Coagadex Drug Information

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 On-demand treatment and control of bleeding episodes Perioperative management of bleeding in patients with mild, moderate and severe hereditary Factor X deficiency

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. Do not exceed a peak level of 120 IU/dL.

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. Repeat at intervals of 24 hours until the bleed stops. 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) = × 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.

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 Figure Figure Figure Figure Figure Figure

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

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.

Spontaneous, traumatic and menorrhagic bleeding episodes were treated with an on-demand dose of 25 IU/kg for up to 2 years. There were 40 exposure days to COAGADEX. Six adverse reactions were reported in 2 of the 18 subjects.

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 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.

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.

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.

Pediatric Use A prospective, open-label, multicenter study was conducted in nine pediatric patients (0-5 years, n=4; 6-11 years, n=5) with severe (n=8) or moderate (n=1) hereditary factor X deficiency, to assess safety, efficacy, and pharmacokinetics of COAGADEX used prophylactically and on-demand. Patients had baseline FX levels < 5 IU/dL, and were dosed to achieve post-treatment levels of at least 5 IU/dL. After ≥26 weeks and ≥50 exposure days, investigators rated pdFX efficacy for preventing/decreasing bleeds.

At end of study, investigators rated pdFX efficacy excellent for all subjects. Trough FX:C levels remained >5 IU/dL for all subjects after achievement of steady state. All AEs were unrelated to treatment; no inhibitor development or clinically significant changes in laboratory parameters were observed.

Six additional pediatric subjects aged 12 to 17 years were included in a prospective, open-label, multicenter study of COAGADEX to treat spontaneous, traumatic and menorrhagic bleeding episodes. Overall efficacy and safety outcomes were comparable to those in the younger age groups.

COAGADEX is contraindicated in patients who have had life-threatening hypersensitivity reactions to COAGADEX. Do not use in patients who have had life-threatening hypersensitivity reactions to COAGADEX.

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.