor X activity in IU is determined using an in vitro chromogenic assay and a Factor X concentrate reference standard calibrated against the WHO 3^rd International Standard for Blood Coagulation Factors II and X, Concentrate.

COAGADEX contains no added biological components such as heparin, albumin or anti-thrombin. The content of Factor II and Factor IX are ≤ 1 IU/mL of the reconstituted product. Factor Xa and Factor IIa were not detectable by Non-activated Partial Thromboplastin Time (NaPTT) or Fibrinogen Clotting Time (FCT) tests for potential thrombogenicity, and comprised < 10 parts per million by weight when tested by more sensitive analytical methods. The specific activity of COAGADEX is typically 80-137 IU per mg protein. The product contains no preservatives.

COAGADEX is manufactured from plasma, obtained from healthy US donors, who have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma.

All plasma donations are screened for antibody to human immunodeficiency virus (HIV)-½, hepatitis C virus (HCV), and hepatitis B surface antigen (HBsAg). Additional testing of donations is carried out in plasma mini-pools (512 donations per pool) with nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis A virus (HAV) and human parvovirus B19. Furthermore, each manufacturing pool is tested to be negative for HBsAg and anti-HIV-½ antibodies. Also, manufacturing pools are non-reactive by nucleic acid test for HAV, HBV, HCV, and HIV-1. The limit for human parvovirus B19 in the manufacturing pools is set not to exceed 10⁴ IU/mL.

Three processing steps specifically designed to remove or inactivate viruses are:

1. Solvent/detergent treatment targeted to inactivate enveloped viruses
2. A 15-nm filtration step designed to remove small viruses including non-enveloped viruses
3. Terminal dry-heat treatment at 80°C for 72 hours in the final container to inactivate enveloped and non-enveloped viruses

The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled-down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other. Table 2 presents the contribution of each process step to virus reduction and the overall process reduction.

Table 2: Viral Reduction by Process Step

Indications

COAGADEX, Coagulation Factor X (Human), is a plasma-derived human blood coagulation Factor indicated in adults and children with hereditary Factor X deficiency for:

• Routine prophylaxis to reduce the frequency of bleeding episodes
• On-demand treatment and control of bleeding episodes
• Perioperative management of bleeding in patients with mild and moderate hereditary Factor X deficiency

Limitation Of Use

Perioperative management of bleeding in major surgery in patients with severe hereditary Factor X deficiency has not been studied.

Dosage And Administration of Coagadex

For intravenous use after reconstitution only

Dose

Estimated Increment of Factor X (IU/dL or % of normal) = [Total Dose (IU)/Body Weight (kg)] × 2

• Dose and duration of the treatment depend on the severity of the Factor X deficiency, location and extent of the bleeding, the patient’s age (<12 years or >12 years) and on the patient’s clinical condition.
• Base the dose and frequency on the individual clinical response. Do not administer more than 60 IU/kg daily.
• Each vial of COAGADEX is labeled with the actual Factor X potency/content in International Units (IU).
• For adolescents and adults (at least 12 years of age), estimate the expected in vivo peak increase in Factor X level expressed as IU/dL (or % of normal) using the following formula:

The dose to achieve a desired in vivo peak increase in Factor X level may be calculated using the following formula:

Dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL or % of normal) × 0.5

Note: The desired Factor X rise is the difference between the patient’s plasma Factor X level and the desired level. The dosing formula is based on the observed recovery of approximately 2 IU/dL per IU/kg for adults and adolescents at least 12 years of age.

Estimated Increment of Factor X (IU/dL or % of normal) = [Total Dose (IU)/Body Weight (kg)] × 1.7

The dose to achieve a desired in vivo peak increase in Factor X level may be calculated using the following formula:

Dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL) × 0.6

• For young children (less than 12 years of age), the incremental recovery is approximately 1.7 IU/dL per IU/kg so the number at the end of each of the above formulae changes as follows:

Prophylaxis of bleeding episodes

On–demand treatment and control of bleeding episodes

Perioperative management of bleeding

Preparation And Reconstitution

Table 1 COAGADEX Reconstitution Instructions

Step 2

Step 3

Step 4

Step 5

Step 6

Step 7

Step 8

• Always work on a clean surface and wash your hands before performing the following procedures.
• To reconstitute, use the diluent (Sterile Water for Injection) and transfer device (Mix2Vial) provided in the COAGADEX carton.
• To administer, you will also need a syringe and suitable needle (not provided in the COAGADEX carton).
• Bring the vials of COAGADEX and the Sterile Water for Injection to room temperature before mixing.
• The reconstitution is performed as follows:
  • Remove the cap from the vial of COAGADEX and clean the top of the rubber stopper with an alcohol swab (not supplied) and allow to dry prior to opening the Mix2Vial package.
  • Repeat this step with the vial of sterile water.
  • Peel back the top of the Mix2Vial package. Do not remove the device from the package.
  • Place the blue end of the Mix2Vial over the water vial and push straight down until the spike penetrates the rubber stopper and snaps into place.
  • Remove the plastic outer packaging from the Mix2Vial and discard it. Do not touch the exposed end of the device.
  • With the COAGADEX vial placed on a flat surface, invert the water vial with the Mix2Vial device still attached.
  • Place the clear end of the Mix2Vial on the product vial and push straight down until the spike penetrates the rubber stopper and snaps into place.
  • The water will automatically transfer into the COAGADEX vial by the vacuum contained within it. Do not use if the water is not pulled into the vial of COAGADEX.
  • Gently swirl the COAGADEX vial to make sure that the powder is fully dissolved. Do not shake the vial.
  • The reconstituted solution should be clear or a slightly pearl-like solution. Do not use if particulate matter or discoloration is observed and contact BPL.
  • Separate the empty water vial and blue part of the Mix2Vial from the clear part that is attached to the COAGADEX vial by unscrewing counter-clockwise.
  • Draw air into an empty, sterile syringe (not supplied) by pulling the plunger to the volume of water added.
  • Connect the syringe to the clear part of the Mix2Vial and push the air in the syringe into the vial.
  • Immediately invert the COAGADEX vial. The solution will automatically be drawn into the syringe. Draw the remaining solution into the syringe by pulling the plunger back slowly.
  • Disconnect the filled syringe from the device.
  • Use the product immediately after reconstitution. Do not store the reconstituted product.

Administration

For intravenous administration only

• If the dose requires more than one vial of COAGADEX:
  • Reconstitute each vial (steps 1 to 5) using a new Mix2Vial for each vial
  • Draw up all of the solution into a single syringe (steps 6 to 8)
• Visually inspect the final solution for particulate matter and discoloration prior to administration, and whenever solution and container permit. Do not use if particulate matter or discoloration is observed
• Attach a suitable needle to the syringe
• Administer by intravenous infusion at a rate of 10 mL/min, but no more than 20 mL/min

How Supplied

Dosage Forms And Strengths

COAGADEX is available as a white or off-white lyophilized powder for reconstitution in single-use vials containing nominally (approximately) 250 IU or 500 IU of Factor X activity. The exact potency/content is listed on the vial label. When reconstituted using the Sterile Water for Injection supplied with the kit, the final concentration is approximately 100 IU/mL.

Factor X activity in COAGADEX is defined in IU and determined using an in vitro chromogenic assay and a Factor X concentrate reference standard calibrated against the World Health Organization (WHO) 3rd International Standard for Blood Coagulation Factors II and X, Concentrate.

COAGADEX is supplied in single-use glass vials containing a nominal (approximate) 250 IU or 500 IU (approximately 100 IU/mL after reconstitution) of Factor X activity, packaged with 2.5 mL or 5 mL of Sterile Water for Injection, respectively, and a Mix2Vial transfer device.

The vials are closed with a synthetic rubber stopper. The stopper is not made with natural rubber latex. The stopper is secured with an aluminum overseal with a flip-off polypropylene cap.

Storage And Handling

• Store COAGADEX in its original package to protect it from light.
• Store the COAGADEX package in a refrigerator or at room temperature at 36°F to 86°F (2°C to 30°C). Do not freeze.
• Do not use COAGADEX or the Sterile Water for Injection after the expiration date printed on the vial and carton labels.
• Use reconstituted COAGADEX within one hour of reconstitution.
• Do not use COAGADEX if the reconstituted solution is cloudy or contains any particles.

Manufactured by: Bio Products Laboratory Ltd., Elstree, WD6 3BX, United Kingdom. Revised: Sep 2018

The most common adverse drug reactions (frequency ≥ 5% of subjects) observed in clinical trials were infusion site erythema, infusion site pain, fatigue, and back pain.

Clinical Trials Experience

As 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 the clinical trial of another drug and may not reflect the rates observed in clinical practice.

During the clinical development of COAGADEX involving three multicenter, open-label, non-randomized clinical studies, 27 individual subjects with hereditary Factor X deficiency received at least one dose of COAGADEX.

Sixteen subjects aged 12 to 58 years with moderate to severe hereditary Factor X deficiency (basal FX:C < 5 IU/dL) received doses of COAGADEX for pharmacokinetic evaluation, on-demand treatment for control of bleeding episodes, and/or perioperative management of minor surgical or dental procedures. A total of 468 infusions were administered, including 242 for on-demand treatment and control of bleeding episodes, 6 for perioperative management and 31 for PK assessments. Spontaneous, traumatic and menorrhagic bleeding episodes were treated with an on-demand dose of 25 IU/kg for up to 2 years.Two subjects aged 55 and 59 years with mild hereditary Factor X deficiency (basal FX:C 6 IU/dL and 8 IU/dL) received COAGADEX for perioperative management of four major surgical procedures. There were 40 exposure days to COAGADEX.

Six adverse reactions were reported in 2 of the 18 subjects. These were infusion site erythema (2 reports in 1 subject [5.6%]), fatigue (2 reports in 1 subject [5.6%]), back pain (1 report [5.6%]) and infusion site pain (1 report [5.6%]).

In a separate study, nine children (aged 2 to 11 years), of whom four were less than 6 years of age, received 537 (mean 59.7) doses of COAGADEX as routine prophylaxis of bleeding episodes during a period of at least 6 months. In addition, 22 infusions were given to treat a bleed, equivalent to 2.1 bleeds per subject per year. There were no adverse drug reactions in this study.

Immunogenicity

All subjects (adults and children) underwent Factor X inhibitor testing (inhibitor screen and Nijmegen-Bethesda assay) at baseline, end of study and at 3-monthly intervals in between. For subjects who underwent surgery, inhibitor testing was done pre-surgery and on discharge. All inhibitor tests were negative. Additionally, comparison of pharmacokinetic (PK) parameters at the repeat PK assessment with those at first dose did not suggest development of any inhibitors to Factor X.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to COAGADEX in the studies described above with the incidence of antibodies in other studies or to other products.

Drug Interactions

Drug interaction studies have not been performed. Use with caution in patients who are receiving other plasma products that may contain Factor X (e.g. fresh frozen plasma, prothrombin complex concentrates). Based on the mechanism of action, COAGADEX is likely to be counteracted by direct and indirect Factor Xa inhibitors [see CLINICAL PHARMACOLOGY].

Included as part of the “PRECAUTIONS” Section

Precautions

Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, are possible. Early signs of hypersensitivity reactions including angioedema, infusion site inflammation (e.g. burning, stinging, erythema), chills, cough, dizziness, fever, flushing, generalized urticaria, headache, hives, hypotension, lethargy, musculoskeletal pains, nausea, pruritus, rash, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing. If hypersensitivity symptoms occur, discontinue use of the product immediately and administer appropriate emergency treatment.

COAGADEX contains traces of human proteins other than Factor X.

Neutralizing Antibodies

The formation of neutralizing antibodies (inhibitors) to Factor X may occur. Monitor all patients treated with COAGADEX for the development of inhibitors by appropriate clinical observations and laboratory tests. If expected Factor X activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures Factor X inhibitor concentration.

Transmissible Infectious Agents

As COAGADEX is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in the product. The risk that the product will transmit viruses has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses during manufacture. Despite these measures, this product may still potentially transmit diseases.

All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare providers to BPL USA Inc. at 1-844-427-5872 or medinfo@bplgroup.com.

Monitoring And Laboratory Tests

Monitor plasma Factor X activity by performing a validated test (e.g. one-stage clotting assay), to confirm that adequate Factor X levels have been achieved and maintained [see DOSAGE AND ADMINISTRATION].

Monitor for the development of Factor X inhibitors. Perform a Nijmegen-Bethesda inhibitor assay if expected Factor X plasma levels are not attained, or if bleeding is not controlled with the expected dose of COAGADEX. Use Nijmegen-Bethesda Units (BU) to report inhibitor levels.

Patient Counseling Information

• Advise the patients to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
• Inform patients to immediately report the following early signs and symptoms of hypersensitivity reactions to their healthcare professional: angioedema, infusion site inflammation (e.g. burning, stinging, erythema), chills, cough, dizziness, fever, flushing, generalized urticaria, headache, hives, hypotension, lethargy, musculoskeletal pains, nausea, pruritus, rash, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing [see WARNINGS AND PRECAUTIONS].
• Inform patients that the development of inhibitors to Factor X is a possible complication of treatment with COAGADEX. Advise the patients to contact their healthcare provider for further treatment and/or assessment if they experience a lack of clinical response to COAGADEX because this may be a manifestation of an inhibitor [see WARNINGS AND PRECAUTIONS].
• Inform patients that COAGADEX is made from human plasma and may contain infectious agents that can cause diseases. While the risk that COAGADEX can transmit an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Nonclinical studies evaluating the carcinogenic or mutagenic potential of COAGADEX have not been conducted. No animal studies regarding impairment of fertility following COAGADEX dosing were conducted; however, no macroscopic or microscopic pathologies in reproductive organs were observed in rats dosed every other day with 6 times the maximum recommended clinical dose of 60 IU/kg COAGADEX for 28 days.

Use In Specific Populations

Pregnancy

Risk Summary

There is limited data with COAGADEX in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted using COAGADEX. It is not known whether COAGADEX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

Risk Summary

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

Pediatric Use

COAGADEX has been studied in 9 young children and 2 adolescents less than 16 years of age (2.1, 6.1, 12.3, 14).

Geriatric Use

Clinical studies of COAGADEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

One case of accidental overdosage was reported in the clinical trials, in which a subject received approximately 80 IU/kg Factor X to treat a bleed. No adverse events were reported relating to this overdose.

Contraindications

COAGADEX is contraindicated in patients who have had life-threatening hypersensitivity reactions to COAGADEX [see DESCRIPTION].

Mechanism Of Action

COAGADEX temporarily replaces the missing Factor X needed for effective hemostasis. Factor X is an inactive zymogen, which can be activated by Factor IXa (via the intrinsic pathway) or by Factor VIIa (via the extrinsic pathway). Factor X is converted from its inactive form to the active form (Factor Xa) by the cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with Factor Va on a phospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in the presence of calcium ions. Thrombin then acts upon soluble fibrinogen and Factor XIII to generate a cross-linked fibrin clot.

Pharmacodynamics

The administration of COAGADEX increases plasma levels of Factor X and can temporarily correct the coagulation defect in these patients, as reflected by decrease in the aPTT and PT.

Pharmacokinetics

In a clinical study of COAGADEX in subjects with severe or moderate Factor X deficiency (basal FX:C < 5 IU/dL), the pharmacokinetics of COAGADEX were assessed after intravenous infusion (mean [range] infusion rate 5.9 [1.3-17.1] mL/min) of 25 IU/kg COAGADEX. Pharmacokinetic (PK) parameters were calculated from plasma Factor X:C activity measurements after subtraction of the pre-dose value. The PK assessment was repeated at least 6 months after the first dose. The PK parameters following a single dose are summarized in Table 3. The pharmacokinetics of COAGADEX were similar following the single and repeat dosing.

Table 3 Mean PK Parameters of COAGADEX Following a Single 25 IU/kg Dose to Subjects 12 years of Age and Older

Incremental recovery in children <12 years of age was assessed at baseline and 6 months after the first dose. Values are summarized in Table 4.

Table 4 Incremental Recovery (IU/mL per IU/kg) in Young Children Under 12 Years of Ag

Studies were not conducted to evaluate the impact of gender or renal/hepatic function on the pharmacokinetics of COAGADEX.

Clinical Studies

On-demand Treatment And Control Of Bleeding Episodes

In a multicenter, open-label, non-randomized clinical trial to evaluate the pharmacokinetics, safety and efficacy of COAGADEX, 16 subjects with moderate to severe hereditary Factor X deficiency (FX:C < 5 IU/dL) received a dose of 25 IU/kg COAGADEX to treat spontaneous, traumatic and menorrhagic bleeding episodes. If hemostasis was not achieved with a single dose of COAGADEX, additional doses could be given until the bleed stopped. Subjects could also continue with treatment after the bleed had stopped to reduce the risk of recurrence of a given bleed. Subjects were aged 12 to 58 years, including 6 pediatric subjects aged 12 to 17 years. Six subjects were male, 10 were female, and 12 were Caucasian.

The efficacy of COAGADEX in treating bleeding episodes was assessed by the subject and/or investigator for each new bleeding episode, using a bleedspecific ordinal rating scale of excellent, good, poor and unassessable for each type of bleed (overt, covert or menorrhagic). Overt bleed: ‘excellent’ if bleeding stopped within 12 hours with a single dose; ‘good’ if within 24 hours with ≤2 doses. Covert bleed: ‘excellent’ if bleeding stopped within 48 hours with 1 or 2 doses; ‘good’ if within 48 hours with ≤3 doses. Menorrhagic bleed: ‘excellent’ if ≤2 doses within 48 hours; ‘good’ if 2 doses over >48 hours. Each bleed was reviewed by a Data Review Committee for its suitability for the efficacy evaluation. Of the 208 bleeding episodes treated with COAGADEX, 187 bleeding episodes in 15 subjects were evaluated for efficacy. Of these 187 bleeding episodes, 79 (42%) occurred spontaneously, 47 (25%) were traumatic and 61 (33%) were menorrhagic. Seventy three (39%) were mucosal in origin, 63 (34%) were joint bleeds, 26 (14%) were muscle bleeds, and 25 (13%) were located elsewhere.

Ninety eight (53%) were major bleeding episodes, and 88 (47%) were minor bleeds (one bleed not assessed). COAGADEX was considered to be good (7%) or excellent (91%) in treating 98% of bleeding episodes. Of the 187 bleeding episodes in the efficacy analysis, a total of 155 bleeds (83%) were treated with one infusion, 28 bleeds (15%) with two infusions, 3 bleeds (2%) with three infusions and 1 bleed (0.5%) with four infusions. The mean dose per infusion and total dose of COAGADEX were 25.4 IU/kg and 30.4 IU/kg, respectively. Four bleeding episodes in two subjects were considered treatment failures.

The recommended dose of 25 IU/kg COAGADEX to treat a bleed was maintained during the study for 14 of the 16 subjects. The other two subjects used doses up to 30 IU/kg and 33 IU/kg.

Prophylaxis Of Bleeding Episodes

In a multicenter, open-label, non-randomized clinical trial, the use of COAGADEX in routine prophylaxis of bleeding episodes was evaluated in nine children aged less than 12 years of age. The mean age was 7.3 (range 2.6 to 11.9) years. Eight subjects had severe FX deficiency and the other had moderate deficiency. Four subjects were between 0 and 5 years of age and five were between 6 and 11 years of age inclusive. The majority of subjects were Asian (7; 77.8%) and the remainder were Caucasian/White (2; 22.2%). After the first dose of COAGADEX 50 IU/kg, given at a rate not exceeding 3 mL/minute, all subjects underwent a 30-minute post-dose incremental recovery assessment. Routine prophylaxis was started on Day 2 or 3 with unit doses of 40-50 IU/kg and during the first 6 weeks trough levels of Factor X were measured to adjust the dosage regimen to maintain a trough level of at least 5 IU/dL. At the end of the study (at least 6 months and at least 50 exposure days) a repeat 30-minute incremental recovery was performed. A total of 537 (mean 59.7 per subject) prophylactic infusions were administered. The median prophylactic dose per infusion per subject was 39.60 IU/kg (mean 38.76 IU/kg), and ranged from 18.0 to 47.3 IU/kg. Median and mean doses per infusion in the four children less than 6 years of age were both 40.1 IU/kg (95% CI 30.70, 49.57) and in the five children 6 to 11 years of age inclusive, median dose was 39.6 IU/kg and mean dose was 37.7 IU/kg (95% CI: 23.42, 51.91). The median dosing interval for all of the nine children was 3 days (range 2 to 8 days). Investigators’ assessment following 6 months of routine prophylaxis was rated excellent in all 9 subjects; excellent was defined as ‘no minor or major bleeds occurred during the study period’ or ‘lower frequency of bleeds than expected, given subject’s medical/treatment history’. In addition, 22 infusions were given to treat a bleed, equivalent to 2.1 bleeds per subject per year. One subject had three episodes of epistaxis and the other bleeds were due to trauma or menorrhagia. All bleeds were treated with a single infusion; the median and mean doses per subject were both 31.7 IU/kg (range 24.6 to 38.8 IU/kg) and all recorded efficacy ratings were categorized as ‘excellent’ i.e. Overt bleed: bleeding stopped within 12 hours with a single dose; Menorrhagic bleed: no additional doses required; Covert bleeds: there were none in this study.

Perioperative Management Of Bleeding

The safety and efficacy of COAGADEX for perioperative management was evaluated in five subjects aged 14 to 59 years with mild (n=2), moderate (n=1), and severe (n=2) disease, who underwent a total of seven surgical procedures.

For all surgical procedures, COAGADEX was assessed as excellent (no post-operative bleeding, no requirement of blood transfusions, and blood loss was no more than ‘as expected’) in controlling blood loss during and after surgery. For major surgeries, a median of 13 infusions (range 2 to 15 infusions) and a median cumulative dose of 181 IU/kg (range 45 to 210 IU/kg) were required to maintain hemostasis. For minor surgeries, a median of 2.5 infusions (range 1 to 4 infusions) and a median cumulative dose of 89 IU/kg (range 51 to 127 IU/kg) were required to maintain hemostasis.

One subject had insertion of a central venous access device (Portacath) and was given 6 infusions of COAGADEX during 5 days, a total of 2,750 IU (27 IU/kg); there were no bleeding complications or safety concerns.