Coagulation Factor X Human

1 INDICATIONS AND USAGE 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, moderate, and severe hereditary Factor X deficiency 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 ( 1 ) On-demand treatment and control of bleeding episodes ( 1 ) Perioperative management of bleeding in patients with mild, moderate and severe hereditary Factor X deficiency ( 1 )

2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only For intravenous use only after reconstitution. Each vial of COAGADEX contains the labeled amount of Factor X in international units (IU) ( 2 ) The dosage and duration of treatment depend on the severity of the Factor X deficiency, the location and extent of the bleeding and the patient's clinical condition ( 2.1 ) For prophylaxis of bleeding episodes ( 2.1 ): Age Initial dose Further management Children: Less than 12 years of age 40 IU/kg twice weekly Monitor trough blood levels of Factor X targeting ≥5 IU/dL and adjust dosage to clinical response and trough levels. Do not exceed a peak level of 120 IU/dL. Adults and adolescents: 12 years of age or older 25 IU/kg twice weekly For treatment of bleeding episodes ( 2.1 ): Age Initial dose Further management Children: Less than 12 years of age 30 IU/kg Infuse at first sign of bleeding. Repeat at intervals of 24 hours until the bleed stops. Adults and adolescents: 12 years of age or older 25 IU/kg For perioperative management ( 2.1 ): Age Initial dose Further management Children: Less than 12 years of age Use a factor of 0.6 to calculate the required dose Pre-surgery: raise plasma Factor X levels to 70-90 IU/dL. Post-surgery: maintain plasma Factor X levels at ≥50 IU/dL until the patient is no longer at risk of bleeding due to surgery. Dose (IU) = body weight (kg) × desired factor X rise † (IU/dL or % of normal) × 0.6 Adults and adolescents: 12 years of age or older Use a factor of 0.5 to calculate the required dose Dose (IU) = body weight (kg) × desired factor X rise ‡ (IU/dL or % of normal) × 0.5 2.1 Dose 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 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). Prophylaxis of bleeding episodes Age Initial dose Further management Children: Less than 12 years of age 40 IU/kg twice weekly Due to inter-and intra-patient variability, it is recommended that trough blood levels of Factor X should be monitored at intervals, especially in the first weeks of therapy or after dosages changes. Adjust dosage regimen to clinical response and trough levels of Factor X of at least 5 IU/dL. Do not exceed a peak level of 120 IU/dL. [For more detailed calculations of dose, see Detailed Dose Calculation (2.1) ] . Adults and adolescents: 12 years of age or older 25 IU/kg twice weekly On–demand treatment and control of bleeding episodes Age Initial dose Further management Children: Less than 12 years of age 30 IU/kg Infuse COAGADEX when the first sign of bleeding occurs [see Clinical Trial Experience (6.1) ] . Repeat at intervals of 24 hours until the bleed stops. [For more detailed calculations of dose, see Detailed Dose Calculation (2.1) ] . Adults and adolescents: 12 years of age or older 25 IU/kg Perioperative management of bleeding Age Initial dose Further management Children: Less than 12 years of age Use a factor of 0.6 to calculate the required dose Measure post-infusion plasma Factor X levels for each patient before and after surgery to ensure that hemostatic levels are obtained and maintained. Pre-surgery : calculate the dose of COAGADEX to raise plasma Factor X levels to 70-90 IU/dL Post-surgery : Repeat dose as necessary to maintain plasma Factor X levels at a minimum of 50 IU/dL until the patient is no longer at risk of bleeding due to surgery Dose (IU) = body weight (kg) × desired factor X rise † (IU/dL or % of normal) × 0.6 Adults and adolescents: 12 years of age or older Use a factor of 0.5 to calculate the required dose Dose (IU) = body weight (kg) × desired factor X rise ‡ (IU/dL or % of normal) × 0.5 Detailed Dose Calculation 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: Dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL) × 0.6 † The desired Factor X rise is the difference between the patient's plasma Factor X level and the maximum desired level. To estimate the expected in vivo maximum increase in plasma Factor X, expressed as IU/dL (or % of normal), use the following formula: Estimated Increment of Factor X (IU/dL or % of normal) = [Total Dose (IU)/Body Weight (kg)] × 1.7 For adolescents and adults (at least 12 years of age) , the incremental recovery is approximately 2.0 IU/dL per IU/kg so the number at the end of each of the above formulae changes as follows: Dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL or % of normal) × 0.5 ‡ The desired Factor X rise is the difference between the patient's plasma Factor X level and the maximum desired level. To estimate the expected in vivo maximum increase in plasma Factor X expressed as IU/dL (or % of normal) use the following formula: Estimated Increment of Factor X (IU/dL or % of normal) = [Total Dose (IU)/Body Weight (kg)]× 2 2.2 Preparation and Reconstitution 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: Table 1 COAGADEX Reconstitution Instructions Step 1 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. Step 2 Peel back the top of the Mix2Vial package. Do not remove the device from the package. Step 3 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. Step 4 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. Step 5 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. Step 6 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. Step 7 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. Step 8 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. Figure Figure Figure Figure Figure Figure 2.3 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. 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

6 ADVERSE REACTIONS 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. 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 ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact BPL USA Inc., at 1-844-427-5872 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 6.2 Immunogenicity Immunogenicity was evaluated in three studies and 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.

12.3 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 First Dose Mean (CV%) (n=16) CV: Coefficient of variation C max (IU/mL) 0.504 (17.2) Half-life (hr) 30.3 (22.8) AUC 0-144h (IU.hr/mL) 17.1 (21.0) AUC( 0-∞ ) (IU.hr/mL) 18.0 (20.9) V ss (mL/kg) 56.3 (24.0) CL (mL/kg/hr) 1.35 (21.7) MRT (hr) 41.8 (21.7) Incremental recovery (IU/dL per IU/kg) Using peak increment within 30 minutes post-dose 2.04 (19.5) 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 Age Pediatric age group Visit 1 First dose of COAGADEX; Mean (Min-Max) End of Study After at least 6 months; Mean (Min-Max) Aged 6-11 years (n = 5) 1.83 (1.6–2.2) 1.99 (1.8–2.2) Aged 0-5 years (n = 4) 1.45 (1.3–1.6) 1.62 (1.3–1.8) Studies were not conducted to evaluate the impact of gender or renal/hepatic function on the pharmacokinetics of COAGADEX.