4. The development of diagnostic-therapeutic algorithms for dental-oral, maxillofacial and otolaryngological procedures (DOMFOPs) according to the risk of triggering angioedema attacks

In the last 12 years, different consensus algorithms and clinical guidelines have been published for managing DOMFOP STP and will be reviewed below.

#### 4.1. The 2003 Hungarian-Canadian consensus algorithm

Case report (gender/age) STP AE type AE

One female of 54 y.o. 500 IU N.AD N.AD C1-INH-HAE

One male of 46 y.o. N.AD N.AD N.AD C1-INH-HAE

One female of 28 y.o. N.AD N.AD N.AD C1-INH-HAE

One female of 49 y.o. N.AD N.AD N.AD C1-INH-HAE

One female of 33 y.o. N.AD N.AD N.AD C1-INH-HAE

One male of 36 y.o. N.AD N.AD N.AD C1-INH-HAE

One female of 28 y.o. N.AD N.AD SC 30 mg C1-INH-HAE

One female of 6 y.o. 500 IU N.AD N.AD C1-INH-HAE

One female of 26 y.o. 1000 IU N.AD N.AD C1-INH-HAE

esterase inhibitor, SC = subcutaneous, STP = short-term prophylaxis and y.o. = years old.

One female of 50 y.o. N.AD N.AD N.AD C1-INH-HAE Laryngeal

One female of 8 y.o. Used N.AD N.AD C1-INH-HAE None

Six males and six females aged between 21 and 50 y.o.

180 A Comprehensive Review of Urticaria and Angioedema

Three females aged between of 27

Two males aged between 19 and 57 y.o. and one female of 20 y.o.

and 32 y.o.

pdhC1INH FFP Icatibant

acetate

type I

type I

type I

type I

type I

type I

type II

type I

type II

type I

type I

1000 IU N.AD N.AD None

One female of 45 y.o. N.AD N.AD SC 30 mg C1-INH-HAE None Angeletti

N.AD N.AD N.AD C1-INH-HAE

FFP = fresh frozen plasma, IU = International Unit, N.AD = not administered, pdhC1INH = plasma-derived human C1

Table 1. Literature review of dental-oral, maxillofacial and ENT procedures in patients with C1-INH-HAE.

type I þ AAE-ACEi

N.AD N.AD N.AD C1-INH-HAE

One male of 4 y.o. N.AD Used N.AD Unknown None Webb et al. [32] One female of 6 y.o. N.AD N.AD N.AD HAE None

N.AD N.AD N.AD C1-INH-HAE

development

Laryngeal oedema

Laryngeal oedema

Laryngeal oedema

Laryngeal oedema

None (danazol)

(danazol)

Laryngeal oedema

Minimal pharyngeal oedema

oedema

None Senaratne

None Narayanan

None Sanuki et al. [41]

None Farkas et al. [31]

None Maeda et al. [33]

> Börk and Barnstedt [18]

> Rice et al. [34]

Van Sickels et al. [35]

Moraes et al. [36]

Baccioglu Kavut [37]

et al. [38]

et al. [39]

et al. [40]

Jurado-Palomo et al. [15]

Forrest et al. [42]

Reference

The 2003 Hungarian-Canadian consensus was the first consensus document on the management of C1-INH-HAE [43]. It attempted to establish a separation between minor and major DOMFOPs but did not go deeper in differentiating clearly which procedures were considered minor or major (Figure 1) [43].

According to the 2003 Hungarian-Canadian consensus, the STP in DOMFOPs should be as follows:


Figure 1. Short-term prophylaxis algorithm for C1-inhibitor deficiency according to the 2003 Hungarian-Canadian consensus [43].

alternative to danazol. pdhC1INH should be available for immediate administration if an AE attack developed [43]. In case of a major surgical procedure or if the patient was being intubated, intravenous pdhC1INH had to be administered 1 hour before surgery. A second pdhC1INH dose should be administered during surgery and even repeated daily or as much as needed until there was no risk of developing AE. If pdhC1INH was not available, STP with danazol or tranexamic acid was recommended. Solvent/detergenttreated fresh frozen plasma (SD-FFP) 1 or more hours before procedure could be another alternative if pdhC1INH was not available; regular FFP would be a fourth option, although less safe than SD-FFP [43].

The algorithm summarizing the recommendations for surgical risk of the Hungarian-Canadian consensus 2003 can be seen in Figure 1 [43].

#### 4.2. The 2005 British consensus algorithm

According to the 2005 British consensus [16], STP was not only indicated before risky procedures or surgeries but also during periods of physiological or psychological stress (also called intermittent long-term prophylaxis). It was the first time that the term "intermittent long-term prophylaxis" was used. The proposed STP scheme was as follows:

	- 4 g/day (1 g 4 times/day)
	- Danazol: 100–600 mg/day
	- Stanozolol: 2–6 mg/day

#### 4.3. The 2007 Hungarian-Canadian consensus algorithm

The 2007 Hungarian-Canadian consensus (published in 2008) continued the distinction between minor or major procedures and intubation (Figure 2) [44].

Unlike the 2003 Hungarian-Canadian algorithm, the recommendation of the use of tranexamic acid in minor manipulations with available pdhC1INH was removed. In addition, in major procedures or intubation, the recommendation of the use of danazol or tranexamic acid was also removed, and recommendations differed according to the availability or non-availability of pdhC1INH.

#### 4.4. The 2010 international consensus algorithm

The International consensus published in Allergy, Asthma and Clinical Immunology (official publication of the Canadian Society of Allergy and Clinical Immunology) in 2010 updated the STP recommendations (Figure 3) [13].

alternative to danazol. pdhC1INH should be available for immediate administration if an AE attack developed [43]. In case of a major surgical procedure or if the patient was being intubated, intravenous pdhC1INH had to be administered 1 hour before surgery. A second pdhC1INH dose should be administered during surgery and even repeated daily or as much as needed until there was no risk of developing AE. If pdhC1INH was not available, STP with danazol or tranexamic acid was recommended. Solvent/detergenttreated fresh frozen plasma (SD-FFP) 1 or more hours before procedure could be another alternative if pdhC1INH was not available; regular FFP would be a fourth option,

The algorithm summarizing the recommendations for surgical risk of the Hungarian-Cana-

According to the 2005 British consensus [16], STP was not only indicated before risky procedures or surgeries but also during periods of physiological or psychological stress (also called intermittent long-term prophylaxis). It was the first time that the term "intermittent

• pdhC1INH (500–1500 U, generally 1000 U) up to 24 hours before. Additional doses may be required later, basically if postoperative infection occurs. It was the treatment of choice

long-term prophylaxis" was used. The proposed STP scheme was as follows:

• Tranexamic acid from 2 to 5 days before procedure until 2 days after procedure

• Attenuated androgens from 2 to 5 days before procedure to 2 days after procedure

The 2007 Hungarian-Canadian consensus (published in 2008) continued the distinction between

Unlike the 2003 Hungarian-Canadian algorithm, the recommendation of the use of tranexamic acid in minor manipulations with available pdhC1INH was removed. In addition, in major procedures or intubation, the recommendation of the use of danazol or tranexamic acid was also removed, and recommendations differed according to the availability or non-availability

The International consensus published in Allergy, Asthma and Clinical Immunology (official publication of the Canadian Society of Allergy and Clinical Immunology) in 2010 updated the

in major dental procedures such as tooth extractions.

4.3. The 2007 Hungarian-Canadian consensus algorithm

minor or major procedures and intubation (Figure 2) [44].

4.4. The 2010 international consensus algorithm

STP recommendations (Figure 3) [13].

although less safe than SD-FFP [43].

182 A Comprehensive Review of Urticaria and Angioedema

4.2. The 2005 British consensus algorithm

– 4 g/day (1 g 4 times/day)

– Danazol: 100–600 mg/day

– Stanozolol: 2–6 mg/day

of pdhC1INH.

dian consensus 2003 can be seen in Figure 1 [43].

Figure 2. Prophylaxis algorithm in C1-inhibitor deficiency of the 2007 Hungarian-Canadian consensus [44].

Figure 3. Prophylaxis algorithm in C1-inhibitor deficiency in the 2010 international consensus [44].

A distinctive feature is that the time period for STP with oral drugs for minor risk procedures was increased from 5 days before the procedure to 2–5 days after the completion of the procedure [13]. It also emphasizes the non-use of danazol during the first two trimesters of pregnancy because of the obvious risks of AAs. Antifibrinolytics are still not recommended for STP in this type of procedures.

In procedures involving a higher AE risk or endotracheal intubation, pdhC1INH should be administered from 1 to 6 hours before the procedure, if available. As in previous consensus documents, it only distinguishes between DOMFOPs of minor or major risk, not considering "intermediate risk".

#### 4.5. The 2011 Spanish consensus algorithm

According to the Spanish consensus [8], STP was indicated in surgery or medical procedures that involve trauma in the cervicofacial region with the risk of laryngeal oedema development (e.g. dental manipulations, tonsillectomy, maxillofacial surgery, endoscopy, bronchoscopy or interventions requiring endotracheal intubation) and to prevent local oedema that could alter the surgeon's work area and may affect the surgical outcome.

Specific acute treatment (pdhC1INH or icatibant acetate) must be available with appropriate monitoring of the patient after surgery, including an action plan.

The recommendations were as follows:

	- Danazol: 400–600 mg/day
	- Stanozolol: 4–6 mg/day
	- EACA
	- Tranexamic acid: 1–4 g/day or 75 mg/kg/day divided into 2–3 doses from 5 days before to 2 days after surgery

Drugs and doses for STP are summarized in Table 2.


Table 2. Short-term prophylaxis in the Spanish 2011 national consensus on C1-INH-HAE.

#### 4.6. The 2012 management guidelines of the World Allergy Organization (WAO)

This was the first guideline on C1-INH-HAE and thus was the first time in which evidence levels were analysed and graded recommendations were given [45].

There was no evidence about the effectiveness of STP. The advice to administer STP was based on Expert Opinion. It was stated that even though STP was used, AE episodes could still occur and sometimes after minor procedures (case reports, series of patients). Nevertheless, several publications had reported a reduction in the incidence of AE with STP in both adults and children. In this guideline, the indications of STP varied according to:


4.5. The 2011 Spanish consensus algorithm

184 A Comprehensive Review of Urticaria and Angioedema

The recommendations were as follows:

– Danazol: 400–600 mg/day

– Stanozolol: 4–6 mg/day

to 2 days after surgery

Drugs and doses for STP are summarized in Table 2.

Tranexamic acid

the procedure.

• Antifibrinolytics

– EACA

Pharmacological

group

Attenuated androgens

Antifibrinolytics (seldom used)

required second dose (if available).

the surgeon's work area and may affect the surgical outcome.

monitoring of the patient after surgery, including an action plan.

According to the Spanish consensus [8], STP was indicated in surgery or medical procedures that involve trauma in the cervicofacial region with the risk of laryngeal oedema development (e.g. dental manipulations, tonsillectomy, maxillofacial surgery, endoscopy, bronchoscopy or interventions requiring endotracheal intubation) and to prevent local oedema that could alter

Specific acute treatment (pdhC1INH or icatibant acetate) must be available with appropriate

• Intravenous pdhC1INH (500 U if the patient weighs less than 50 kg and 1000 U if he/she weighs more than 50 kg) administered from 1 to 4 hours prior to the procedure, with a

• Intravenous SD-FFP (if pdhC1INH is not available), two units administered 1 hour before

• AAs from 5 to 7 days before to 2–3 days after the procedure (in case of postoperative complications such as infections, AAs should be continued for more than 5 days.)

– Tranexamic acid: 1–4 g/day or 75 mg/kg/day divided into 2–3 doses from 5 days before

FFP 2 U (400 ml), 1 hour before procedure 10 mL/kg 1 hour before procedure

10 mg/kg/day for 5–7 days before to

500 mg/6 hours for 2 days before and

2–3 days post-event

2 days post-event

Drug Adults Children

C1-INH replacement pdhC1INH 500–1500 U, 1–4 hours before event 20 U/kg, 1 hour before event

1 g/6 hours for 5 days before and 2 days

Danazol 400–600 mg/24 hours for 5–7 days before and 2–3 days post-event

Stanozolol 4–6 mg/24 hours for 5 days before and 3 days

post-event

post-event

Table 2. Short-term prophylaxis in the Spanish 2011 national consensus on C1-INH-HAE.

• Periods of high risk of attacks (due to increased likelihood of AE attacks or increased consequences of AE attack): periods of stress, tests

STP administration had to be considered prior to surgery, especially in the case of dental/ intraoral procedures, in which endotracheal intubation was required, when the airway or pharynx was manipulated and before bronchoscopy or endoscopy. This statement had a level of evidence D (adapted from previous consensus document or "statement" based on an expert opinion poll during a consensus conference) and a strength of recommendation A.

In DOMFOPs with minimal risk or if there was availability of safe drugs for on-demand treatment of "upper airway edema" (UAE) attacks, STP could be omitted. Two doses of pdhC1INH, ecallantide or icatibant had to be available for possible immediate administration. The patient had to know the risks and have a plan of action and treatment for AE attacks.

The recommendations were as follows:

	- Danazol: 2.5–10 mg/kg/day, to a maximum dose of 600 mg/day
	- Stanozolol: 4–6 mg/day
	- Tranexamic acid: 25 mg/kg/day divided into 2–3 doses

#### 4.7. The 2013 guidelines for the management of HAE, C1-INH-AAE and ACEi-AAE

All HAE patients are candidates for STP when exposed to situations that could likely trigger an AE attack [46].

Two statements are particularly relevant in this field:


The drugs and doses recommended are as follows:

	- Danazol: 6–10 mg/kg/day into divided doses; maximum 200 mg, 3 times per day or equivalent

There are no comparative studies between pdhC1INH and AAs. The decision on the drug to be prescribed should be based on an individualized assessment of damage/burden compared to the benefits, costs and patient preferences. In emergency procedures, pdhC1INH is the treatment of choice. Specific treatment for AE attacks (pdhC1INH, ecallantide or icatibant) should be available during and after any procedure.

#### 4.8. The 2014 Canadian consensus

STP should be considered prior to the patient's specific known triggers and before any medical, surgical or dental procedures [47]. Evidence level is low, and the strength of the recommendation is strong.

Specific treatments for the acute attack of C1-INH-HAE should be available during and after the procedure. The level of evidence is low (our confidence in the estimated effect is limited: the true effect may be substantially different from the estimated effect). The strength of the recommendation is strong.

The drugs and doses recommended were as follows:

	- Cinryze®: 1000 U up to 24 hours before, though there is not enough evidence that confirms that administering the drug more than 6 hours before the procedure is safe
	- Berinert®: 1000 U up to 6 hours before
	- Danazol: 2.5–10 mg/kg/day, up to a maximum dose of 600 mg/day

4.7. The 2013 guidelines for the management of HAE, C1-INH-AAE and ACEi-AAE

dence or recommendation extrapolated from category I evidence).

deficiency syndromes are warranted. Strength of recommendation D.

• Intravenous SD-FFP 2 U: several hours (up to 12 hours) before the procedure

• Oral 17-alpha-alkylated AAs, for 5–10 days before to 2 days after the procedure

– Danazol: 6–10 mg/kg/day into divided doses; maximum 200 mg, 3 times per day or

There are no comparative studies between pdhC1INH and AAs. The decision on the drug to be prescribed should be based on an individualized assessment of damage/burden compared to the benefits, costs and patient preferences. In emergency procedures, pdhC1INH is the treatment of choice. Specific treatment for AE attacks (pdhC1INH, ecallantide or icatibant)

STP should be considered prior to the patient's specific known triggers and before any medical, surgical or dental procedures [47]. Evidence level is low, and the strength of the recommendation

Specific treatments for the acute attack of C1-INH-HAE should be available during and after the procedure. The level of evidence is low (our confidence in the estimated effect is limited: the true effect may be substantially different from the estimated effect). The strength of the

• pdhC1INH: pdhC1INH was recommended, although there were no data on the most

– Cinryze®: 1000 U up to 24 hours before, though there is not enough evidence that confirms that administering the drug more than 6 hours before the procedure is safe

appropriate dose. In Europe, it was marketed under the following brands:

an AE attack [46].

Two statements are particularly relevant in this field:

186 A Comprehensive Review of Urticaria and Angioedema

The drugs and doses recommended are as follows:

should be available during and after any procedure.

The drugs and doses recommended were as follows:

– Berinert®: 1000 U up to 6 hours before

4.8. The 2014 Canadian consensus

recommendation is strong.

• Intravenous pdhC1INH: 1000–2000 U

equivalent

is strong.

All HAE patients are candidates for STP when exposed to situations that could likely trigger

1. Summary statement 20: STP can be achieved by using FFP, pdhC1INH and high doses of AAs for short periods. Recommendation strength B (directly based on category II evi-

2. Summary statement 25: New drugs for the treatment of C1-INH deficiency syndromes are costlier than the alternative treatment with AAs. Official studies of cost-utility and costeffectiveness in helping healthcare providers in the management of patients with C1-INH – Tranexamic acid: 25 mg/kg/day (up to a maximum dose of 3000–6000 mg/day) divided into 2–3 doses from 5 days before to 2–5 days after the surgery or when a trigger was anticipated. Its effectiveness in preventing attacks was unknown, so it should only be used if other drugs were not available

#### 4.9. The 2013 Spanish algorithm for short-term prophylaxis

A group of allergists along with clinical pharmacologists from different hospitals in Spain developed algorithms for the diagnosis, prophylaxis and treatment of C1-INH-HAE [48].

STP was not indicated in minor procedures with the availability of specific treatment for acute AE attacks. STP was indicated in all the procedures that involved trauma in the cervicofacial region because of the risk of developing AE in the upper airway and in any diagnostic or therapeutic procedure in order to avoid local edema in the working area so that the procedure result was not altered.

pdhC1INH was the election treatment for STP. Both Cinryze® 1000 U (1–24 horas preprocedure) and Berinert® 10–20 U/kg (1–6 hours of pre-procedure) were available for their 20 use in adults.

In case pdhC1INH was not available, attenuated androgens (danazol, estanozolol) and antifibrinolytics (tranexamic acid, epsilon aminocaproic acid) were alternatives in programmed procedures and SD-FFP in case of emergency procedures.


It was advised that any patient receiving STP should be observed and the specific treatment for acute attacks should be available for 48 hours after the procedure, as the risk for AE is not totally cancelled with STP.

These authors specified STP for children. The election treatment was also intravenous pdhC1INH (Berinert®: 10–20 U/kg, 1–6 hours pre-procedure or Cinryze® 1000 U).

In case pdhC1INH was not available, they advised to use attenuated androgens or tranexamic acid:


#### 4.10. International consensus for the management of children with C1-INH-HAE

According to the international consensus for the management of children [49] (Figure 4), indications for STP in paediatrics (as in adults) include patient-specific triggers, medical and dental procedures. For most "minor interventions", the recommendation is to choose an ondemand treatment if a swelling event is precipitated rather than prophylaxis, provided that a licensed on-demand medication is immediately available in the case of emergency (level III evidence).

#### 4.11. US consensus for the management of children with C1-INH-HAE

Only Berinert® is approved for the treatment of children < 12 y.o. [50]. Berinert®, at 20 U/kg, has less risk of containing an infectious agent, is approved by the Food and Drug Administration (FDA) in children and is preferable when available [51–53].

FFP given empirically at 2 U per patient immediately before surgery has been reported to provide effective STP in adults and poses less risk [19]. It is critically important that effective on-demand treatment be available, whether the patient is given STP prophylaxis or not. Therapeutic approaches for C1-INH-HAE have been studied carefully in adults, but not all have not been investigated with the same level of care in children (Table 3).

Figure 4. Prophylaxis algorithm in C1-inhibitor deficiency in the 2017 international consensus for the management of children [49].


Table 3. Drugs for prophylaxis and for the acute treatment of hereditary angioedema (modified Frank et al.) [50].

#### 4.12. Available treatments for STP in C1-INH-HAE

• Danazol: 10 mg/kg/day (divided into 2–3 doses/day—from 5 to 7 days pre-procedure to

• Tranexamic acid: 500 mg/6 hours (from 5 days pre-procedure to 2–3 days post-procedure)

According to the international consensus for the management of children [49] (Figure 4), indications for STP in paediatrics (as in adults) include patient-specific triggers, medical and dental procedures. For most "minor interventions", the recommendation is to choose an ondemand treatment if a swelling event is precipitated rather than prophylaxis, provided that a licensed on-demand medication is immediately available in the case of emergency (level III

Only Berinert® is approved for the treatment of children < 12 y.o. [50]. Berinert®, at 20 U/kg, has less risk of containing an infectious agent, is approved by the Food and Drug Administra-

FFP given empirically at 2 U per patient immediately before surgery has been reported to provide effective STP in adults and poses less risk [19]. It is critically important that effective on-demand treatment be available, whether the patient is given STP prophylaxis or not. Therapeutic approaches for C1-INH-HAE have been studied carefully in adults, but not all

Figure 4. Prophylaxis algorithm in C1-inhibitor deficiency in the 2017 international consensus for the management of

4.10. International consensus for the management of children with C1-INH-HAE

4.11. US consensus for the management of children with C1-INH-HAE

have not been investigated with the same level of care in children (Table 3).

tion (FDA) in children and is preferable when available [51–53].

2–3 days post-procedure)

188 A Comprehensive Review of Urticaria and Angioedema

evidence).

children [49].

#### 4.12.1. Plasma-derived C1 esterase inhibitor concentrate (pdhC1INH)

pdhC1INH consists of a replacement therapy for the lacking C1-INH. There are currently several pdhC1INH pharmaceutical presentations: Berinert® (CSL-Behring GmbH, Marburg, Germany), Cebitor® (Sanquin, Amsterdam, The Netherlands) and Cinryze® (Shire HGT, Zug, Switzerland) (see Table 4 for a comparison of the available drugs for short-term prophylaxis in C1-INH-HAE).

For nearly 25 years, Berinert-P (CSL-Behring GmbH) was available in Spain through the Foreign Medications office [8]. Afterwards, it was finally marketed in Spain as Berinert® in August 2009 [8]. Berinert® is a purified, pasteurized, nanofiltred pdhC1INH. It is presented in 500 U vials of a lyophilized product for intravenous administration, which has to be stored at 2–25C [8], and when reconstituted, a 50 IU/mL solution is formed. It has an excellent safety post-launch record after more than 35 years of its availability [54–56].

Berinert® is currently approved by the FDA for the treatment of AE attacks in adults and adolescents, 12 years and older, with C1-INH-HAE, and by the European Medical Agencies (EMA) for the treatment of AE attacks and short-term prophylaxis in adults and children with C1-INH-HAE [56].

Cebitor® is only available in a few European countries.

Cinryze® comes in a package with two lyophilized 500 U C1 inhibitor (human) vials. After reconstitution, each vial contains a 100 U/ml solution. It has to be stored from 2 to 25C.

The FDA approved Cinryze in October 2008 for long-term prophylaxis in adults (> 18 years) [8]. In 2010, the European Medicines Agency (EMA) approved the marketing of Cinryze® for long-term prophylaxis, short-term-prophylaxis and the treatment of acute attacks in adolescents and adults [57].



Drug Human

Berinert®

CSL-Behring

 Human plasma-derived

C1-esterase

inhibitor

plasmaderived C1-

INH

Human

Cebitor®,

Sanquin, Shire

Human

C1-INH

Intravenous

 1000 U, 1–24 hours before

procedure2

plasma-derived

replacement

C1-esterase

inhibitor

HGT

Cinryze®

plasmaderived C1-

INH

Conestat-alfa

Rhucin®/

Pharming NV

human

inhibitor of C1-

esterase

(produced in

transgenic

rabbits)

Recombinant

C1-INH

Intravenous

 No

Rare: risk of anaphylaxis (screening for IgE antibodies

against rabbit dander is

advised by EMA)

replacement

Ruconest®3

(recombinant

human C1INH produced

in transgenic

rabbits)

Icatibant

Firazyr®

Shire HGT

 Synthetic

Blockage of B2R

Subcutaneous

 No

Common: local swelling, pain

and pruritus at injection site

Attack can recur in the

following 48 hours

Theoretical:

ongoing acute coronary artery

disease

Common:

Uncommon: risk of

anaphylaxis

administered

professionals)

Transmission

agents: only S/D treatment

inactivates

but not Risk of volumes can overload the

circulatory

Allergenic potential: large

 system

 enveloped viruses

non-enveloped

hypervolaemia:

 large

 ones

 of infectious

 by healthcare

 (must be

prolonged PTT

 worsening of an

peptide (10 aa)

acetate

Ecallantide

Solvent/

Several

 Plasma

Replacement

deficient C1-INH

protein

 of

Intravenous

 Adults: 2–4 U Children: 10 mL/kg

1–6 hours before

procedure4

derivative

detergenttreated plasma

(SD-FFP)

 Kalbitor®

Shire HGT

human protein

of plasma kallikrein

(60 aa)

Recombinant

Selective inhibitor

Subcutaneous

 No

Trade name

 Company

 Drug

Mechanism

 of

Administration

Indication for STP

 Adverse events

route

description

action

C1-INH

Intravenous

 - Adults: 1000 IU, 1–6

Rare: risk of

thrombosis

Theoretical:

infectious agent

transmission

 of

190 A Comprehensive Review of Urticaria and Angioedema

anaphylaxis,

hours before procedure


hours before procedure

replacement1

Table 4. Drugs for the treatment of C1-INH-HAE with special focus on STP.

longer than 6 hours prior to procedure.

3 Conestat alfa is 4 As close to procedure as possible.

commercialized

 as Ruconest® in Europe and Rhucin® in other parts of the world.

Short‐Term Prophylaxis in Odontostomatological, Maxillofacial and ENT Procedures in Patients with… http://dx.doi.org/10.5772/67713 191

Both Berinert® and Cinryze® are currently authorized for intravenous self-administration by trained patients or their relatives.

The recommended doses for STP are 1000 U for adults both for Berinert® and Cinryze® and 15–30 IU/kg for children for Berinert®, 1–6 hours before procedure. Although the Cinryze® Summary of Products Characteristics (SPC) indicates 1–24 hours, most authors consider that it should be administered as close as possible to the procedure and no longer than 6 hours prior to procedure [58]. For long, complex surgeries and in the case of infection or other trigger factors, the pdhC1INH dose may have to be repeated.

At least one dose of a specific drug for the treatment of acute AE attacks (C1-INH concentrate, rhC1INH, ecallantide or icatibant) should be available for on-demand treatment in case it is needed.

#### 4.12.2. Fresh frozen plasma

In countries where pdhC1INH is not available, fresh frozen plasma (FFP) is an alternative. FFP should be virally inactivated with solvents and detergents (SD-FFP) to be safer. FFP acts by supplying lacking C1-INH [8]. SD-FFP dosage for C1-INH-HAE has not been studied, and the generally used dose is the same than in coagulation disorders: 2 units of 200 mL each [8].

Among the possible FFP side effects are alloimmunization, anaphylactic or allergic reactions, transmission of infectious diseases (viruses, Creutzfeldt-Jakob disease) and excessive intravascular volume with the risk of hypervolemia and heart failure [8].

#### 4.12.3. Attenuated androgens

Danazol and stanozolol are 17-α-alkylated synthetic derivatives, which are very effective and have fewer side effects than other androgens. Their mechanism of action in C1-INH-HAE is not well known. Several actions may contribute to their effectiveness. First, a significant increase in C1-INH plasma levels was reported with high AA doses. Second, an increase in the expression of C1-INH mRNA in mononuclear cells with the minimum effective dose was shown. Finally, an increase in the plasma levels of aminopeptidase P, one of the BK catabolizing enzymes, was published [8].

Danazol is a potent gonadotropic inhibitor with partial antigestagenic, anabolic and androgenic activity, whereas stanozolol is an anabolic steroid with certain anticoagulant properties [8].

Oxandrolone is another AA, which has been used in C1-INH-HAE to a lesser extent [8].

AAs have considerable side effects when used as long-term prophylaxis for long periods of time or at high doses [8]. The main secondary effects are disorders of libido, impotence, weight gain, menstrual irregularities, breast atrophy/hypotrophy, acne, voice changes, increased atherogenic index, polycythemia, hypertension, haematuria, transient increases in transaminases, hepatic necrosis, cholestatic hepatitis, hepatosplenic peliosis, transient increases in muscle enzymes (creatine phosphokinase and aldolase) and rhabdomyolysis. There have also been some cases of hepatic adenoma and adenocarcinoma. However, the data on increased risk of atherosclerosis are controversial. AAs used for short periods of time as STP are much better tolerated, and thus, they were advised as STP for children and pregnant women in the first consensus documents on C1-INH-HAE.

The effect of AAs takes approximately 5 days, and thus, AAs cannot be used in emergency situations that require STP. AA doses for STP can be seen in Table 3.

These drugs may have to be administered for more than 5 days after the procedure in the case of postoperative complications, especially infection [8].

#### 4.12.4. Antifibrinolytic agents

Both Berinert® and Cinryze® are currently authorized for intravenous self-administration by

The recommended doses for STP are 1000 U for adults both for Berinert® and Cinryze® and 15–30 IU/kg for children for Berinert®, 1–6 hours before procedure. Although the Cinryze® Summary of Products Characteristics (SPC) indicates 1–24 hours, most authors consider that it should be administered as close as possible to the procedure and no longer than 6 hours prior to procedure [58]. For long, complex surgeries and in the case of infection or other trigger

At least one dose of a specific drug for the treatment of acute AE attacks (C1-INH concentrate, rhC1INH, ecallantide or icatibant) should be available for on-demand treatment in case it is needed.

In countries where pdhC1INH is not available, fresh frozen plasma (FFP) is an alternative. FFP should be virally inactivated with solvents and detergents (SD-FFP) to be safer. FFP acts by supplying lacking C1-INH [8]. SD-FFP dosage for C1-INH-HAE has not been studied, and the generally used dose is the same than in coagulation disorders: 2 units of 200 mL each [8].

Among the possible FFP side effects are alloimmunization, anaphylactic or allergic reactions, transmission of infectious diseases (viruses, Creutzfeldt-Jakob disease) and excessive intravas-

Danazol and stanozolol are 17-α-alkylated synthetic derivatives, which are very effective and have fewer side effects than other androgens. Their mechanism of action in C1-INH-HAE is not well known. Several actions may contribute to their effectiveness. First, a significant increase in C1-INH plasma levels was reported with high AA doses. Second, an increase in the expression of C1-INH mRNA in mononuclear cells with the minimum effective dose was shown. Finally, an increase in the plasma levels of aminopeptidase P, one of the BK catabolizing enzymes, was

Danazol is a potent gonadotropic inhibitor with partial antigestagenic, anabolic and androgenic activity, whereas stanozolol is an anabolic steroid with certain anticoagulant properties [8]. Oxandrolone is another AA, which has been used in C1-INH-HAE to a lesser extent [8].

AAs have considerable side effects when used as long-term prophylaxis for long periods of time or at high doses [8]. The main secondary effects are disorders of libido, impotence, weight gain, menstrual irregularities, breast atrophy/hypotrophy, acne, voice changes, increased atherogenic index, polycythemia, hypertension, haematuria, transient increases in transaminases, hepatic necrosis, cholestatic hepatitis, hepatosplenic peliosis, transient increases in muscle enzymes (creatine phosphokinase and aldolase) and rhabdomyolysis. There have also been some cases of hepatic adenoma and adenocarcinoma. However, the data on increased risk of atherosclerosis are controversial. AAs used for short periods of time as STP are much better tolerated, and thus, they were advised as STP for children and pregnant women in the first

trained patients or their relatives.

192 A Comprehensive Review of Urticaria and Angioedema

4.12.2. Fresh frozen plasma

4.12.3. Attenuated androgens

consensus documents on C1-INH-HAE.

published [8].

factors, the pdhC1INH dose may have to be repeated.

cular volume with the risk of hypervolemia and heart failure [8].

The mechanism of action of antifibrinolytic agents in C1-INH-HAE is unknown.

#### 4.12.4.1. ε-Aminocaproic acid

ε-Aminocaproic acid (EACA) (Amycar®, Rottapharm Madaus, Milan, Italy) is effective in preventing AE attacks in C1-INH-HAE if taken as long-term prophylaxis [8, 14]. There is a scarcity of data about its use as STP, although some consensus documents advise on its use [13, 44].

The most frequent side effect is a transient increase in creatine phosphokinase and aldolase associated with muscle pain, weakness and fatigue. Other side effects are thrombosis and extensive muscle necrosis [8].

### 4.12.4.2. Tranexamic acid

Tranexamic acid (Amchafibrin®, Rottapharm Madaus, Milan, Italy) is a cyclic derivative of EACA and has been proven efficacious in preventing AE attacks in patients with C1-INH-HAE [8, 14]. Tranexamic acid competitively inhibits the activation of plasminogen, which, under normal conditions, is inhibited by C1-INH, thus reducing the conversion of plasminogen to plasmin (fibrinolysis) [8].

Muscle cramps, nausea, diarrhoea, hypotension, dizziness and fatigue are among its described side effects.

The dose for STP is 1 g 4 times a day or 75 mg/kg/day divided into 2–3 doses from 5 days before to 2 days after the surgery or medical procedure.

Antifibrinolytics are seldom used in countries where other treatments are available. Antifibrinolytics should be discontinued before the surgery, as they may theoretically promote thromboembolic events [8].

#### 4.12.5. Icatibant acetate

Icatibant acetate (Firazyr®, Shire HGT, Zug, Switzerland) is a synthetic decapeptide similar to BK and a highly specific, potent and competitive antagonist of the BK B2 receptor (B2R), inhibiting the vasodilation produced by BK [8]. Its effectiveness as the treatment for AE acute attacks in C1-INH-HAE has been shown in clinical trials and patient series [8] and in patient registries [59–61]. No serious adverse reactions have been reported, the only significant side effect being injection site reactions (in more than 95% of cases), consisting of self-limiting erythema, oedema, pruritus and pain [8]. The European Medicines Agency (EMA) approved icatibant acetate for the treatment of acute AE attacks in adult patients (≥ 18 y.o.) with C1-INH-HAE in July 2008, and it has been available in Spain since March 2009. It was approved by the FDA in 2011. Icatibant acetate's self-administration was authorized by EMA in 2011. A registry on the use of icatibant acetate in real life has confirmed its safety [61].

Icatibant acetate is only approved for adults. A study on its safety and efficacy in children is currently going on. There is no information about its safety profile in women who are pregnant. Regarding breastfeeding, lactation should be avoided 12 hours after icatibant acetate's administration. According to prescribing information, icatibant acetate should not be used in patients with active ischemic heart disease or those who have had an ischemic stroke in the preceding 2 weeks [8].

Isolated cases of STP with off-label icatibant acetate prior to some medical, dental or surgical procedures in patients with C1-INH-HAE have been published [38, 62, 63]. First, a thyroid biopsy without later local oedema was published [62].

However, controlled studies are necessary. The short half-life (1–2 hours) of this agent and the fact that it blocks B2R but does not diminish the BK production may restrict its use in shortterm prophylaxis, as there is a theoretical risk of late local oedema. The trauma may result in an increase in local BK through FXII activation. While B2R blockage continues, no oedema is produced, but when B2Rs are released (after icatibant is eliminated from the body), an oedema episode could develop 6–8 hours after the surgery if BK remains high [8]. Other authors do not support its use as short-term prophylaxis due to its short half-life [64].

#### 4.12.6. Ecallantide (Kalbitor®, Shire HGT, Zug, Switzerland)

Ecallantide is a very potent, reversible and highly specific human plasma kallikrein inhibitor, whose half-life is 2.0 0.5 hours [8]. Its effectiveness has been demonstrated in different clinical trials [8, 14, 58, 65].

The United States Food and Drug Administration approved its use in December 2009 for the treatment of acute AE episodes in patients aged 16 years and older with C1-INH-HAE. Later, its use was extended to adolescents.

Acute allergic reactions, as well as anaphylaxis, have been reported [8].

It is administered subcutaneously at 30 mg (divided into 3 doses) and should be stored refrigerated [8]. One isolated case of STP with a low dose of ecallantide (10 mg) plus FFP, which did not result in AE, was reported [66].

However, the short half-life of ecallantide (2.0 0.5 hours) could restrict its use as short-term prophylaxis [8, 64]. It is necessary to carry out controlled studies or gain more experience in order to recommend its use in this indication.

#### 4.12.7. Recombinant human C1 inhibitor

Recombinant human C1-INH (rhC1INH) (Ruconest®/Rhucin®, Pharming Group NV, Leiden, The Netherlands) is produced in transgenic female rabbits in which the human C1NH gene has been inserted. The resulting rhC1INH is excreted in the rabbit milk, from which it is obtained by purification. The active substance is also termed conestat alfa. rhC1INH is effective in the treatment of acute AE attacks. rhC1INH is a C1-INH replacement therapy but with the advantages of the absence of the potential risk of transmitting blood-borne human infections and its suitability for large-scale production. It has a similar inhibitory potency and high structural analogy with phC1INH, although with a lower half-life (3 hours), due to differences in glycosylation. rhC1INH can be kept at room temperature (2–25C). A 50 U/kg dose (maximum 4200 U) was approved by the EMA in October 2010 for the treatment of acute AE attacks in > 18 years with C1-INH-HAE, although it has not yet been marketed in Spain. In 2016, its approval was extended to adolescents.

FDA in 2011. Icatibant acetate's self-administration was authorized by EMA in 2011. A registry

Icatibant acetate is only approved for adults. A study on its safety and efficacy in children is currently going on. There is no information about its safety profile in women who are pregnant. Regarding breastfeeding, lactation should be avoided 12 hours after icatibant acetate's administration. According to prescribing information, icatibant acetate should not be used in patients with active ischemic heart disease or those who have had an ischemic stroke in the

Isolated cases of STP with off-label icatibant acetate prior to some medical, dental or surgical procedures in patients with C1-INH-HAE have been published [38, 62, 63]. First, a thyroid

However, controlled studies are necessary. The short half-life (1–2 hours) of this agent and the fact that it blocks B2R but does not diminish the BK production may restrict its use in shortterm prophylaxis, as there is a theoretical risk of late local oedema. The trauma may result in an increase in local BK through FXII activation. While B2R blockage continues, no oedema is produced, but when B2Rs are released (after icatibant is eliminated from the body), an oedema episode could develop 6–8 hours after the surgery if BK remains high [8]. Other authors do not

Ecallantide is a very potent, reversible and highly specific human plasma kallikrein inhibitor, whose half-life is 2.0 0.5 hours [8]. Its effectiveness has been demonstrated in different

The United States Food and Drug Administration approved its use in December 2009 for the treatment of acute AE episodes in patients aged 16 years and older with C1-INH-HAE. Later,

It is administered subcutaneously at 30 mg (divided into 3 doses) and should be stored refrigerated [8]. One isolated case of STP with a low dose of ecallantide (10 mg) plus FFP, which did not

However, the short half-life of ecallantide (2.0 0.5 hours) could restrict its use as short-term prophylaxis [8, 64]. It is necessary to carry out controlled studies or gain more experience in

Recombinant human C1-INH (rhC1INH) (Ruconest®/Rhucin®, Pharming Group NV, Leiden, The Netherlands) is produced in transgenic female rabbits in which the human C1NH gene has been inserted. The resulting rhC1INH is excreted in the rabbit milk, from which it is obtained by purification. The active substance is also termed conestat alfa. rhC1INH is effective in the treatment of acute AE attacks. rhC1INH is a C1-INH replacement therapy but with

on the use of icatibant acetate in real life has confirmed its safety [61].

support its use as short-term prophylaxis due to its short half-life [64].

Acute allergic reactions, as well as anaphylaxis, have been reported [8].

biopsy without later local oedema was published [62].

4.12.6. Ecallantide (Kalbitor®, Shire HGT, Zug, Switzerland)

preceding 2 weeks [8].

194 A Comprehensive Review of Urticaria and Angioedema

clinical trials [8, 14, 58, 65].

its use was extended to adolescents.

result in AE, was reported [66].

order to recommend its use in this indication.

4.12.7. Recombinant human C1 inhibitor

FDA approved rhC1INH in 2014 for the treatment of acute AE attacks in adolescents and adult patients with C1-INH-HAE. The approved dose is 50 U/kg with a maximum dose of 4200 U administered intravenously.

A possible disadvantage of recombinant products is being potentially immunogenic and having the risk of producing neutralizing antibodies and/or allergic reactions. However, data on immunological safety are good, with no antibody production and no adverse immunological effects observed, except for an anaphylactic reaction in one patient with undisclosed rabbit allergy in a phase I clinical trial [8, 57].

rhC1INH is not recommended for short-term prophylactic management of C1-INH-HAE due to its short half-life [64].

Two consensus for the management of C1-INH-HAE in children have been published in 22 2016 [50, 65, 66].

Caballero et al. published a consensus document in which the management of STP in female patients was reviewed [67]. This information was updated later for HAE with and without C1-inhibitor deficiency [68].

The unavailability of STP should not delay an urgent procedure [69]. C1-INH-HAE should not be an obstacle for routine procedures [69].

In DOMFOP, it is advisable, provided that it is possible, to use regional anaesthesia to avoid the trauma that supposes oropharyngeal intubation [8, 13, 70].

It is impossible to predict which patients will develop angioedema after a determined medical/ surgical procedure. Moreover, a single patient could present or not present AE after the same procedure [70–72]. There are no controlled studies that assess STP efficacy; current available data come from observational studies: The risk of perioperative AE without STP (not taking into account dental procedures) is 6–31% [73]. There is no increased risk related to the procedure location or surgical area size [73]. The prevalence of AE attacks after dental procedures performed without STP varies from 5 to 37% of patients [71–73]. Farkas et al. observed that 40% of the patients who had not performed STP developed AE post-procedures, when assessing all the interventions as a whole [74]. Most times, AE is local, but distant AE has also been described [72, 73]. AE can be triggered by minor procedures, such as local injection of a local anesthetic [43], suture of a hand cut or an aesthetic injection of hyaluronic acid in the lips [72]. In some patients, perioperative angioedema was the first manifestation of C1-INH-HAE [72].

The study of STP use in large patients' series has shown that STP with pdhC1INH or AAs reduced the number of patients who present AE attacks after medical/surgical procedures [15, 71, 73]. pdhC1INH reduced the AE risk more after invasive procedures than AAs and AAs more than tranexamic acid [73]. It is important to emphasize that the AE risk after surgical/medical procedures is not completely avoided with STP [71, 73] and is independent of C1-INH-HAE severity [15] and thus, at least one therapeutic dose of a specific treatment for acute AE attacks should be available during and after the procedure [8, 74]. If the procedure involves the ENT area, the patient should be informed about the possibility to develop a laryngeal oedema, not only in the 12 hours following the procedure but also later [72], and one should establish an action plan for the patient.
