Factor X is a parenteral, human plasma-derived coagulation factor indicated for the control and prevention of bleeding, including perioperative management of bleeding, in persons with hereditary factor X deficiency. During a multicenter non-randomized trial, factor X effectively controlled 98% of bleeding episodes (spontaneous, traumatic, and menorrhagic) in 16 subjects (208 bleeding episodes; 6 pediatric subjects 12 to 17 years) with moderate to severe hereditary factor X deficiency. Factor X also controlled blood loss before and after surgery in 5 subjects (age range: 14 to 59 years) with mild, moderate, or severe deficiency who underwent 7 surgical procedures. In a postmarketing registry study, 3 subjects with severe hereditary factor X deficiency (age range: 21 to 30 years) received factor X perioperatively and all achieved hemostatic efficacy outcomes. Additionally, no minor or major bleeds, or a lower frequency of bleeds than expected, were reported in a study of 9 children (age range: 2.6 to 11.9 years) receiving factor X for routine bleeding prophylaxis during a 6-month period, and there were no safety concerns identified. Factor X was evaluated for prophylactic and on-demand use in 9 infants and children (age range: 0 to 11 years) with moderate (n = 1) or severe (n = 8) hereditary factor X deficiency. A total of 10 bleeding events (6 major bleeding, 3 minor bleeding, and 1 not assessed for bleeding severity) occurred in 3 subjects. Trough factor X concentrations remained more than 5 International Units/dL for all subjects and all adverse events were unrelated to treatment. Hereditary factor X deficiency, which causes blood not to clot properly, is rare, affecting an estimated 1 in 500,000 to 1,000,000 individuals worldwide. Until the orphan drug approval of factor X, no specific coagulation factor replacement was available for persons with hereditary factor X deficiency; treatment primarily included fresh-frozen plasma or plasma-derived prothrombin complex concentrates. Factor X availability increases treatment options for persons with this rare bleeding disorder.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Factor X activity is expressed in International Units. Factor X potency is assigned using an in vitro chromagenic assay and a factor X concentrate reference standard calibrated against the World Health Organization (WHO) international standard for blood coagulation factors II and X, concentrate.
-The actual potency per vial of factor X is stated on each vial and is approximately 250 or 500 International Units. When reconstituted, the final concentration is approximately 100 International Units/mL.
Route-Specific Administration
Injectable Administration
-Visually inspect the final solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear or slightly pearl-like. Do not use if discolored or particulate matter is present.
Intravenous Administration
Reconstitution:
-Use aseptic technique and a flat work surface throughout the entire reconstitution process.
-Allow vials of factor X and diluent (Sterile Water for Injection, provided) to reach room temperature.
-Peel back the top of the Mix2Vial package (provided). 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.
-Invert the water vial with the Mix2Vial device still attached over the factor X vial. Place the clear end of the Mix2Vial on the factor X vial, and push straight down until the spike penetrates the rubber stopper and snaps into place.
-The water will automatically transfer into the factor X vial. Do not use if the water is not pulled into the factor X vial.
-Gently swirl the factor X vial to ensure powder is fully dissolved. Do not shake.
-Separate the empty water vial and the blue part of the Mix2Vial from the clear part that is attached to the factor X vial by unscrewing counter-clockwise.
-Draw air into an empty syringe 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 factor X 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.
-If the dose requires more then one vial of factor X, reconstitute each vial as described above, and draw up all the solution into a single syringe.
-Use immediately. Do not store reconstituted product.
Administration:
-Administer by intravenous infusion at a recommended rate of 10 mL/min and no more than 20 mL/min.
Hypersensitivity reactions including anaphylactoid reactions are possible with the administration of factor X. If such reactions occur, discontinue factor X immediately and initiate appropriate emergency treatment. Early signs of hypersensitivity reactions include angioedema, infusion site inflammation (e.g., burning, stinging, erythema), chills, cough, dizziness, fever, flushing, generalized urticaria, headache, hives, hypotension, lethargy, musculoskeletal pain, nausea, pruritus, rash, restlessness, tachycardia, chest tightness, tingling, vomiting, and wheezing. During clinical trials in patients 12 years and older (n = 18), infusion-related reactions occurred in 2 patients; infusion site erythema was reported twice in 1 patient (5.6%) and infusion site pain was reported in 1 patient (5.6%). No adverse reactions were reported in a separate study evaluating 9 children (age: 2 to 11 years).
Antibody formation inhibiting factor X may occur with the administration of factor X replacement. If plasma factor X activity concentrations are not achieved or if bleeding is not controlled with the expected dose, perform an Nijmegen-Bethesda inhibitor assay.
During clinical trials of factor X in patients 12 years and older (n = 18), fatigue was reported twice in 1 patient (5.6%), and back pain was reported in 1 patient (5.6%). No adverse reactions were reported in a separate study evaluating 9 children (age: 2 to 11 years).
Factor X is contraindicated in patients who have had life-threatening hypersensitivity reactions to factor X or its components.
Factor X is derived from human plasma and may contain infectious agents such as viruses, and theoretically, the Creutzfeldt-Jakob disease agent. There is also the possibility that other unknown infectious agents may be present in the product. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents. Human plasma used in the production of factor X is purified by a combination of solvent/detergent treatment targeted to inactivate enveloped viruses, filtration designed to remove small viruses including non-enveloped viruses, and a dry-heat treatment to inactivate both enveloped and non-enveloped viruses. Despite these measures, factor X may still potentially transmit diseases. Report any infection thought to have been possibly transmitted by factor X to the manufacturer or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The formation of factor X inhibitors (neutralizing antibodies) may occur during therapy with factor X. Monitor patients for the development of inhibitors by appropriate clinical observation and laboratory tests. If plasma factor X activity concentrations are not achieved or if bleeding is not controlled with the expected dose, perform an Nijmegen-Bethesda inhibitor assay to measure factor X inhibitor concentration.
Sufficient numbers of geriatric patients were not included in clinical trials of factor X to determine whether they respond differently from younger patients. 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, starting at the low end of the dosage range.
It is unknown if factor X can cause fetal harm when administered during pregnancy or if it can affect reproduction capacity. There is limited data with factor X in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted with factor X.
There is no data regarding the presence of factor X in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for factor X and any potential adverse effects on the breast-fed infant from factor X or the underlying maternal condition.
-Dose and duration of treatment depend on the severity of factor X deficiency, the location and extent of bleeding, and the individual's age and clinical condition. Base the dose and frequency on the individual clinical response.
-Each vial states the factor X potency in International Units.
-Generally 1 International Unit/kg increases the circulating factor X concentration by 2 International Units/dL in adults and adolescents 12 to 17 years and by 1.7 International Units/dL in children younger than 12 years. Carefully monitor clinical effects and adjust dosage and/or frequency as needed. The following formulas may be used to estimate the required dose or the desired in vivo peak increase in factor X concentration:
--Adults and Adolescents 12 to 17 years: Dose (International Units) = Body Weight (kg) x Desired Factor X Rise (International Units/dL or % of normal) x 0.5 or Estimated Increment of Factor X (International Units/dL or % of normal) = [Total Dose (International Units)/Body Weight (kg)] x 2.
-Children younger than 12 years: Dose (International Units) = Body Weight (kg) x Desired Factor X Rise (International Units/dL) x 0.6 or Estimated Increment of Factor X (International Units/dL or % of normal) = [Total Dose (International Units)/Body Weight (kg)] x 1.7.
For the on-demand treatment and control of hemorrhage in persons with hereditary factor X deficiency:
Intravenous dosage:
Adults: 25 International Units/kg IV with the first sign of bleeding. Repeat every 24 hours until bleeding stops. Max: 60 International Units/kg/day.
Children and Adolescents 12 to 17 years: 25 International Units/kg IV with the first sign of bleeding. Repeat every 24 hours until bleeding stops. Max: 60 International Units/kg/day.
Children 1 to 11 years: 30 International Units/kg IV with the first sign of bleeding. Repeat every 24 hours until bleeding stops. Max: 60 International Units/kg/day.
For the perioperative management of surgical bleeding in persons with hereditary factor X deficiency:
Intravenous dosage:
Adults: Dose and duration of treatment depend on the severity of factor X deficiency, the location and extent of bleeding, and the patient's clinical condition. The circulating factor X activity required preoperatively is 70 to 90 International Units/dL. The following formulas may be used to estimate the required dose or the in vivo peak increase in factor X concentration: Dose (International Units) = Body Weight (kg) x Desired Factor X Rise (International Units/dL or % of normal) x 0.5 or Estimated Increment of Factor X (International Units/dL or % of normal) = [Dose (International Units)/Body Weight (kg)] x 2. Repeat the dose as necessary to maintain plasma factor X concentrations of at least 50 International Units/dL until the patient is no longer at risk of bleeding due to surgery. Max: 60 International Units/kg/day. Monitor post-infusion plasma factor X concentrations before and after surgery to confirm adequate concentrations are achieved and maintained.
Children and Adolescents 12 to 17 years: Dose and duration of treatment depend on the severity of factor X deficiency, the location and extent of bleeding, and the patient's clinical condition. The circulating factor X activity required preoperatively is 70 to 90 International Units/dL. The following formulas may be used to estimate the required dose or the in vivo peak increase in factor X concentration: Dose (International Units) = Body Weight (kg) x Desired Factor X Rise (International Units/dL or % of normal) x 0.5 or Estimated Increment of Factor X (International Units/dL or % of normal) = [Dose (International Units)/Body Weight (kg)] x 2. Repeat the dose as necessary to maintain plasma factor X concentrations of at least 50 International Units/dL until the patient is no longer at risk of bleeding due to surgery. Max: 60 International Units/kg/day. Monitor postinfusion plasma factor X concentrations before and after surgery to confirm adequate concentrations are achieved and maintained.
Children 1 to 11 years: Dose and duration of treatment depend on the severity of factor X deficiency, the location and extent of bleeding, and the patient's clinical condition. The circulating factor X activity required preoperatively is 70 to 90 International Units/dL. The following formulas may be used to estimate the required dose or the in vivo peak increase in factor X concentration: Dose (International Units) = Body Weight (kg) x Desired Factor X Rise (International Units/dL or % of normal) x 0.6 or Estimated Increment of Factor X (International Units/dL or % of normal) = [Dose (International Units)/Body Weight (kg)] x 1.7. Repeat the dose as necessary to maintain plasma factor X concentrations of at least 50 International Units/dL until the patient is no longer at risk of bleeding due to surgery. Max: 60 International Units/kg/day. Monitor postinfusion plasma factor X concentrations before and after surgery to confirm adequate concentrations are achieved and maintained.
For routine bleeding prophylaxis to reduce the frequency of bleeding episodes in persons with hereditary factor X deficiency:
Intravenous dosage:
Adults: 25 International Units/kg IV twice weekly. Monitor factor X concentrations intermittently, especially in the first weeks of therapy or after dose changes. Adjust dose based on clinical response and maintain a factor X trough concentration of at least 5 International Units/dL. Do not exceed a factor X peak concentration of 120 International Units/dL. Max: 60 International Units/kg/day.
Children and Adolescents 12 to 17 years: 25 International Units/kg IV twice weekly. Monitor factor X concentrations intermittently, especially in the first weeks of therapy or after dose changes. Adjust dose based on clinical response and maintain a factor X trough concentration of at least 5 International Units/dL. Do not exceed a factor X peak concentration of 120 International Units/dL. Max: 60 International Units/kg/day.
Children 1 to 11 years: 40 International Units/kg IV twice weekly. Monitor factor X concentrations intermittently, especially in the first weeks of therapy or after dose changes. Adjust dose based on clinical response and maintain a factor X trough concentration of at least 5 International Units/dL. Do not exceed a factor X peak concentration of 120 International Units/dL. Max: 60 International Units/kg/day.
Maximum Dosage Limits:
-Adults
60 International Units/kg/day IV.
-Geriatric
60 International Units/kg/day IV.
-Adolescents
60 International Units/kg/day IV.
-Children
60 International Units/kg/day IV.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Apixaban: (Contraindicated) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
Betrixaban: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as betrixaban.
Edoxaban: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
Fondaparinux: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
Protein C Concentrate, Human: (Major) Use factor X cautiously with other plasma products that may contain factor X (e.g., fresh frozen plasma, prothrombin complex concentrate, human).
Prothrombin Complex Concentrate, Human: (Major) Use factor X cautiously with other plasma products that may contain factor X (e.g., fresh frozen plasma, prothrombin complex concentrate, human).
Rivaroxaban: (Major) The actions of factor X are likely to be counteracted by factor Xa inhibitors such as rivaroxaban.
Factor X is a vitamin K-dependent serine protease that serves as the first enzyme in the common pathways of thrombus formation. 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. After conversion to its active form (factor Xa), it 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. The administration of factor X to patients with hereditary deficiency temporarily restores the missing factor X that is required for effective hemostasis.
Factor X is administered intravenously. The pharmacokinetic (PK) parameters of factor X were assessed after a single IV infusion of 25 International Units/kg (mean infusion rate: 5.9 mL/minute) in patients 12 years and older with moderate or severe factor X deficiency (n = 16). Mean PK parameters were as follows: Vd = 56.3 mL/kg; Cmax = 0.504 International Units/mL; AUC = 18 International Units x hour/mL; CL = 1.35 mL/kg/hour; half-life = 30.3 hours. Mean residence time (MRT) was 41.8 hours and incremental recovery was 2.04 International Units/dL per International Units/kg. 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. PK parameters were similar with single and repeat dosing.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Special Populations
Pediatrics
Children and Adolescents 12 to 17 years
Mean incremental recovery (International Units per International Unit/kg) was 2.04 using peak increment within 30 minutes after the first dose of factor X.
Children 6 to 11 years
Mean incremental recovery (International Units per International Unit/kg) was 1.83 after the first dose of factor X and 1.99 after at least 6 months of therapy.
Infants and Children 1 to 5 years
Mean incremental recovery (International Units per International Unit/kg) was 1.45 after the first dose of factor X and 1.62 after at least 6 months of therapy.