Table 1 presents an overview of the current approval status of drugs used in the management of HAE. The individual HAE therapeutics and study results obtained in adults and children are summarized below; an overview of specific risks and adverse events for the treatment with the available drugs is provided in Table 2 and an assessment on use in pediatrics is provided in Table 3.
The consensus meeting relating to children and adolescents did not consider data from studies in pregnant and nursing mothers.
Human plasma-derived C1-INH (pdC1-INH) concentrates
Human C1-INH, a single-chain glycoprotein consisting of 478 amino acids with a molecular weight of approximately 105 kDa, is a member of the serine protease inhibitor family (SERPIN). Its main function is to inhibit the early activation steps of the complement and kallikrein–kinin systems (see Fig. 1).
Berinert is derived from human plasma. The risk of virus transmission is reduced by pasteurization, hydrophobic interaction chromatography, and virus filtration (nanofiltration) using two filters in series. The dosing recommendation is 20 U/kg body weight, intravenous. Berinert is approved for treating acute attacks of HAE in all pediatric age groups (Table 1).
In the randomized, double-blind, placebo-controlled study I.M.P.A.C.T.1, 124 patients (6 to 72 years of age) were treated for each attack (abdominal or facial) with 10 or 20 U/kg of Berinert or with placebo . With 20 U/kg Berinert, the median time to the onset of symptom relief was significantly shorter compared to placebo (0.50 vs. 1.5 h; p = 0.0025), whereas this time was not significantly shorter compared to placebo in patients receiving 10 U/kg Berinert (1.2 h). With 20 U/kg Berinert, the median time to the complete resolution of all HAE symptoms was significantly shorter compared to placebo (4.92 vs. 7.79 h; p = 0.0237).
In I.M.P.A.C.T.2, an open-label extension study of I.M.P.A.C.T.1, which investigated long-term therapy with Berinert, 1,085 attacks at any body location in 57 patients (10 to 53 years of age) were treated with 20 U/kg of Berinert . The median time to the onset of symptom relief was 0.46 h and was comparable for attacks at all body locations. The median time to complete resolution of all symptoms was 15.5 h (shortest for laryngeal attacks, 5.8 h). In 99 % of all attacks (1,073 of 1,085), a single dose of 20 U/kg was sufficient. One 10 year-old child and six adolescents between 12 and 16 years of age participated in the study; subgroup analyses indicated that the results were comparable across all age groups. There were no serious adverse effects, and no neutralizing anti-C1-INH antibodies were detected.
A retrospective study showed that 500 U of Berinert were efficacious for short-term prophylaxis . In a study on short-term prophylaxis with Berinert in adults and children, swelling attacks occurred in approximately 20 % of 577 tooth extractions performed without short-term prophylaxis, whereas they occurred in <12 % of the 128 tooth extractions with short-term prophylaxis . Evidence for effective long-term prophylaxis with Berinert has been recently published [14, 31].
In a recently published retrospective study, home therapy with Berinert was shown to be effective and safe in children and adolescents . In a pharmacokinetic study in 6 children and 34 adults (receiving on-demand treatment or individual replacement therapy), the median half-life of C1-INH activity was 32.9 h in children and 39.1 h (on-demand therapy) and 30.9 h (individual replacement therapy), respectively, in adult patients .
Cinryze is derived from human plasma. The risk of virus transmission is reduced by polyethylene glycol precipitation, pasteurization, and virus filtration (nanofiltration) using two filters in series. The dosing recommendation is 1,000 U (two vials), intravenous, irrespective of the body weight. Cinryze is also approved in adolescents for treating acute attacks of HAE, as well as for short-term and long-term prophylaxis (Table 1).
Two double-blind, randomized, placebo-controlled studies were conducted, one on the treatment of acute swelling attacks and another one on long-term prophylaxis . In both studies, there were no serious adverse effects.
In the acute-treatment study, 71 patients with swelling attacks involving the face, abdomen, or external genitalia were treated with 1,000 U of Cinryze or placebo. Patients not responding within 1 h received a second dose. If the symptoms did not subside or worsened after 4 h elapsed, the patients received another dose of 1,000 U (open-label rescue medication). The median time to onset of unequivocal relief with Cinryze was 2 h (placebo, 4 h; p = 0.048). The median time to the complete resolution of symptoms with Cinryze was 12.3 h (placebo, 25.0 h; p = 0.004).
In the long-term prophylaxis study, 24 patients (from the acute-treatment study) with at least 2 attacks per month received 1,000 U of Cinryze or placebo every 3 to 4 days (crossover after 12 weeks). During the 12 week treatment period, the number of swelling attacks was significantly lower with Cinryze compared to placebo (mean, 6.1 vs. 12.7 attacks; p < 0.0001).
In an interim analysis of an open-label extension study (median duration, 11 months), 88 patients had received Cinryze, some repeatedly, for the treatment of acute attacks, including laryngeal attacks . The repeated treatment also proved effective. Data on home therapy with Cinryze have not been published yet.
In various studies, a total of 46 patients <18 years of age were treated with Cinryze (2 to 5 years, 3 patients; 6 to 11 years, 17 patients; 12 to 17 years, 26 patients) . Overall, the safety, tolerability, and efficacy of Cinryze were comparable with those of adults in both acute treatment and long-term prophylaxis.
Recombinant human C1-INH concentrate (Ruconest®)
The active ingredient of Ruconest, conestat alfa, is a recombinant analogue of human C1-INH (a single-chain glycoprotein with a molecular weight of 71 kDa). Its glycosylation is not identical to that of human C1-INH, which is presumably the reason for its shorter half-life . Ruconest is produced recombinantly in transgenic New Zealand rabbits and purified from their milk. The dosing recommendation is 50 U/kg, intravenous (maximum dose of 4,200 U in patients with body weight >84 kg, maximum of two doses within of 24 h).
Two randomized, double-blind, placebo-controlled studies have been conducted for dose finding (100 U/kg vs. placebo and 50 vs. 100 U/kg vs. placebo) . Relief of symptoms was similar and significantly faster with 50 and 100 U/kg compared with placebo. There were no serious adverse effects. To date, no data have been published on use in children.
Kallikrein inhibitor and bradykinin receptor antagonists
Icatibant, a chemically synthesized decapeptide with a bradykinin-like structure, is a selective antagonist of the bradykinin B2 receptor. Its amino acid sequence makes icatibant resistant to enzymatic degradation. The dosing recommendation is 30 mg, subcutaneous (prefilled syringe), with a maximum of three doses within 24 h.
In the randomized, double-blind studies FAST-1 (placebo-controlled) and FAST-2 (tranexamic acid-controlled), 56 and 74 adults, respectively, received treatment with icatibant or the respective comparator for 1 attack . In FAST-1, the median time to clinically significant improvement was achieved after 2.5 h with icatibant (placebo, 4.6 h) and, in FAST-2, after 2.0 h (tranexamic acid, 12.0 h). No serious adverse effects were observed. A study in children and adolescents is currently in the concrete planning stage.
Ecallantide (DX-88) is a 60-amino-acid recombinant protein that reversibly inhibits the activity of kallikrein  (see Fig. 1). The dosing recommendation is 3 × 10 mg given subcutaneously, with a maximum of two doses within 24 h.
Two randomized, double-blind, placebo-controlled studies for approval in the USA with a similar study design have been published on the acute treatment of HAE. In the EDEMA3 study, 71 patients (minimum age, 10 years) were treated with 30 mg ecallantide or placebo for acute attacks . There was a significant improvement in the primary endpoint of the study (treatment outcome score 4 h after administration) for the active drug group compared to placebo.
In the EDEMA4 study in 96 patients, the mean symptom complex severity score and the treatment outcome score showed a significant improvement after 4 h in the active drug group compared to placebo . In a combined analysis of data from EDEMA3 and EDEMA4, the product was also demonstrated to have good efficacy and good tolerability . The most frequent adverse effects were headache, nausea, fever, diarrhea, nasopharyngitis, or local injection-site reactions [10, 19, 24, 30].
In many parts of the world, androgen derivatives (methyltestosterone, danazol, stanozolol, and oxandrolone) are used for short-term and long-term prophylaxis. C1-INH plasma levels rise with the administration of attenuated androgens, which provides at least a partial explanation for their effect.
The approval status differs in German-speaking countries (see Table 1). For long-term prophylaxis in adolescents, danazol is only approved in Switzerland . The prescribing information of this country states that adolescents >12 years of age should receive an initial daily dose of 400 to 600 mg and that the dose should be incrementally reduced down to the lowest effective dose. Experts explicitly do not recommend androgen therapy for long-term prophylaxis in children [6, 9, 27]. The dose recommended for short-term prophylaxis is 2.5 to 10 mg/kg daily (maximum, 600 mg daily) for 5 days before to 2 days after the intervention . The experts at the current consensus meeting considered this international recommendation as problematic for pediatric patients (see below).
There are no clinical studies in children and adolescents with HAE. A small case collection provides some data on the efficacy and tolerability at low doses .
Antifibrinolytics (ε-aminocaproic acid or tranexamic acid [cyclic analogue of ε-aminocaproic acid]) are chemically synthesized and exert their action in HAE by inhibiting the conversion of plasminogen to plasmin (see Fig. 1). Antifibrinolytics are less effective than attenuated androgens . The dosing recommendation for tranexamic acid is 20 to 50 mg/kg daily; the lowest effective dose should be aimed for .
Earlier double-blind, placebo-controlled studies on these compounds (in 5 to 18 patients, only a few children) showed a reduction in the frequency of attacks [18, 20, 29]. A recent prospective study comparing long-term prophylaxis in patients with and without tranexamic acid did not demonstrate any effect .