Management of hereditary angioedema involves treating acute attacks, preventing attacks, and improving quality of life. Treatment strategies include treating acute attacks, preventing attacks short-term before procedures, and long-term prophylaxis. Therapies include C1 inhibitor replacement, bradykinin receptor antagonists, attenuated androgens, and antifibrinolytics. An individualized treatment plan is recommended based on a patient's attack frequency, severity and location, as well as their medication access and preferences.

1. Management of hereditary
angioedema (HAE)
Marwa Abo Elmaaty Besar
Lecturer Of Internal Medicine
(Rheumatology Immunology Unit)
(Pediatric Rheumatology)
Mansoura University

2. Treatment of hereditary angioedema:-
• Since HAE-C1-INH is a genetic disease, a causal treatment is not currently
viable.
• Therapeutic strategies:-
The reversal and/or prevention of attacks,
Reduction of morbidity and mortality,
Improvement in quality of life.
Long term
prophylaxis
(LTP)
Short-term
prophylaxis
(STP)
Acute
“on-
demand”

3. Consensus Guidelines for an Individualized Care Plan for Patients with HAE
HAE, hereditary angioedema; HAEA, Hereditary Angioedema Association; HAWK, Hereditary Angioedema International Working group; LTP, long-term prophylaxis; WAO, World Allergy Organization
1. Zuraw BL, et al. J Allergy Clin Immunol Pract. 2013;1:458–67; 2. Cicardi M, et al. Allergy 2012;67:147–57; 3. Maurer M, et al. Allergy 2018;73:1575–96
| VV-MEDCOM-1845 | Updated November 2019
Recommend an individualized care plan for patients with HAE1–3
US Hereditary Angioedema
Association (HAEA) Medical
Advisory Board1
Hereditary Angioedema
International Working Group
(HAWK)2
World Allergy Organization
(European Academy of Allergy
and Clinical Immunology
(WAO/EAACI)3
Acute
(On-Demand)
Treatment
Short-term/
pre-procedural
prophylaxis
Long-term
prophylaxis
(LTP)
• Patients should be evaluated for LTP at every visit, with disease burden and patient preference taken into
consideration, and regularly assessed for the efficacy and safety of their LTP regimen; on-demand therapy should
also be available to treat breakthrough attacks3

4. The international WAO/EAACI guideline for the management of hereditary
angioedema—The 2021 revision and update
The international WAO/EAACI guideline for the management of hereditary angioedema 2021
RECOMMENDATION 4
We recommend that all attacks are considered for on-
demand treatment.
98% agreement, evidence level D
RECOMMENDATION 5
We recommend that any attack affecting or potentially
affecting the upper airway is treated.
100% agreement, evidence level C
RECOMMENDATION 6
We recommend that attacks are treated as early as
possible.
100% agreement, evidence level B
RECOMMENDATION 9
We recommend that all patients have sufficient
medication for on-demand treatment of at least two
attacks and carry on-demand medication at all times
100% agreement, evidence level D
RECOMMENDATION 10
We recommend considering short-term prophylaxis
before medical, surgical or dental procedures as well as
exposure to other angioedema attack-inducing events
94% agreement, evidence level C
RECOMMENDATION 12
We suggest considering prophylaxis prior to exposure to
patient-specific angioedema-inducing situations
90% agreement, evidence level D
RECOMMENDATION 14
We recommend that patients are evaluated for long-term
prophylaxis at every visit, taking disease activity, burden,
and control as well as patient preference into
consideration
96% agreement, evidence level D

5. For all types of C1-INH deficiency exacerbation of
angioedema
Supportive methods:
• The maintenance of a free airway.
• Early and accurate treatment,
• Severe oropharyngeal angioedema;
• Emergency intubation and/or tracheostomy.
• Monitored closely in a hospital setting until the attack
resolves.
British Journal of Hospital Medicine, July 2019, Vol 80, No 7

6. Acute attack “on demand”
• Usually works within 1 hour.
• Is used to ameliorate symptoms of attack.
• If requiring a repeat dose within 24 hours indicates worsening of an
attack.
• For abdominal attacks that require a second dose.
• Consideration should be given for other causes of an acute
abdomen.
• Decisions on which “on-demand” therapy to use should implement
shared decision strategies so patients can determine which treatment is
most suitable to their lifestyle and needs.

7. Acute attack “on demand”
4 S. Kesh and J.A. Bernstein / Ann Allergy Asthma Immunol 00
(2022) 1−10

8. Acute attack “on demand”
I-No evidence exists for efficacy of epinephrine, H1 and H2 antihistamines, or
corticosteroids????
These drugs for patients presenting with life threatening attacks.
II-Infusions of fresh frozen plasma; before 2009;
Administrated successfully as treatment of severe attacks
“double-edged sword”
it is a valuable alternative for C1-INH concentrate.
III-The attenuated synthetic androgen (danazol and, more recently,
stanazolol).
Danazol; 50 mg to 600 mg daily, (Occasionally alternate-day therapy)
Stanozolol; less masculinising potential.
During administration; C4 and C2 levels rise along with C1-INH levels with a stable C1-
INH activity.
Generally clinical remission is obtained within 1 to 2 weeks after start of therapy.
Not recommended in children, during pregnancy.
Gelfand et al, 1976

9. Acute attack “on demand”
IV-Antifibrinolytic agents, e-aminocaproic acid, analogue (tranexamic acid)
In dosages up to 8 g intravenously or orally
Shown to be beneficial, only when is started early.
No consequent increase in C4 and/or C1-INH, and probably act through inhibition
of plasmin.
Side effects e.g Muscle necrosis and a potential thrombotic effect.
Prescription of these agents has diminished in favour of the attenuated
androgens.
Constitutes:-
A valuable alternative in patients in which attenuated androgens are contra-
indicated.
That are suffering from severe or frequent attacks. Acta Clinica Belgica, 2000; 55-1

10. The treatment for acute attacks:-
• The treatment of choice is replacement therapy with purified
vapour-heated C1-INH.
Plasma-derived nanofiltered C1-INH (Berinert), IV
Recombinant human C1-INH (Ruconest), IV
• The use of the kallikrein inhibitor aprotinin (Trasylol®), SC
Is questionable, due to allergic reactions.
• Effective bradykinin receptor antagonists (Icatibant), SC
appear to be a promising approach to treatment of HAE
attacks.
Bork et al, 2008a; Zanichelli et al, 2015

11. Replacement therapy:
Purified vapour-heated C1-INH
• Safe, effective and well-tolerated.
• Indicated in patients in which the other available drugs are contra-
indicated or not tolerated.
• Plasma-derived C1-INH (pdC1-INH, Cinryze) is approved by (FDA) for
LTP, but it can be used clinically, if necessary, as on-demand therapy
• Value: are sufficient to stop severe attacks within 30-60 minutes.
• Dose; 1,000 to 2,000 u of C1-INH concentrate.
• Mech; recombinant cytokine activation of C1-INH genes, recombinant product
of a serpine gene mutated for increased C1-INH activity,
• Unfortunately, the presence of C1-INH antibodies; may need up to 10,000 U in
order to revert a severe attack.
Bork K., etal 1989
Visentin DE, etal 1988

12. Special situation:
I- Elective surgery, especially in the oropharyngeal region;
Prophylaxis against possible exacerbation.
Short-term prophylactic treatment with
• Attenuated androgens, increase dose for 5-10 days pre-operatively and 3 days
postoperatively (danazol 200 mg t.I.D., Stanozolol 1 mg q.I.D.).
+
• With fresh frozen plasma shortly prior to intervention
or
• An increment of the maintenance dosage (purified C1-INH concentrates).
• Preoperative administration, especially when time is pressing.

13. II-During labour:
• Pre-delivery administration of purified C1-INH concentrates;
Performed successfully
C1-INH does not cross the placental barrier,
Substitution of the mothers will not interfere with the
measurement of C1-INH in the new born.

14. Short-term Prophylaxis (STP)
• STP should be a shared decision process based on
Risk of the procedure,
Cost,
Patient preference.
Magerl
M,etal2017
Low risk
procedure
• Not to proceed with STP
• On-demand therapy be available for
the patient.
High risk
procedure
• Major dental surgery,
intubation,
• Oral surgery,
• Stressful events
Bork et al, 2011

15. Short-term Prophylaxis (STP)
• The two plasma-derived C1-INH concentrates (PdC1-INH) or
Recombinant C1-INH treatments as first-line treatments.
• If neither of the former are available,
1. Anabolic androgens
2. Subcutaneous plasma kallikrein inhibitor and bradykinin 2
receptor antagonist
Should not be used, their short half-life.
Effective only if IV C1-INH therapies are not available
British Journal of Hospital Medicine, July 2019, Vol 80, No

16. Long-term Prophylaxis (LTP).
• LTP is used to
Minimize the frequency and severity of attacks.
Optimize the patient’s quality of life.
• The need for LTP should be shared decision making with the patient.
• Initiation of LTP depends on
Frequency, severity, and location of attacks,
Availability of on-demand medications, as some insurance carriers limit 3
doses a month.
• Choice of therapy should be dependent on the patient’s age, route of
administration, and cost considerations.
• Patients should be monitored regularly for efficacy and tolerability of treatment
and on-demand therapy should be available to treat breakthrough attacks
Busse Pj,etal 2021
Longhurst and Zinser, 2017

17. Long-term Prophylaxis (LTP).
I- Plasma-derived C1-INH concentrates are commonly used as
prophylaxis.
• (Cinryze) was the only plasma-derived formulation licensed for long-term
prophylaxis.
Well tolerated and effective.
Requires intravenous administration, which may be a limiting factor.
• Subcutaneous C1-INH, haegarda (CSL behring),
Licensed in the USA for long-term prophylaxis.
More convenient
Easier for patients requiring long-term prophylaxis.
Maurer et al, 2018
Longhurst et al, 2017

18. Long-term Prophylaxis (LTP).
II-Attenuated androgens :
long-term prophylaxis for a long time.
Oral administration,
their effectiveness is high (83% average attack reduction)
often dose-dependent, side effects
the minimal effective dose, (maximum 100–200 mg/day danazol)
III-Tranexamic acid:
Not as effective as attenuated androgens,
Commonly used in children.
Is not generally recommended for long-term prophylaxis
Bork et al, 2008
Maurer et al, 2018

19. Home therapy and self-administration
• The World Allergy Organization recommends that patients have access to on-
demand therapy and are taught to self-administer.
Safely administered by the patient at home,
Reduces the duration and frequency of HAE attacks
Self-administration is also more convenient,
Improves patients’ quality of life and independence.
• Self-administration training includes a home therapy partner, who usually
provides support and may also be trained to administer the therapy.
• The intravenous C1-INH concentrates (Berinert, Cinryze and Ruconest) are
licensed for self-administration in children, adolescents and adults,
• The Subcutaneous C1-INH Haegarda is approved for self-administration in
adolescents and adults.
• Icatibant (Firazyr) is licensed for self-administration in adults and by a caregiver
for children.
Longhurst et al, 2010
Bygum et al, 2009

20. Treatment of HAE pipeline:
• A monoclonal antibody against plasma kallikrein, subcutaneous
lanadelumab,
For prophylactic treatment of hereditary angioedema attacks,
significantly reduced the mean attack rate.
• An oral plasma kallikrein inhibitor, BCX7353,
Is currently in development, Phase 1,2.
For the prevention of hereditary angioedema attacks
Significantly reduced the rate of hereditary angioedema attacks
Gastrointestinal adverse events
Riedl et al, 2017
Banerji et al, 2018

21. 4 S. Kesh and J.A. Bernstein / Ann Allergy Asthma Immunol 00

22. C1 Inhibitor (Cinryze):
 Indications
 Mechanism of Action
 Dosing

23. 1. All medical,
2. Dental procedures
Associated with any
mechanical impact to the
upper aerodigestive tract,
3. Surgical procedures
The international WAO/EAACI guideline for the management of hereditary
angioedema— C1 Inhibtor (Cinryze)
RECOMMENDATION 7
We recommend that attacks are treated with either intravenous C1
inhibitor, ecallantide or icatibant
96% agreement, evidence level A
RECOMMENDATION 11
We recommend the use of intravenous plasma-derived C1
inhibitor as first-line short-term prophylaxis
91% agreement, evidence level C RECOMMENDATION 15
We recommend the use of plasma-derived C1 inhibitor as
first-line long-term prophylaxis
87% agreement, evidence level A
On Demand
Long-term Prophylaxis
Short-Term Prophylaxis
RECOMMENDATION 22
We recommend plasma-derived C1 inhibitor as the
preferred therapy during pregnancy and lactation
100% agreement, evidence level D
Pregnancy & Lactation
The international WAO/EAACI guideline for the management of hereditary angioedema 2021

24. • Cinryze is made from purified human blood that is collected from selected
plasma donors.
• Samples go through a complex purification process (involving
pasteurisation and nanofiltration) to inactivate or remove viruses.
• However, the possibility of human blood or plasma passing on infection
cannot be totally excluded.
How is Cinryze made?

25. British Journal of Hospital Medicine, July 2019, Vol 80, N
Pathway of contact system activation and interaction with fibrinolytic system.

26. 3.1
KEY POINT
Indication:2
• Treatment and pre-procedural prevention of angioedema attacks in
adults, adolescents and children (>2 years of age) with hereditary angioedema (HAE)
• Routine prevention of angioedema attacks in
adults, adolescents and children (>6 years of age) with severe and recurrent attacks of HAE
who are
• intolerant of, or insufficiently protected by, oral prevention treatments,
• or patients who are inadequately managed with repeated acute treatment
*Cinryze is indicated for the second-line treatment of HAE
C1 Inhibitor
(Cinryze):-
KEY POINT
No drug-related AEs were associated with pre-
procedural Cinryze.
KEY POINT
Demonstrated efficacy with studies showing that, compared to placebo:
•Prophylaxis with Cinryze resulted in >2-fold reduction in the number
of HAE attacks, and attacks were also less severe.
•Acute treatment with Cinryze (within 4 hours of onset) resulted in >2-
fold decrease in the time to beginning of relief of the defining symptom.
KEY POINT
Repeated administration of Cinryze was well tolerated and
did not give rise to any safety concerns.

27. https://www.cinryze
.com/hereditary-
angioedema-
patient-videos*

28. Cinryze – product overview:
Dosing details for adults and adolescents

29. HAE
Learning
Module
3
3.3
Cinryze – product overview:
Dosing details for Pediatrics
For paediatric patients aged 2–11
years who are >25kg, 1000 Units of
Cinryze is recommended at the first
sign of the onset of an acute attack
A second dose of 1000 Units may
be administered if the patient has
not responded adequately after 60
minutes
For paediatric patients aged 2–11
years <25kg, 500 Units of Cinryze
is recommended at the first sign
of the onset of an acute attack
A second dose of 500 Units may
be administered if the patient has
not responded adequately after
60 minutes
Recommended for pediatrics
patients aged 6–11 years for
routine prevention against
angioedema attacks
500 Units of Cinryze every 3
or 4 days is recommended as
the starting dose. This may
need to be adjusted according
to individual response
The continued need for
regular prophylaxis with
Cinryze should be
reviewed on a regular
basis
500 Units of Cinryze within 24
hours before a medical,
dental, or surgical procedure
11 years, >25kg:
1000 Units of Cinryze within
24 hours before a medical,
dental, or surgical procedure
2–11 years, 10–25kg:

30. Clinical studies have shown that:
•Within 1 hour after intravenous administration of Cinryze, there was a
significant increase in systemic levels of antigenic and functional C1-INH
•Administration of C1-INH increases serum levels of C1-INH activity and
temporarily restores the natural regulation of the contact, complement, and
fibrinolytic systems, thereby controlling the swelling or the propensity to
swell.
•Treatment with Cinryze resulted in elevation of C4 levels at 12 hours.
•The pharmacokinetics and excretion of Cinryze are not expected to be altered
by renal or hepatic impairment.
•The mean elimination half-life of functional C1 inhibitor after administration
of Cinryze was
• 56 hours for a single dose.
• 62 hours for the double dose.
Davis AE, III. Clin Immunol 2005; 114(1): 3–9

32. Cinryze,
C1-INH
Safe
Effective
Available
Cost

33. Reference:
• Maurer M et al. Allergy 2018; 73(8): 1575–1596.
• Shire. Cinryze (C1 inhibitor [human]) Summary of Product Characteristics (date of revision: April 2018) European Medicines Agency. Available at:
https://www.medicines.org.uk/emc/product/2808/s mpc [accessed September 2018].
• Zuraw BL and Kalfus I. Am J Med 2012; 125(9): 938.e1–7.
• Terpstra FG, Kleijn M, Koenderman AH, et al. Biologicals 2007; 35(3): 173–181.
• Kramer C, van Beem R, Koenderman A et al. Poster presented at the 6th International HAE Conference, Budapest, Hungary, 2009.
• Tse K and Zuraw BL. Cleve Clin J Med 2013; 80(5): 297–308.
• Cicardi M, Aberer W, Banerji A et al. Allergy 2014; 69: 602–616.
• Davis AE, III. Clin Immunol 2005; 114(1): 3–9.
• Zhang G et al. Bioanalysis 2017; 9(19): 1477–1491
• Busse PJ, Christiansen SC, Riedl MA, Banerji A, Bernstein JA, Castaldo AJ, et al. US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin
Immunol Pract. 2021;9(1):132–150. e3.
• Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Eng J Med 1976; 295: 1444-8.
• Magerl M, Frank M, Lumry W, Bernstein J, Busse P, Craig T, et al. Short-term prophylactic use of C1-inhibitor concentrate in hereditary angioedema: findings from an international patient
registry. Ann Allergy Asthma Immunol. 2017;118(1):110– 112.
• Chappatte O, De Swiet M. Hereditary angioneurotic edema and pregnancy: case reports and review of the literature. Br J Obstet Gynaecol 1988; 95: 938-42.
• Visentin DE, Yang WH, Karsh J. C1-esterase inhibitor transfusions in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80: 457-61.
• Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996; 334: 1630-4.
• Bork K, Witzke G. Long-term prophylaxis with C1-inhibitor concentrate in patients with recurrent angioedema caused by hereditary or acquired C1-inhibitor deficiency. J Allergy Clin
Immunol 1989; 83: 677-82.
• Cicardi M, Castelli R, Zingale LC. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin
Immunol 1997; 99: 194-6.