HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use COAGADEX ® safely and effectively. See full prescribing information for COAGADEX ®.
COAGADEX ® (Coagulation Factor X (Human))
Lyophilized Powder for Solution for Intravenous Injection
Initial U.S. Approval: [2015]
INDICATIONS AND USAGE
COAGADEX, Coagulation Factor X (Human), is a plasma-derived human blood coagulation factor indicated in adults and children (aged 12 years and above) with hereditary Factor X deficiency for:
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On-demand treatment and control of bleeding episodes (1)
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Perioperative management of bleeding in patients with mild hereditary Factor X deficiency (1).
Limitation of Use
Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied.
DOSAGE AND ADMINISTRATION
For intravenous use only after reconstitution.
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Each vial of COAGADEX contains the labeled amount of Factor X in international units (IU) (2).
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The dosage and duration of treatment depend on the severity of the Factor X deficiency, on the location and extent of the bleeding and on the patient's clinical condition (2.1).
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For treatment of bleeding episodes: use 25 IU per kg body weight, repeated at intervals of 24 hours until the bleed stops (2.1).
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For perioperative management:
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Pre-surgery, raise plasma Factor X levels to 70-90 IU/dL.
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Post-surgery, 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.
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Required dose (IU) = Body weight (kg) × Desired Factor X rise (IU/dL or % of normal) × 0.5
DOSAGE FORMS AND STRENGTHS
COAGADEX is available as a lyophilized powder for reconstitution in single-use vials containing nominally (approximately) 250 IU or 500 IU of Factor X activity. When reconstituted using the Sterile Water for Injection supplied with the kit, the final concentration is approximately 100 IU/mL (3).
CONTRAINDICATIONS
Do not use in patients who have had life-threatening hypersensitivity reactions to COAGADEX or any of the components (4).
WARNINGS AND PRECAUTIONS
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Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, discontinue COAGADEX and administer appropriate treatment (5.1).
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Development of neutralizing antibodies (inhibitors) may occur. If expected plasma Factor X activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor X inhibitor concentration (5.2).
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COAGADEX is made from human blood and therefore carries a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob Disease (CJD) agent (5.4).
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 (6).
To report SUSPECTED ADVERSE REACTIONS, contact BPL Inc, at 1-866-398-0825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
COAGADEX, Coagulation Factor X (Human), is a plasma-derived human blood coagulation Factor indicated in adults and children (aged 12 years and above) with hereditary Factor X deficiency for:
-
On-demand treatment and control of bleeding episodes
-
Perioperative management of bleeding in patients with mild hereditary Factor X deficiency.
Limitation of Use
Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied.
2 DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only.
2.1 Dose
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Dose and duration of the treatment depend on the severity of the Factor X deficiency, location and extent of the bleeding, and on the patient's clinical condition.
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Base the dose and frequency on the individual clinical response. Do not administer more than 60 IU/kg daily.
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Each vial of COAGADEX is labeled with the actual Factor X potency/content in International Units (IU).
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Estimate the expected in vivo peak increase in Factor X level expressed as IU/dL (or % of normal) using the following formula:
Estimated Increment of Factor X (IU/dL or % of normal) = [Total Dose (IU)/Body Weight (kg)] × 2
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) × 0.5
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 2 IU/dL per IU/kg.
On-demand Treatment and Control of Bleeding Episodes
Infuse 25 IU/kg of COAGADEX when the first sign of bleeding occurs. Repeat at intervals of 24 hours until the bleed stops.
Perioperative Management of Bleeding
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 using the following formula:
Required dose (IU) = Body Weight (kg) × Desired Factor X Rise (IU/dL) × 0.5
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.
2.2 Preparation and Reconstitution
The procedures below are provided as general guidelines for the preparation and reconstitution of COAGADEX.
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Always work on a clean surface and wash your hands before performing the following procedures.
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To reconstitute, use the diluent (Sterile Water for Injection) and transfer device (Mix2Vial) provided in the COAGADEX carton.
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To administer, you will also need a syringe and suitable needle (not provided in the COAGADEX carton).
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Bring the vials of COAGADEX and the Sterile Water for Injection to room temperature before mixing.
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The reconstitution is performed as follows:
2.3 Administration
For intravenous administration only
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If the dose requires more than one vial of COAGADEX:
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Reconstitute each vial (steps 1 to 5) using a new Mix2Vial for each vial.
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Draw up all the solution into a single syringe (steps 6 to 8).
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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.
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Attach a suitable needle to the syringe.
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Administer by intravenous infusion at a rate of 10 mL/min, but no more than 20 mL/min.
3 DOSAGE FORMS AND STRENGTHS
COAGADEX is available as 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 per 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.
4 CONTRAINDICATIONS(What is this?)
COAGADEX is contraindicated in patients who have had life-threatening hypersensitivity reactions to COAGADEX or any of the components [see Description (11)].
5 WARNINGS AND PRECAUTIONS
5.1 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.
5.2 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.
5.3 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 Inc. at 1-866-398-0825.
5.4 Monitoring and Laboratory Tests
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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 (2)].
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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.
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.
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 two multicenter, open-label, non-randomized clinical studies, 18 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 eva luation, on-demand treatment and 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%]).
6.2 Immunogenicity
All subjects 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.
7 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 (12.1)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data with COAGADEX use 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. COAGADEX should be given to a pregnant woman only if clearly needed. 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.
8.2 Lactation
Risk Summary
There is no information regarding the presence of COAGADEX in human milk, the effects 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 COAGADEX and any potential adverse effects on the breast-fed infant from COAGADEX or from the underlying maternal condition.
8.4 Pediatric Use
Safety and efficacy in patients under the age of 12 years have not been studied.
8.5 Geriatric Use
Clinical studies of COAGADEX did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. Individualize dose selection for geriatric patients.
10 OVERDOSAGE
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.
11 DESCRIPTION
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 3rd 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)-1/2 and 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), HCV, hepatitis A virus (HAV) and human parvovirus B19. Furthermore, each manufacturing pool is tested to be negative for HBsAg and anti-HIV-1/2 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:
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1)
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Solvent/detergent treatment targeted to inactivate enveloped viruses;
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2)
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A 15-nm filtration step designed to remove small viruses including non-enveloped viruses; and
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3)
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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.
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