C1 Esterase Inhibitor (human)

C1 esterase inhibitor (human)For the prevention and treatment of acute attacks of Hereditary Angioedema

Reid NakagawaNovember 31, 2013OUtlineHereditary AngioedemaDefinitionEpidemiologyPathophysiologyC1 esterase inhibitor (human)Indications & UsageDosing & AdministrationMechanism of ActionPharmacokineticsDrug Interactions

Clinical ManifestationsTreatment

Adverse EffectsPrecautionsPregnancy & LactationReconstitutionPlace in Practice

angioedemaAngioedema is the result of localized blood vessel dilation and increased permeability that causes rapid swelling of the subcutaneous, mucosal, and submucosal tissues.

Hereditary Angioedema Triggers: Dental work, trauma, anxiety, stress, etc.Attacks can occur spontaneously in the absence of triggersEpidemiologyAffects approximately 1 in 50,000 individuals (1:10,000 1:150,000)Males and females are affected equallyThe prevalence of HAE is highest in Europe and North AmericaMean age of onset is 8 to 12 years75% experience first attack by the age of 15 yearsPathophysiologyHereditary Angioedema (HAE) is an autosomal dominant disorder where there is a deficiency or dysfunction in endogenous C1 esterase inhibitor (C1-INH)Type 1: deficiency in C1-INH (~85%)Type II HAE: dysfunctional CI-INH (~15%)HAE with normal C1-INH: mutations in Factor XII?Acquired C1-INH deficiency: associated with autoimmune disordersC1 esterase inhibitor (C1-INH) is a member of the serine protease inhibitors serpin superfamily. It is an inhibitor of the kinin-generating, coagulation, and fibrinolytic pathways.

6Clinical ManifestationsProdromal symptoms: fatigue, irritability, nausea, myalgias, flu-like symptoms, erythema marginatumAffected areas: Skin, GI tract, GU tract, and upper airwayEdema involves the subcutaneous, mucosal, and submucosal tissuesUrticaria and pruritis are absent,Severity: inconvenient cutaneous edema - life-threatening laryngeal edemaDuration of attacks: 48-96 hours

9TreatmentPatients with HAE tend not to respond to epinephrine, antihistamines, or glucocorticoidsPlasma kalikrein inhibitorEcallantide (Kalbitor)Bradykinin receptor antagonistIcatibant acetate (Firazyr)C1 esterase inhibitor C1 esterase inhibitor, human (Cinryze, Berinert)C1 Esterase inhibitor

C1 esterase inhibitorINDICATIONS & USAGE: For routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (Cinryze).For the treatment of acute abdominal, facial, or laryngeal attacks of Hereditary Angioedema in adult and adolescent patients (Berinert).

Mechanism of action

Pharmacokinetics / dynamicsSingle DoseDouble DoseCbaseline (units/mL)0.31 +/- 0.200.33 +/- 0.20Cmax(units/mL) 0.68 +/- 0.080.85 +/- 0.12Tmax (hours)3.9 +/- 7.32.7 +/- 1.9T1/2 (hours)56 +/- 3662 +/- 38Onset of action: 1 hour or lessVd: 0.43 dL/kgNo known drug-drug interactionsPrecautionsSevere hypersensitivity reactions may occur.CONTRAINDICATIONThrombotic Events Thrombotic events have been reported following the administration of high doses of CI-INHTransmissible Infectious AgentsC1-INH has the risk of transmitting infectious agents, e.g. HIV, HepC, CJD, etc.

Adverse effectsCommonHeadacheNauseaRashSinusitisURISeriousHypersensitivity DVTPE7.0% - 28%1.8% - 18%3.5% - 10%5% or greater1.8% or greater

MICVAPregnancy & breastfeedingPregnancy Category: C (All Trimesters)No animal data are availableNo adequate and well-controlled studies were conducted in pregnant womenC1-INH should be given to pregnant women only if clearly neededBreastfeeding:It is not known whether C1-INH is excreted in breast milkCaution should be exercised when C1-INH is administered to a nursing motherStorage and HandlingStorage: 2OC 22OC (36OF 77OF)Do not freezeStore the vial in the original container to protect it from light

Reconstitution

Dosing & AdministrationFor intravenous use only.Can be given as either an IV push over 10 minutes or as an IV drip over 10 minutesAdminister within 3 hours of reconstitution

HAE, Prophylaxis (Cinryze):1,000 Units IV push/infusion over 10 minutes Q3 - 4 daysHAE, abdominal, facial, or laryngeal attacks (Berinert): 20 International Units/kg IV infusion at a rate of approximately 4 mL/minTraditional Place in practiceProphylaxisThe use of C1-INH for prophylaxis against Hereditary Angioedema attacks has been establishedC1-INH can either be administered by a healthcare provider in clinic or self-administered by the patient at homeTreatmentFor acute attacks of HAE in patients presenting to the Emergency DepartmentCinryze is FDA approved for treatment of HAE, but has been studiedDosing: 1,000 units IV over 10 minutes; 2nd dose may be administered 60 minutes after first dose if no improvement in symptoms is seen- or -20 units/kg IV; rate not to exceend 4 mL/minEfficacyEfficacy

Treatment trial37 sites, N = 68 patientsStudy drug : 35 patients1,000 units (10 mL) IV over 10 minutes; repeat x 1 if no symptomatic relief after 60 minutesPlacebo: 33 patients10 mL NS over 10 minutesPrimary EndpointTime from administration of the study drug to unequivocal relief of symptoms at the defining siteSecondary EndpointsPercentage of subjects who had an onset of unequivocal relief of symptoms w/in 4 hours after receiving treatmentTime to complete resolution of the attackTreatment TrialMedian time to symptom relief2 hours VS 4 hours (CI: 1.17 4.95) P =0.02Percentage of subjects with onset of relief within 4 hours60% VS 42%; P =0.06Time to complete resolution of attack12.3 hours VS 25.0 hours; P =0.004

Prophylaxis TrialN = 22 patients24 week crossoverPrimary EndpointNumber of attacks of angioedema during each treatment periodAverage severity of attacks (on a scale of 1-3)1-mild 2-moderate3-severeAverage duration of attacksNumber of open label injections of C1-INHTotal number of days of swellingProphylaxis trialNumber of angioedema attacks6.26 VS 12.73 (CI: 4.21 8.73) P