1. Global Guidelines for the Care of Patients with Hereditary Angioedema
World Allergy Organization

2. General Advisors
WAO President Ruby Pawankar, Professor, Nippon Medical School, Tokyo
WAO Past President (Initiator of the guideline development)
Richard Lockey, Professor of Medicine, University of South Florida
Steering Committee Chair:
Timothy Craig, Professor of Medicine and Pediatrics, Penn State University
Members of the Steering committee:
Emel Aygoren-Pursun, Professor of Medicine, University of Frankfurt
Konrad Bork, Professor of Medicine, Johannes Gutenberg University Mainz
Tom Bowen, Professor of Medicine, Universiy of Calgary
Henrik Boysen, Executive Director, HAEi-International Patient Organization
Marco Cicardi, Professor of Medicine, University of Milan
Henriette Farkas, Professor of Medicine, Semmelweis University
Anete Grumach, Faculty of Medicine, University of Sao Paulo
Connie Katelaris, Professor of Medicine, Allergy University of Western Syndney
Hilary Longhurst, Consultant Immunologist, Barts and the London NHS Trust
William R. Lumry, Professor of Medicine, University of Texas Southwestern
Inmaculada Martinez-Saguer, Professor of Medicine, University of Frankfurt
Marcus Maurer, Professor of Dermatology and Allergy, Charité - Universitätsmedizin Berlin
Bruce Ritchie, Professor of Medicine, University of Alberta
Bruce Zuraw, Professor of Medicine, University of California San Diego

3. Pharmaceutical Supporters of the Guidelines in Alphabetical Order
CSL Behring
Dyax
Shire
Viropharma

4. World Allergy Organization’s HAE Global Guidelines
Objective: To develop a global approach for the management of patients with Hereditary Angioedema (HAE) so as to improve the quality of care delivered to patients with HAE globally, to increase the availability of HAE medications globally, and to encourage all physicians, patients, pharmaceutical companies and governments to ensure that patients with HAE are given similar access to therapies and care in an appropriate manner worldwide.

5. C1-esterase Inhibitor Protein (C1INH)
Major inhibitor of several complement proteases (C1r, C1s, and mannose-binding lectin–associated serine protease [MASP] 1 and 2) and contact-system proteases (plasma kallikrein and coagulation factor XIIa) and a relatively minor inhibitor of the fibrinolytic protease plasmin and the coagulation protease factor XIa.
C1-INH is deficient (type 1) or abnormal in function (type 2), but normal in type III HAE

6. C1-INH involved in 3 systems → C1-INH depletion
Factor XII
Factor XIIa
C1-INH C1
Contact System
C1-INH
Prekallikrein
Complement System
HMW-K C4 C2
Kallikrein
C1rs
C1-INH
C1-INH
C1-INH
Plasminogen
Animation script
Opening: Triggers, such as trauma and infection, activate the complement system.
Click 1: Triggers also activate the contact system and the fibrinolytic system. In a normal person, C1-INH regulates these systems by blocking pathways. This prevents the systems from becoming over-active.
Click 2: Patients with HAE have low reserves of C1-INH. Once depleted, the systems will be unopposed, resulting in an over-production of bradykinin. Bradykinin is believed to be responsible for the swelling symptoms.
Click 3: If C1-INH is replenished, bradykinin production will be controlled and balance can be restored (optional).
This slide illustrates some of the processes involved in activation of the complement, contact, and fibrinolytic system
Clinically, attacks of HAE appear to have a number of environmental and pathophysiological triggers: prolonged mechanical pressure, trauma, emotional stress, drug therapy
Chronically low levels of C1-INH—approximately 30% of normal—suggest the possibility of complement and contact systems activation even during apparently symptom-free periods, so-called autoactivation of the plasma cascade systems. Any further reductions in available C1-INH would be associated with development of angioedema symptoms during an HAE attack
Chronic, low-level activation of the complement pathway could lead to the inappropriate activation of the contact pathway via activation of factor XI and kallikrein. Vascular permeability and edema would result from the rapid and excessive synthesis of bradykinin
Activation of factors and proteases may modulate between and among systems
Plasmin and plasminogen in the fibrinolytic pathway may serve to activate C1 in the complement pathway, while factor XIIa or kallikrein in the contact pathway may generate plasmin from plasminogen in the fibrinolytic pathway
Bradykinin
Plasmin
Fibrinolytic System
Increased vascular permeability  ANGIOEDEMA

7. Bradykinin is Responsible for the Angioedema associated with HAE
Complement and contact plasma proteolytic cascades are activated with the potential to generate several vasoactive compounds.
Bradykinin is generated through activation of the contact system
Bradykinin is the primary mediator of swelling
Plasma kallikrein and factor XII are normally inhibited by C1INH
Plasma kallikrein cleaves high molecular weight kininogen

8. How Does BK Cause Angioedema?
Increased vascular permeability
VE-cadherin
Actin stress fibers
Non stimulated
Stimulated
from Tiruppathi C, et al. Vascul Pharmacol. 2003;39: 8

9. Suspect HAE when a patient presents with angioedema, especially if free of urticaria, that is unpredictable in onset, but frequently follows a trigger such as trauma, and is associated with recurrent abdominal pain and upper airway swelling. (100% consensus)
Triggers for HAE
Estrogen
ACE-inhibitors
Trauma
Dental and surgical procedures
Stress
Infections
Menstruation
Pregnancy

10. HAE Attacks can Involve
Face
Extremities
Upper airways
Gastrointestinal system
Genital-urinary system

11. Intestinal swelling during an Abdominal attach

12. Patients with suspicion of HAE and family members of patients with HAE should be screened so that appropriate therapy can be available for treatment, especially since the first event may manifest in the upper airway and potentially may be fatal without appropriate therapy. (100% consensus)
All patients with HAE should have an action plan.
Patients may be asymptomatic even later in life; however, preparation is needed to have therapy available for procedures that can trigger HAE
In order to be prepared, all patients with suspected HAE and all family members of patients diagnosed with HAE should be screened for at least C4 and if positive, they should have an action plan and 2 doses of on demand therapy.

13. DIAGNOSING HAE Clinical symptoms + Familial history C4 Normal Low
Confirm C4 during attack
Consider HAE type III or AE due to medications
C1INH level
HAE type I
C1q
Functional C1INH
HAE type II
Consider other causes of C4 consumption
AAE

14. Treatment of HAE Acute treatment of attacks (On Demand)
Short Term Prophylaxis (pre-procedural)
Long Term Prophylaxis (Suppression of attacks)

15. On Demand Therapies C1-esterase inhibitor (C1=INH)
Recombinant C1-INH (rcC1-INH)
Ecallantide
Icatibant
Fresh Frozen Plasma

16. Indications of C1-INH are partially off label and all plasma derived products can be used in place of each other (100%)
Berinert® all types of attacks in adults, children, pregnant women also during breastfeeding. Dose is 20units/kg Cinryze ® all types of attacks in adults, children, pregnant women also during breastfeeding. Dose is 1000 units Cetor ® all types of attacks in adults, children, pregnant women also during breastfeeding. Dose is 1000 units

17. Use of C1-INH in HAE Recommendation:
The risk versus benefits of C1INH favors benefits. Few adverse events have been reported. All 3 products are equal in efficacy and adverse effect profile; however, the need for repeat dosing is less with the initial use of 20 units/kg. The risk is minimal, but absolute safety cannot be assumed since it is a human blood product. (100%)
Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol Mar;101(3):
Bork K, Meng G, Staubach P, Hardt J. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion Nov;45(11):
Farkas H, Jakab L, Temesszentandrási G, Visy B, Harmat G, Füst G, Széplaki G, Fekete B, Karádi I, Varga L. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin

18. ADVANTAGES of C1-INH DRAWBACKS A natural product
Inhibits all cascade systems involved in the generation of bradykinin
Its half-life is longer than those of other drugs for AT; it rapidly reaches peak plasma concentration
Rapid onset of action
Lack of rebound angioedema
Effective in all types of attacks
Appears to be safe for children
Appears to be safe for pregnant women
Safe for home use
Minimal allergic reaction
No tachyphylaxis
Long (30 years of) clinical experience
Expensive (but its price is not higher than those of other drugs except FFP)
Potential risk for the transmission of other diseases and infective agents
Intravenous administration
Frequent and repetitive use may influence attack frequency and severity
Off label administration of high doses is associated with thrombotic events
Martinez-Saguer I, Rusicke E, Aygören-Pürsün E, von Hentig N, Klingebiel T, Kreuz W. Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study. Transfusion Feb;50(2): Epub 2009 Sep 24. PubMed PMID:
Wilson DA, Bork K, Shea EP, Rentz AM, Blaustein MB, Pullman WE. Economic costs associated with acute attacks and long-term management of hereditary angioedema. Ann Allergy Asthma Immunol Apr;104(4):
Longhurst HJ, Carr S, Khair K. C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol Jan;147(1):11-7.
Varga L, Széplaki G, Visy B, Füst G, Harmat G, Miklós K, Németh J, Cervenak L, Karádi I, Farkas H. C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema. Strong correlation with the severity of disease in C1-INH concentrate naïve patients. Mol Immunol Feb;44(6):
Bork K, Hardt J. Hereditary Angioedema: Long-Term Treatment with One or More Injections of C1 Inhibitor Concentrate per Week. Int Arch Allergy Immunol Jul 27;154(1):81-88.
Bork K, Hardt J. Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate. Am J Med Aug;122(8):780-3. 18

19. Recommendation: For on demand therapy recombinant C1-INH appears to be equally effective to plasma derived C1-INH
Differences between rcC1-INH and C1-INH
rcC1-INH half-life is 3 hours
Contains traces of rabbit antigen
Contraindicated in rabbit allergy
Unique polysaccharides are added to the protein during production. Which shorten half life and may be allergenic
No human blood-borne disease associated with it

20. Recommendation: The recommended rcC1-INH dose for the routine treatment of acute attacks is 50 U/kg body weight (100%)
Test for rabbit antibodies before using the rcC1-INH
Contains 2100 units per vial
concentration of 150 units/ml
treatment of acute attacks is 50 U/kg body weight
maximum of 4200 U (2 vials) for patients of or over 84kg body weight
second injection may be given if the patient does not improve satisfactorily after the first dose

21. ADVANTAGES of rcC1-INH DRAWBACKS
Inhibits all cascade systems involved in the generation of bradykinin
Rapid onset of action
Lack of rebound angioedema
Effective in all types of attacks
Safe for children
Safe for pregnant women
Minimal allergic reaction
No tachyphylaxis
No viral transmission
Unlimited supply
Expensive (but its price is not higher than those of other drugs except FFP)
Potential risk for anaphylaxis
Intravenous administration
Potential, but not described, for neutralizing antibodies and IgE to polysaccharide added to the protein
Martinez-Saguer I, Rusicke E, Aygören-Pürsün E, von Hentig N, Klingebiel T, Kreuz W. Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study. Transfusion Feb;50(2): Epub 2009 Sep 24. PubMed PMID:
Wilson DA, Bork K, Shea EP, Rentz AM, Blaustein MB, Pullman WE. Economic costs associated with acute attacks and long-term management of hereditary angioedema. Ann Allergy Asthma Immunol Apr;104(4):
Longhurst HJ, Carr S, Khair K. C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol Jan;147(1):11-7.
Varga L, Széplaki G, Visy B, Füst G, Harmat G, Miklós K, Németh J, Cervenak L, Karádi I, Farkas H. C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema. Strong correlation with the severity of disease in C1-INH concentrate naïve patients. Mol Immunol Feb;44(6):
Bork K, Hardt J. Hereditary Angioedema: Long-Term Treatment with One or More Injections of C1 Inhibitor Concentrate per Week. Int Arch Allergy Immunol Jul 27;154(1):81-88.
Bork K, Hardt J. Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate. Am J Med Aug;122(8):780-3. 21

22. Treatment of HAE: Icatibant
Recommendation: Icatibant is effective for the treatment of HAE attacks at all locations with a dose of 30 mg SQ (100%)
Recommendation: Repeat dosing of icatibant is necessary in up to 10% of attacks and 1% require a third dose to treat an HAE attack. (not voted)

23. Positives Negatives Ease of Use Rapid to Administer
Appear to have good safety profile
Not blood product
Not immunogenic
Alternative to C1 inhibitor
Ideal for self administration
May address problem of delays in accessing treatment
Not Intravenous
Short half life-probably not suitable for prophylaxis
Need for repeat dosing
Not currently recommended for pregnant women or children
No action on other systems regulated by C1 inhibitor
Pain and burning at injection site
Cicardi et al NEJM 2010 23 23

24. Treatment of HAE: Ecallantide
Recommendation: Ecallantide at 30 mg SQ can be used to treat HAE attacks at all locations (100%)
Recommendation: Self injection of ecallantide should be avoided secondary to a small, but real risk of anaphylaxis (100%)

25. Treatment of HAE: Ecallantide
Allergic reactions occur in approximately 3% of patients that receive ecallantide.
IgG and IgE antibodies are produced against ecallantide, but the IgG does not appear to be neutralizing.
Approved in the USA to be giving at home by a health care provider equipped and trained to treat anaphylaxis

26. action- replaces C1-INH
Recommendation: Fresh Frozen Plasma should only be used for on-demand therapy when other medications are not available (100%)
action- replaces C1-INH
indication- not indicated unless no other treatments are available
method- 2 units for adults, weight based for children
adverse events – anaphylaxis, worsening of HAE, viral transmission
positives and negatives- negatives out-weigh positives and FFP should be avoided if other therapies are available

27. How Do the Newer Drugs Compare?
Advantages
Disadvantages
Best use
Status
Plasma-derived
C1-INH
Extensive clinical experience
Corrects the fundamental defect
long half-life
Infectious risk
Needs IV access
Limited supply
Acute attacks
Short-term
Long-term prophylaxis
Prodromes
Berinert P: approved for attacks
Cinryze: approved for prophylaxis and attacks
Cetor approved for attacks
Recombinant
No human virus risk
Scalable supply
Short half-life
Potential for allergic reactions
Short prophylaxis
Prodrome?
Rhucin: used for attacks
Ecallantide
More potent than C1-INH
No infectious risk
Subcutaneous administration
Antibodies may cause allergic reaction or neutralization
Acute attacks in office or by HCP in home
Kalbitor approved for administration by HCP for attacks
Icatibant
Stable at room temperature
Subcutaneous
Local pain or irritation
Home treatment of acute attacks
Firazyr: used for attacks
Slide 27
How do the newer drugs compare with each other?
Plasma-derived C1-INH is clearly very effective and has an excellent safety record; however, it is not convenient for home use and carries the theoretical risk of infection. The lack of convenient home use is less of an issue for prophylaxis and, as mentioned, Cinryze is already approved for prophylactic use.
Recombinant C1-INH has a profile similar to plasma-derived C1-INH except that it does not have the same concern about viral safety; however, the shorter half-life makes prophylaxis more problematic, and the risk of allergic reactions is unknown but likely small.
Ecallantide does not have any infectious risk and can be conveniently administered by subcutaneous injection. The risk of allergic reactions, however, precludes its home use at the present time.
Icatibant also doesn’t have an infectious risk and can be conveniently administered by subcutaneous injection. It could conceivably be self-administered at home; however, the failure of the US phase III study means that it is unlikely to be approved in the short-term. 27

28. Short-term or pre-procedural therapy: Indication
Prior to some surgeries; especially
dental/ intraoral surgery
where intubation is required
major surgery
To cover periods of high risk for attacks
increased likelihood of attack
increased consequence of attack
Evidence limited to case reports/ small series – recommendation based on expert opinion

29. Short term prophylaxis for lower risk procedures
For lower risk procedures, or where safe prophylactic agents are not available, prophylaxis may be omitted
the patient should be aware of the risk of and have a management plan for attacks, which are more likely to occur after surgery.
Two doses of C1 inhibitor, ecallantide or icatibant should be immediately available.
[100% agreement. Observational/ case series]

30. Short-term or pre-procedural therapy: Attenuated Androgens - REGIMEN
Document
Recommendation
Alternative
Children
Duration
UK Consensus 2005
Danazol mg
Stanozolol 2-6 mg od
Danazol
300mg od
5 days before, 2 days after procedure
International (Canadian/
Hungarian) Consensus 2010
Danazol mg/kg//day: max 600 mg /
Stanozolol 4-6 mg od
Farkas 2010
Danazol 600mg
4 days before and after procedure
Doses are based on expert opinion: not evidence-based

31. Androgens as short term prophylaxis
Advantages
Disadvantages
Ease of use
Well tolerated in short term (usually)
Have been used in children without problem
Have been used in pregnancy (3rd trimester) without problem
Low cost
Broad availability
Perceived inferior efficacy to C1 inhibitor
Need to start several days prior to procedure
Concern of side effects, but minimal
Not suitable for most children
Not suitable for most pregnant women and during breast feeding
Unavailable in some countries

32. Advantages and disadvantages for C1-inhibitor for short term prophylaxis
Some evidence for efficacy
Good theoretical rationale for use
Intravenous
Well tolerated
Lack of availability in some countries
Treatment of choice in children and pregnancy
Cost
May give additional doses if swellings occur

33. Therapies not to be used for short term prophylaxis
The following are not recommended:
Plasma (FFP/SDP)*. (only if no other therapies are available)
Icatibant
Ecallantide
Methyl testosterone
Probably effective.
Ruconest/ Rhucin
[100% agreement except for plasma (75% agreement). Expert opinion]

34. Recommendation: Chronic Prophylaxis is indicated when on demand therapy fails to improve the quality of life of a patient with HAE (100%)

35. Chronic Prophylaxis: Anti-fibrinolytics
Recommendation: Anti-fibrinolytics are have little benefit, have adverse events and are not indicated for use in prophylaxis of HAE (65%)
Recommendation: The minority recommended use in pre-puberty children for HAE prophylaxis (35%)
Recommendation: Avoid use of anti-fibrinolytics during pregnancy and lactation (80%)

36. Anti-fibrinolytic use for chronic prophylaxis
advantages
disadvantages
Inexpensive
Availability
Adverse effects
Few data to support effectiveness
Multiple daily dosing
Unsure of status during pregnancy, lactation and pre-puberty

37. Chronic Prophylaxis: Androgens
Recommendation: Androgens are effective to control the symptoms of HAE, but secondary to the potential adverse effects the dose should not exceed Danazol 200 mg a day or an equivalent dose of an alternate androgen and the dose should be reduced to the least effective dose (100%)
Recommendation: Androgens should be avoided during pregnancy, lactation and in most children before puberty (100%)

38. Monitoring for adverse events when using androgens for Chronic Prophylaxis (100%)
Before use and every 6 months:
• Fasting lipid profile
• Liver function studies and biochemistry
• Complete blood cell count
• Urinalysis
• Alfa-fetal protein
Before use and every 12 months:
abdominal liver ultrasonography

39. 8.5 Monitoring while receiving treatment with Androgens
Before
Follow up
Liver Functional Tests
Every 6 months
Lipid profile
Every 6 months
Urine analysis
Abdominal ultrasound
Once/year
Alpha fetoprotein
CBC

40. Use of C1-INH for chronic prophylaxis
Recommendation: C1-INH that is human plasma derived can be used at 1000 units IV twice a week to suppress HAE attacks. Doses as low as 500 units may be effective in some and others may require greater than 1000 units. (100%- rating A)
Recommendation: Human derived C1-INH products should be equally effective, but the shorter half-life of recombinant C1-INH may limit its use for chronic prophylaxis (90%)

41. Dosing C1-INH for Chronic Prophylaxis
The approved dose is 1000 units twice a week.
At this dose breakthrough attacks are not infrequent
Higher doses and more frequent dosing may be necessary to prevent breakthrough attacks.
Optimal dosing of C1-INH for chronic use has not yet be determined

42. Use of C1-INH for Chronic Prophylaxis
Recommendation: Before starting C1-INH hepatitis B, C, HIV and parvovirus titers should be obtained and monitored on a yearly basis (100%)
Recommendation: Upon prescribing C1-INH hepatitis B and A vaccine series should be started (no vote)
Recommendation: Because of the risk of thrombosis with central lines indwelling central lines and catheters should be avoided when administered C1-INH for chronic prophylaxis (100%)

43. Use of C1-INH for Chronic Prophylaxis
Advantages
Disadvantages
Effective
Few adverse events
Long safety record from over 3 decades use in the EU
Dose ranging studies are lacking
Human plasma derived
Breakthrough attacks occur despite 1000 units twice a week
Intravenous dosing necessary
Expensive

44. Preventive and long term care of the patient with HAE
Recommendation: All patients with HAE should have at least an annual assessment by an HAE specialist. (100%)
Recommendation: All patients with HAE should have an action plan and product available to treat an attack of HAE. (100%)

45. Preventive and long term care of the patient with HAE
All HAE patients have a potential for receiving human blood products. Because of this all HAE patients should be screened as early as possible for Hepatitis B and C and HIV. In addition, vaccination for Hepatitis B and possibly A should be stressed. Annual assessment for infections with hepatitis and HIV are suggested. (100%)

46. Drugs to avoid in HAE Estrogen birth control
Estrogen hormone replacement
ACE-inhibitors for blood pressure, CHF and other diseases
Agreement: 100%

47. Plasma derived C1INH/ Plasma
8.8 screening summary
Tests
Androgens
Plasmin inhibitors
Plasma derived C1INH/ Plasma
Liver Functional Tests
Q 6 mth
Lipid profile
Renal function
Urine analysis
Abdominal ultrasound
Q 12 mth
Alpha fetoprotein
CPK
Eye pressure
Thrombophilia tests?
At start of therapy
Serology for HIV, hepatitis B, C, E, Parvovirus
Start of therapy and every year

48. Why Children with HAE are Unique
Teachers and health care personnel responsible for the child at school should be informed in writing of the diagnosis.
Special medication and an action plan for emergency treatment should be made available at home, at school, and field trips.
A proportion of attacks can be prevented through appropriate counseling and lifestyle modifications aimed at eliminating triggering factors.
Stigmatization by peers is more frequent in children, than in adults.
Farkas H, Varga L, Szeplaki G, Visy B, Harmat G, Bowen T. Management of hereditary angioedema in pediatric patients. Pediatrics 2007; 120(3):e
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol Jul 28;6(1)

49. Treating attacks of HAE
C1-INH concentrate is effective and safe.
Probably the best dose should be based on 20 units/kg since other weight based dosing is not available
No experience is as yet available with the pediatric use of the innovative drugs (bradykinin receptor B2 antagonist, kallikrein inhibitor, recombinant C1-INH concentrate).
Bork K, Staubach P, Hardt J. Treatment of skin swellings with C1-inhibitor concentrate in patients with hereditary angio-oedema. Allergy 2008; 63(6):751-7.
Farkas H, Jakab L, Temesszentandrasi G et al. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol 2007; 120(4):941-7.
Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001; 161(5):714-8.
Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, Rusicke E, Heller C, Klingebiel T. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion 2009; 49(9):
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol Jul 28;6(1)

50. Treatment of Children with HAE
Drugs and the indications for their use are the same as in adults.
Short-Term Prophylaxis (STP)
Short term use of androgens is tolerated well.
Preferred pre-procedural treatment is with C1-inhibitor.
FFP can be utilized, but only in cases C1-inhibitor is not available.
Chronic Prophylaxis
In severe cases uncontrolled by on demand therapy of acute attacks chronic prophylaxis may be necessary
C1-inhibitor prophylaxis is preferred in children
Androgens can be used, but toxicity often exceeds benefits and should be reserved only in severe uncontrolled cases where other therapies are not available.
Anti-fibrinolytics have minimal efficacy, but may be tried in children
Farkas H, Jakab L, Temesszentandrasi G et al. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol 2007; 120(4):941-7.
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol Jul 28;6(1)

51. Treatment during Gestation and Lactation
Recommendation: Because of the lack of safety data with icatibant and ecallantide and the toxicity of androgens and antifibrinolytics during pregnancy, C1INH is the preferred drug during pregnancy and lactation.
(100% expert opinion)

52. On-Demand Therapy during Gestation and Lactation
C1-inhibitor is the preferred therapy. Presently, until further information is available the dose would be 20 units/kg (majority). Minority opinion is 500 or 1000 units for an attack (minority opinion)
FFP (heat treated) can be substituted if C1-inhibitor is not available, but risk is greater than with C1-inhibitor
Anti-fibrinolytics should be avoided
No data are available for eccalantide or icatibant and both should be avoided until safety data exists

53. Prophylaxis During Gestation and Lactation
Elimination of Triggering Factors The measures for non-pregnant females apply.
Drug Prophylaxis
Chronic prophylaxis:
Pd C1-INH concentrate is thought to be safe and effective during both pregnancy and lactation.
Anti-fibrinolytics are not recommended to use during pregnancy. AFs cross the placenta. They are not teratogenic in animals, but are excreted into breast milk. These drugs are not recommended during breastfeeding.
Androgens are not recommended, as these drugs cross the placenta. They cause masculinization of the female fetus, placental insufficiency, and fetal growth retardation. No mutagenicity has been shown in animal models. Excretion into breast milk is unknown, but androgens should be avoided during lactation.
Heat-treated fresh frozen plasma (FFP): Only limited data exist on the use of FFP during pregnancy. Use only if no C1-inhibitor is available
ELIMINATION OF TRIGER FACTORS: The measures for non-pregnant females apply.
DRUG PROPHYLAXIS
LTP:
Pd C1-INH concentrate: safe and effective during pregnancy and lactation. (Raychaudhuri K, Br J Hosp Med Sep 17-30;58(6): Obtulowicz K, Porebski G, Bilo B, Stobiecki M, Obtulowicz A. Hereditary angioedema in pregnancy – case series study. The 6th C1-INH Deficiency Workshop, May, Budapest, abstract book page 58.;. Czaller Eu J Obstet Gynecol Reprod Biol 2010, Martinez Am J Obstet Gynecol 2010, Gorman PJ. Can Fam Physician Mar;54(3): Farkas H, J Allergy Clin Immunol. 2007
AF’s: if pd C1-INH is unavailable. AFs cross the placenta, no teratogenic effects in animals, excreted into breast milk, not recommended during breastfeeding Kullander S, Obstet Gynecol Scand. 1970;49(3): Walzman M,. Arch Toxicol Suppl. 1982;5:214-20; Cyklokapron (Pharmacia). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association; p
AA’s: are not recommended, cross the placenta, masculinization of the female fetus, placental insufficiency, fetal growth retardation. No mutagenicity in animal models, excretion into breast milk unknown, discontinuation breastfeeding before introduction of the AA recommended, terminating lactation itself may reduce attack frequency . (Manikkam M, Endocrinology Feb;145(2):790-8; Duck SC, Fertil Steril Feb;35(2):230-1; Cicardi M, J Allergy Clin Immunol Apr;87(4):768-73; Reschini E, Lancet May 25;1(8439):1226 Sathishkumar K , Biology of reproduction 81 : 250. (2009) ABSTRACT 250 Elnicki DM. Hereditary angioedema South Med J Apr;87(4): Oxymetholone package insert (Anadrol-50, Unimed—US), Rev 06/17/97, Rec 03/16/98. Berglund F, Acta Obstet Gynecol Scand Suppl. 1984;126:1-55. ) Seven patients took danazol during the initial weeks of their pregnancies; however, masculinization was not observed in any of their female neonates. Czaller Eu J Obstet Gynecol Reprod Biol 2010,)
Heat-treated Fresh frozen plasma (FFP) Limited data exist on the long-term use of FFP during pregnancy. (Galan HL, J Reprod Med Jul;41(7): Prematta M, Ann Allergy Asthma Immunol Apr;98(4):383-8.)

54. Home Therapy
Recommendation: Patients with HAE should be encouraged to provide self care and home care to allow early, effective and cost effective care
Agreement: 100%
A evidence

55. Action Plans
Recommendation: All patients with HAE should have an acute action plan to include location to acquire care, therapies available or in possession, dose and route of administration
Agreement: 100%

56. World Wide Access to Therapies
Recommendation: Associations, doctors, patients, health care providers, and pharmaceutical companies should petition to have therapies available world wide for all patients with HAE.
Agreement: 100%

57. Summary
This short slide set and the document and comprehensive slide set that accompanies it are intended for the better dissemination of the care and treatment of patients with HAE. These slides are available on the WAO website to be used for self learning, patient care and teaching. Feel free to use them.