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| {{DrugProjectFormSinglePage
| | #REDIRECT [[Factor XIII]] |
| |authorTag={{AV}}<!--Overview-->
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| |genericName=factor xiii concentrate
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| |aOrAn=a
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| |drugClass=[[hemostatic]]
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| |indicationType=treatment
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| |indication=surgical [[bleeding]] in adult and pediatric patients with [[FXIII deficiency|congenital FXIII deficiency]]
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| |adverseReactions=[[erythema]] , [[pruritus]] of skin, [[rash]], [[serum lactate dehydrogenase level elevated]], [[blood coagulation disorder]], [[hematoma]], [[arthralgia]], [[arthritis]], [[headache]]<!--Black Box Warning-->
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| |blackBoxWarningTitle=Title
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| |blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
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| * Content
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| <!--Adult Indications and Dosage-->
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| <!--FDA-Labeled Indications and Dosage (Adult)-->
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| |fdaLIADAdult=*Factor xiii concentrate is a Factor XIII Concentrate indicated for routine prophylactic treatment and peri-operative management of surgical bleeding in adult and pediatric patients with congenital [[FXIII deficiency]].
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| =====Dosage=====
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| *40 International Units (IU) per kg body weight at a rate not to exceed 4 mL per minute
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| *Adjust dose ±5 IU per kg to maintain 5% to 20% trough level of FXIII activity as provided in the example below
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| *Dose Adjustment Using the Berichrom Activity Assay
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| : [[File:{{PAGENAME}}02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| =====Administration=====
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| *Administer at a rate not exceeding 4 mL per minute
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| *For routine prophylaxis, administer every 28 days
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| *For peri-operative management of surgical bleeding:
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| *Dosing should be individualized based on the patient's FXIII activity level, type of surgery, and clinical response
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| *Monitor patient's FXIII activity levels during and after surgery
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| *Following are dose adjustment examples for peri-operative management in reference to the patient's last prophylactic dose:
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| Dose Adjustment for Peri-operative Management
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| : [[File:{{PAGENAME}}03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *The potency expressed in International Units is determined using the Berichrom activity assay, referenced to the current International Standard for Blood Coagulation [[Factor XIII]], Plasma.
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| =====Reconstitution=====
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| *Perform a visual inspection of the reconstituted solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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| *The procedures below are provided as general guidelines for the preparation and reconstitution of congenital [[FXIII deficiency]].
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| *Reconstitute factor xiii concentratate room temperature as follows:
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| : [[File:{{PAGENAME}}04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| <!--Off-Label Use and Dosage (Adult)-->
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| <!--Guideline-Supported Use (Adult)-->
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| |offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
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| <!--Non–Guideline-Supported Use (Adult)-->
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| |offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
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| <!--Pediatric Indications and Dosage-->
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| <!--FDA-Labeled Indications and Dosage (Pediatric)-->
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| |fdaLIADPed=There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
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| <!--Off-Label Use and Dosage (Pediatric)-->
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| <!--Guideline-Supported Use (Pediatric)-->
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| |offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
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| <!--Non–Guideline-Supported Use (Pediatric)-->
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| |offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
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| <!--Contraindications-->
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| |contraindications=*Factor xiii concentrate is contraindicated in patients with known [[anaphylactic]] or severe systemic reactions to human plasma-derived products
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| <!--Warnings-->
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| |warnings=
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| =====Hypersensitivity=====
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| *[[Hypersensitivity]] reactions have been observed with factor xiii concentrate. If signs or symptoms of [[anaphylaxis]] or [[hypersensitivity]] reactions (including [[urticaria]], [[rash]], tightness of the chest, [[wheezing]], [[hypotension]]) occur, immediately discontinue administration and institute appropriate treatment.
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| =====Immunogenicity=====
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| *Development of inhibitory antibodies against FXIII has been detected in patients receiving factor xiii concentrate. Monitor patients for development of inhibitory antibodies. Presence of inhibitory antibodies may manifest as an inadequate response to treatment. If expected plasma FXIII activity levels are not attained, or if breakthrough [[bleeding]] occurs while receiving prophylaxis, perform an assay that measures FXIII inhibitory antibody concentrations.
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| =====Thromboembolic Risk=====
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| *[[Thromboembolic]] complications have been reported. Monitor patients with known risk factors for [[thrombotic events]].
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| =====Transmission of Infectious Agents=====
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| *Factor xiii concentrate is made from human plasma. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the [[Creutzfeld-Jakob disease]] (CJD) agent. This also applies to unknown or emerging viruses and other pathogens.
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| *All [[infections]] thought by a physician to have been possibly transmitted by this product are to be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance
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| <!--Adverse Reactions-->
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| <!--Clinical Trials Experience-->
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| |clinicalTrials=*The most common adverse reactions reported in frequency >1% are joint inflammation, [[hypersensitivity]], [[rash]], [[pruritus]], [[erythema]], [[hematoma]], [[arthralgia]], [[headache]], elevated [[thrombin]]-[[antithrombin]] levels, and increased [[blood lactate dehydrogenase]].
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| *The serious adverse reactions, reported in one subject each (frequency 0.5%), were [[hypersensitivity]], acute [[ischemia]], and neutralizing antibodies against [[FXIII]].
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| =====Clinical Trials Experience=====
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| *Because 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 trials of another drug and may not reflect the rates observed in practice.
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| *Twelve clinical studies included a total of 188 subjects, 108 subjects were <16 years of age and a total of approximately 4314 infusions of factor xiii concentrate were administered in the studies.
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| =====Efficacy and Safety Study=====
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| *A 12-month, prospective, open-label, multicenter efficacy and safety study was conducted in 25 males and 16 females ranging in age from less than 1 year to 42 years old (2 infants, 8 children, 8 adolescents, and 23 adults). There were no reports of deaths, life-threatening events, or adverse events that led to discontinuation or withdrawal from the study. Four subjects received FXIII in the peri-operative setting, and no treatment-related AEs were reported. An additional subject was pre-treated with plasma and experienced a [[hypersensitivity]] reaction.
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| =====Immunogenicity=====
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| *A case of neutralizing antibodies against FXIII was reported in the postmarketing clinical study. The patient received prophylactic treatment with factor xiii concentrate for ten years. Concomitant medications included [[interferon]] for [[hepatitis C]] [[infection]]. This patient presented with [[bruising]], and post-infusion FXIII levels were found to be lower than expected. Over several weeks, FXIII recovery values decreased, so the dose and frequency of treatments were increased. Neutralizing antibodies to FXIII were detected, [[interferon]] treatment was discontinued, and the subject underwent [[plasmapheresis]]. Within a month, neutralizing antibodies were no longer detectable, FXIII recovery levels improved, and the previous prophylactic regimen was resumed.
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| <!--Postmarketing Experience-->
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| |postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
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| <!--Drug Interactions-->
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| |drugInteractions=<!--Use in Specific Populations-->
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| |FDAPregCat=C
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| |useInPregnancyFDA=*Animal reproduction studies have not been conducted with factor xiii concentrate. Safety and effectiveness in [[pregnancy]] have not been established. It is also not known whether factor xiii concentrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. factor xiii concentrate should be given to a pregnant woman only if clearly needed.
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| |useInPregnancyAUS=There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
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| |useInLaborDelivery=*Factor xiii concentrate has not been studied for use during labor and delivery. Safety and effectiveness in labor and delivery is unknown.
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| |useInNursing=*It is not known whether factor xiii concentrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when factor xiii concentrate is administered to a nursing woman.
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| |useInPed=*Of the 188 subjects in the factor xiii concentrate clinical studies, 108 were subjects <16 years of age at the time of enrollment
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| : [[File:{{PAGENAME}}05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *In the pharmacokinetic study , 5 of the 14 subjects ranged in age from 2 to <16 years. Subjects less than 16 years had a shorter half-life (5.7 ± 1.00 days) and faster clearance (0.29 ± 0.12 mL/hr/kg) compared to adults (half-life: 7.1 ± 2.74 days, clearance: 0.22 ± 0.07 mL/hr/kg). Dose adjustments may be needed for patients <16 years of age. There were no differences in the safety profile in children as compared to adults.
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| |useInGeri=*The safety and efficacy of factor xiii concentrate in the geriatric population have not been established.
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| |useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
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| |useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
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| |useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with [[renal impairment]].
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| |useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with [[hepatic impairment]].
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| |useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
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| |useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are [[immunocompromised]].
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| <!--Administration and Monitoring-->
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| |administration=* Intravenous
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| |monitoring=*Monitor patient's trough FXIII activity level during treatment with factor xiii concentrate
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| *If breakthrough [[bleeding]] occurs, or if expected peak plasma FXIII activity levels are not attained, perform an investigation to determine the presence of FXIII inhibitory antibodies
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| <!--IV Compatibility-->
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| |IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
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| <!--Overdosage-->
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| |overdose=There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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| <!--Pharmacology-->
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| <!--Drug box 2-->
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| |drugBox=
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| <!--Mechanism of Action-->
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| |mechAction=*Factor xiii concentrate(FXIII) is an endogenous plasma [[glycoprotein]] consisting of two A-subunits and two B-subunits. FXIIIa promotes cross-linking of [[fibrin]] during coagulation and is essential to the physiological protection of the clot against [[fibrinolysis]]. FXIIIa is a [[transglutaminase]] enzyme that catalyzes the cross-linking of the fibrin α- and γ-chains for [[fibrin]] stabilization and renders the [[fibrin]] clot more elastic and resistant to [[fibrinolysis]].FXIIIa also cross-links [[α2-plasmin inhibitor]] to the α-chain of fibrin, resulting in protection of the fibrin clot from degradation by [[plasmin]]. Cross-linked [[fibrin]] is the end result of the coagulation cascade, and provides tensile strength to a primary [[hemostatic]] platelet plug.
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| *The B-subunits in plasma have no enzymatic activity, and function as carrier molecules for the A-subunits. They stabilize the structure of the A-subunits and protect them from [[proteolysis]].
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| <!--Structure-->
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| |structure=*Factor XIII Concentrate (Human), is a heat-treated, lyophilized concentrate of coagulation factor XIII for reconstitution for intravenous use. Factor xiii concentrate(FXIII) consists of two A-subunits and two B-subunits, and is made from pooled human plasma. Each vial contains 1000-1600 units FXIII, 120 to 200 mg human albumin, 120 to 320 mg total protein, 80 to 120 mg glucose and 140 to 220 mg sodium chloride. [[Sodium hydroxide]] may have been used to adjust the pH.
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| *All plasma used in the manufacture of factor xiii concentrate is obtained from US donors and is tested using serological assays for [[hepatitis B]] surface antigen and antibodies to HIV-1/2 and [[HCV]]. The plasma is tested with Nucleic Acid Testing (NAT) for [[HCV]], HIV-1, HAV and HBV and found to be non-reactive (negative), and the plasma is also tested by NAT for Human [[Parvovirus B19]]. Only plasma that passed virus screening is used for production, and the limit for [[Parvovirus B19]] in the fractionation pool is set not to exceed 104 International Units of [[Parvovirus B19]] DNA per mL.
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| *factor xiii concentrate is manufactured from cryo-depleted plasma into an [[ethanol]] precipitate, which is then purified by the following four steps:
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| :*Precipitation/adsorption
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| :*Ion exchange [[chromatography]]
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| :*Heat-treatment (+60°C for 10 hours in an aqueous solution)
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| :*Virus filtration over two 20 nm filters in series
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| *The sterile filtered final bulk solution is filled into vials and lyophilized. These four manufacturing steps were independently validated in a series of in vitro experiments for their capacity to inactivate or remove both enveloped and non-enveloped viruses. Table 2 shows the virus clearance capacity of the factor xiii concentrate manufacturing process, expressed as mean log10 reduction factor.
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| : [[File:{{PAGENAME}}01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| <!--Pharmacodynamics-->
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| |PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
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| <!--Pharmacokinetics-->
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| |PK=*A 12-week prospective, open-label, multicenter pharmacokinetic and safety study was conducted in 7 females and 7 males with congenital [[FXIII deficiency]], ranging in age from 5 to 42 years (3 children, 2 adolescents, 9 adults). One adult male did not complete the pharmacokinetic study.
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| *Each subject received 40 units per kg factor xiii concentrate intravenously every 28 days for a total of three doses administered at approximately 250 units per minute. Blood samples for doses 1 and 2 were drawn from patients to determine the FXIII activity level at baseline and 30 and 60 minutes after the infusion. Following the infusion of the third dose of factor xiii concentrate, blood samples were drawn at regular intervals up to 28 days to determine the pharmacokinetic parameters. The mean increase in FXIII activity levels was 83% with a range of 48 to 114% over the baseline after the third dose. The pharmacokinetic parameters based on baseline adjusted FXIII activity (Berichrom assay) are shown in TABLE 3.
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| : [[File:{{PAGENAME}}06.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| <!--Nonclinical Toxicology-->
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| |nonClinToxic======Animal Toxicology and/or Pharmacology=====
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| *Factor xiii concentrate was studied in an acute toxicity study in mice and rats at doses up to 3550 units per kg and 1420 units per kg, respectively. Repeat dose toxicity was studied in rats at daily doses up to 350 units per kg for a period of 14 days. No signs of toxicity were observed in the single dose and repeat dose studies.
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| *A local tolerance study in rabbits demonstrated no clinical or histopathological changes at the injection site after intravenous, intra-arterial or para-venous administration of factor xiii concentrate.
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| *A [[thrombogenicity test]] was performed in rabbits at doses up to 350 units per kg. Factor xiii concentrate showed no thrombogenic potential at the doses tested.
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| <!--Clinical Studies-->
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| |clinicalStudies=*The postmarketing efficacy and safety trial conducted in 41 subjects who received routine prophylactic treatment (40 U/kg every 28 days for 52 weeks) for congenital [[FXIII deficiency]], was to verify the clinical benefit of factor xiii concentrate by showing correlation between trough levels of FXIII activity and clinical efficacy. The clinical benefit of factor xiii concentrate was also demonstrated by comparing the incidence of bleeding in factor xiii concentrate-treated subjects to historical control with congenital FXIII deficiency.
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| *The incidence of spontaneous [[bleeding]] episodes requiring treatment was evaluated. Treatment was defined as an administration of a FXIII-containing product to treat the bleeding episode. None of the 5 subjects who experienced a spontaneous [[bleeding]] episode (2 nose bleeds, 2 rectal bleeds, and 1 episode of [[hematuria]] associated with a urinary tract infection, and an indwelling urinary catheter) required treatment with a FXIII-containing product.
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| *An annualized [[bleeding]] rate of 0 episodes per subject per year for spontaneous [[bleeding]] was established when compared to a historical annualized [[bleeding]] rate of 2.5 episodes per subject per year in patients receiving on-demand treatment of acute [[bleeding]] in patients with congenital FXIII deficiency.
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| *Eight [[bleeding]] episodes secondary to trauma, and one associated with surgery were also reported during the 52 weeks of the trial. In the eight [[bleeding]] episodes secondary to trauma, six did not require treatment with a FXIII-containing product, and two were successfully treated with a FXIII-containing product (one was treated with factor xiii concentrate and one with plasma).
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| *The prophylactic administration of Factor XIII Concentrate (Human) every 28 days in subjects with congenital FXIII deficiency achieved mean FXIII activity levels between 5% and 20%. FXIII activity was maintained at ≥5% in ≥97% of subjects and ≥10% in ≥85% of subjects. Of the 533 doses administered to 41 subjects, dose adjustment was required on only eight occasions, supporting that 40 U/kg every 28 days is the appropriate dose for the majority of patients.
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| *Five subjects underwent surgical procedures, four were elective and one was an emergency. Of the four elective surgeries, three subjects received factor xiii concentrate prior to surgery (0 to 7 days prior to surgery) with no post-operative bleeding. One subject who received factor xiii concentrate 7 days prior to surgery experienced [[bleeding]] post-extraction of all four wisdom teeth. The [[bleeding]] was stopped four hours after the oral surgery with an additional dose of factor xiii concentrate(50% of the subject's routine dose). One subject who required emergency surgery was pre-treated with plasma.
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| <!--How Supplied-->
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| |howSupplied=: [[File:{{PAGENAME}}07.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
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| *Refrigerate factor xiii concentrate at 2-8°C (36-46°F). Keep in original carton to protect from light. Do not freeze.
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| *Factor xiii concentrate is stable for 24 months, up to the expiration date on the carton and vial labels. Within the expiration date, factor xiii concentrate may be stored at room temperature not to exceed 25°C (77°F) for up to 6 months.
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| :*Do not return the product to the refrigerator after it is stored at room temperature. Clearly mark the beginning date of room temperature storage on the carton label.
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| :*Do not use beyond the expiration date on the carton and vial labels, or end of the period for room temperature storage, whichever comes first.
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| *This product does not contain a preservative and must be used within 4 hours after reconstitution. Do not refrigerate or freeze the reconstituted solution.
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| <!--Patient Counseling Information-->
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| |fdaPatientInfo=*Inform patients of the signs and symptoms of allergic [[hypersensitivity]] reactions, such as [[urticaria]], [[rash]], tightness of the chest, [[wheezing]], [[hypotension]] and/or [[anaphylaxis]] experienced during or after injection of factor xiii concentrate.
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| *Inform patients of the signs and symptoms of [[immunogenicity]] such as breakthrough [[bleeding]] .
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| *Inform patients of signs and symptoms of [[thrombosis]], such as limb or abdomen swelling and/or pain, [[chest pain]], [[shortness of breath]], loss of sensation or motor power, altered [[consciousness]], [[vision]], or speech.
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| *Inform patients that because factor xiii concentrate is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the [[Creutzfeldt-Jakob disease]] (CJD) agent<!--Precautions with Alcohol-->
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| |alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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| <!--Brand Names-->
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| |brandNames=*Corifact
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| <!--Look-Alike Drug Names-->
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| |lookAlike=<!--Drug Shortage Status-->
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| |drugShortage=
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| }}
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| <!--Pill Image-->
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| <!--Label Display Image-->
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| {{LabelImage
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| |fileName={{PAGENAME}}08.png|This image is provided by the National Library of Medicine.
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| {{LabelImage
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| |fileName={{PAGENAME}}09.png|This image is provided by the National Library of Medicine.
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| {{LabelImage
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| |fileName={{PAGENAME}}10.png|This image is provided by the National Library of Medicine.
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| <!--Category-->
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| [[Category:Drug]]
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