C1 ESTERASE
INHIBITOR (HUMAN)
For the prevention and treatment of
acute attacks of Hereditary Angioedema
Reid Nakagawa
November 31, 2013
OUTLINE
 Hereditary Angioedema
 Definition
 Clinical Manifestations
 Epidemiology
 Treatment
 Pathophysiology
 C1 esterase inhibitor (human)
 Indications & Usage
 Dosing & Administration
 Mechanism of Action
 Pharmacokinetics
 Drug Interactions
 Adverse Effects
 Precautions
 Pregnancy & Lactation
 Reconstitution
 Place in Practice
ANGIOEDEMA
 Angioedema 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
EPIDEMIOLOGY
 Affects approximately 1 in 50,000 individuals (1:10,000 – 1:150,000)
 Males and females are affected equally
 The prevalence of HAE is highest in Europe and North America
 Mean age of onset is 8 to 12 years
 75% experience first attack by the age of 15 years
PATHOPHYSIOLOGY
 Hereditary 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 disorders
 C1 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.
CLINICAL MANIFESTATIONS
 Prodromal symptoms: fatigue, irritability, nausea, myalgias, flu-like
symptoms, erythema marginatum
 Affected areas: Skin, GI tract, GU tract, and upper airway
 Edema involves the subcutaneous, mucosal, and submucosal tissues
 Urticaria and pruritis are absent,
 Severity: inconvenient cutaneous edema - life-threatening laryngeal edema
 Duration of attacks: 48-96 hours
TREATMENT
 Patients with HAE tend not to respond to epinephrine, antihistamines,
or glucocorticoids
 Plasma kalikrein inhibitor
 Ecallantide (Kalbitor)
 Bradykinin receptor antagonist
 Icatibant acetate (Firazyr)
 C1 esterase inhibitor
 C1 esterase inhibitor, human (Cinryze, Berinert)
C1 ESTERASE INHIBITOR
C1 ESTERASE INHIBITOR
 INDICATIONS & 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 / DYNAMICS
Single Dose
Double Dose
Cbaseline (units/mL)
0.31 +/- 0.20
0.33 +/- 0.20
Cmax(units/mL)
0.68 +/- 0.08
0.85 +/- 0.12
Tmax (hours)
3.9 +/- 7.3
2.7 +/- 1.9
T1/2 (hours)
56 +/- 36
62 +/- 38
 Onset of action: 1 hour or less
 Vd: 0.43 dL/kg
 No known drug-drug interactions
PRECAUTIONS
 Severe hypersensitivity reactions may occur.
 CONTRAINDICATION
 Thrombotic Events
 Thrombotic events have been reported following the administration of high doses of
CI-INH
 Transmissible Infectious Agents
 C1-INH has the risk of transmitting infectious agents, e.g. HIV, HepC, CJD, etc.
ADVERSE EFFECTS
 Common
 Headache
7.0% - 28%
 Nausea
1.8% - 18%
 Rash
3.5% - 10%
 Sinusitis
5% or greater
 URI
1.8% or greater
 Serious
 Hypersensitivity
 MI
 DVT
 CVA
 PE
PREGNANCY & BREASTFEEDING
 Pregnancy Category: C (All Trimesters)
 No animal data are available
 No adequate and well-controlled studies were conducted in pregnant women
 C1-INH should be given to pregnant women only if clearly needed
 Breastfeeding:
 It is not known whether C1-INH is excreted in breast milk
 Caution should be exercised when C1-INH is administered to a nursing mother
STORAGE AND HANDLING
 Storage: 2 C – 22 C (36 F – 77 F)
O
O
O
O
 Do not freeze
 Store the vial in the original container to protect it from light
RECONSTITUTION
DOSING & ADMINISTRATION
 For intravenous use only.
 Can be given as either an IV push over 10 minutes or as an IV drip over
10 minutes
 Administer within 3 hours of reconstitution
 HAE, Prophylaxis (Cinryze):
 1,000 Units IV push/infusion over 10 minutes Q3 - 4 days
 HAE, abdominal, facial, or laryngeal attacks (Berinert):
 20 International Units/kg IV infusion at a rate of approximately 4 mL/min
TRADITIONAL PLACE IN PRACTICE
 Prophylaxis
 The use of C1-INH for prophylaxis against Hereditary Angioedema attacks has been
established
 C1-INH can either be administered by a healthcare provider in clinic or
self-administered by the patient at home
 Treatment
 For acute attacks of HAE in patients presenting to the Emergency Department
 Cinryze is FDA approved for treatment of HAE, but has been studied
 Dosing: 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
EFFICACY
EFFICACY
TREATMENT TRIAL
 37 sites, N = 68 patients
 Study drug : 35 patients
 1,000 units (10 mL) IV over 10 minutes; repeat x 1 if no symptomatic relief after 60 minutes
 Placebo: 33 patients
 10 mL NS over 10 minutes
 Primary Endpoint
 Time from administration of the study drug to unequivocal relief of symptoms at the
defining site
 Secondary Endpoints
 Percentage of subjects who had an onset of unequivocal relief of symptoms w/in 4
hours after receiving treatment
 Time to complete resolution of the attack
TREATMENT TRIAL
Median time to symptom relief
 2 hours VS 4 hours
(CI: 1.17 – 4.95) P =0.02
Percentage of subjects with onset of
relief within 4 hours
 60% VS 42%; P =0.06
Time to complete resolution of attack
 12.3 hours VS 25.0 hours; P =0.004
PROPHYLAXIS TRIAL
 N = 22 patients
 24 week crossover
 Primary Endpoint
 Number of attacks of angioedema during each treatment period
 Average severity of attacks (on a scale of 1-3)
 1-mild
2-moderate
3-severe
 Average duration of attacks
 Number of open label injections of C1-INH
 Total number of days of swelling
PROPHYLAXIS TRIAL
Number of angioedema attacks
 6.26 VS 12.73
(CI: 4.21 – 8.73) P<0.001
Average severity of attacks
 1.3 +/- 0.85 VS 1.9 +/- 0.36 P<0.001
Average duration of attacks
 2.1 +/- 1.13 d VS 3.4 +/- 1.39 d P=0.002
Number of open-label injections
 4.7 +/- 8.66 VS 15.4 +/- 8.41 P<0.001
Total number of days of swelling
 10.22 +/- 10.73 d VS 29.6 +/- 16.9 d
P<0.001
NEXT FRONTIER
 C1-INH in patients with HAE with normal C1-INH levels
 Patients are usually refractory to epinephrine, antihistamines, and glucocorticoids
 C1-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 population
 C1-INH in patients with Idiopathic Angioedema
 2 main types
 Histaminergic angioedema
 Bradykinergic angioedema
 Most patients do not respond to epinephrine, antihistamines, and glucocorticoids
 The use of C1-INH in this patient population is currently being discussed by experts
QUESTIONS
REFERENCES
 Berinert [package insert]. Kankakee, IL: CSL Behring LLC; 2012
 Cinryze [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.