For the prevention and treatment of acute attacks of Hereditary Angioedema Reid Nakagawa November 31 2013 OUtline Hereditary Angioedema Definition Epidemiology Pathophysiology C1 esterase inhibitor human ID: 998923
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1. C1 esterase inhibitor (human)For the prevention and treatment of acute attacks of Hereditary AngioedemaReid NakagawaNovember 31, 2013
2. OUtlineHereditary AngioedemaDefinitionEpidemiologyPathophysiologyC1 esterase inhibitor (human)Indications & UsageDosing & AdministrationMechanism of ActionPharmacokineticsDrug InteractionsClinical ManifestationsTreatmentAdverse EffectsPrecautionsPregnancy & LactationReconstitutionPlace in Practice
3. 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 triggers
4. EpidemiologyAffects 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 years
5. PathophysiologyHereditary 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.
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7. Clinical 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
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10. TreatmentPatients 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)
11. C1 Esterase inhibitor
12. 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).
13. Mechanism of action
14. 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 interactions
15. PrecautionsSevere 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.
16. Adverse effectsCommonHeadache Nausea Rash Sinusitis URI SeriousHypersensitivity DVTPE 7.0% - 28% 1.8% - 18% 3.5% - 10% 5% or greater 1.8% or greaterMICVA
17. Pregnancy & 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 mother
18. Storage and HandlingStorage: 2OC – 22OC (36OF – 77OF)Do not freezeStore the vial in the original container to protect it from light
19. Reconstitution
20. 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 reconstitutionHAE, 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/min
21. Traditional 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/min
22. Efficacy
23. Efficacy
24. 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 attack
25. Treatment 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
26. 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-moderate 3-severeAverage duration of attacksNumber of open label injections of C1-INHTotal number of days of swelling
27. Prophylaxis trialNumber of angioedema attacks6.26 VS 12.73 (CI: 4.21 – 8.73) P<0.001Average severity of attacks1.3 +/- 0.85 VS 1.9 +/- 0.36 P<0.001Average duration of attacks2.1 +/- 1.13 d VS 3.4 +/- 1.39 d P=0.002Number of open-label injections4.7 +/- 8.66 VS 15.4 +/- 8.41 P<0.001Total number of days of swelling10.22 +/- 10.73 d VS 29.6 +/- 16.9 d P<0.001
28. Next FrontierC1-INH in patients with HAE with normal C1-INH levelsPatients are usually refractory to epinephrine, antihistamines, and glucocorticoidsC1-INH has been used in these patients to presumably raise the set point for activation of kallikrein and generation of bradykinin.Further research is needed to validate its use in this patient populationC1-INH in patients with Idiopathic Angioedema2 main typesHistaminergic angioedemaBradykinergic angioedemaMost patients do not respond to epinephrine, antihistamines, and glucocorticoidsThe use of C1-INH in this patient population is currently being discussed by experts
29. Questions
30. ReferencesBerinert [package insert]. Kankakee, IL: CSL Behring LLC; 2012Cinryze [package insert]. Exton, PA: ViroPharm Biologics, Inc.; 2010-2013.Lang DM, Aberer W, Bernstein JA, et al. International Consensus on Hereditary and Acuired Angioedema. Ann Allergy Asthma Immunol 2012;109:395-402.Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema. N Engl J Med 2010;363: 513-22.