Hereditary Angioedema (HAE)

Ruconest® is a recombinant C1 esterase inhibitor indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults and adolescents.1 This is a prescription medication developed by Pharming Technologies B.V. that was approved by the European Medicines Agency (EMA) in 2010 and the US Food and Drug Administration (FDA) in 2014.1,2 Hereditary angioedema is an autosomal dominant disease characterized by localized episodes of swelling that typically result from the deficiency or malfunctioning of the plasma C1 inhibitor protein (C1-INH).3

Mode of Action and Use of Ruconest

In HAE, C1-INH plays a vital role in inhibiting proteases that regulate inflammation and preventing the activation of the complement and contact system. C1-INH blocks the activation of kallikrein, the formation of bradykinin is compromised. High levels of bradykinin are linked to HAE symptoms.4 Patients with HAE present with low levels of C1-INH, and Ruconest functions as a replacement therapy to increase the levels of functional C1-INH in the plasma.1,4

Ruconest is a recombinant analog of the human C1 esterase inhibitor that is purified from the milk of transgenic rabbits. The manufacturing process of this medication includes steps for the removal and inactivation of viruses.1 This drug is reconstituted in sterile water for injection and administered intravenously over about 5 minutes.1,2 

The recommended dose for treating an HAE attack varies with body weight and is 50 U/kg of body weight for adults weighing up to 84 kg. For adults who weigh more than 84 kg, 2 vials of Ruconest (4200 U) are recommended. A second vial may also be administered if an HAE attack persists, however, no more than 2 vials should be administered within a 24-hour period.1 

Ruconest is contraindicated in patients who are allergic to rabbits or rabbit-derived products and in patients who have a history of immediate hypersensitivity reactions. The most common adverse reactions reported are headache, nausea, and diarrhea.1

Get full prescribing information for Ruconest at MPR

Ruconest in Clinical Trials

The efficacy of Ruconest in preventing acute HAE attacks was evaluated in a multicenter, randomized, double-blind, placebo-controlled crossover phase 2 trial (NCT02247739).5 The trial revealed that prophylaxis with Ruconest reduced the frequency of HAE attacks.6 A different phase 2 trial that aimed to determine the safety, efficacy, and pharmacokinetics of Ruconest in HAE patients aged 2 to 13 years was also completed (NCT01359969).7 This trial granted the extension of Ruconest use for children who are at least 2 years of age.8

Two similar and independent randomized, double-blind, placebo-controlled phase 2/3 studies were performed in North America and Europe, with patients from Israel and Argentina also enrolled in the European trial. These studies aimed to assess the safety and efficacy of Ruconest in the treatment of HAE attacks (NCT00225147 and NCT00262301).9,10 In these trials, patients were randomized to receive either recombinant C1-INH or a placebo (saline). Efficacy was evaluated via patient-reported visual analog scale outcomes, and safety was evaluated by observing the adverse events and immunogenicity associated with the administration of the drug. The reported results of these trials showed that the administration of Ruconest at 100 U/kg and 50 U/kg was effective in the treatment of HAE attacks, causing a significant reduction in the time to the beginning of symptom relief when compared to the placebo (66 minutes, 122 minutes, and 495 minutes for 100 U/kg of Ruconest, 50 U/kg of Ruconest, and placebo, respectively). Additionally, the formation of antibodies following Ruconest administration was not detected.11 

A post hoc analysis of both randomized trials has been published, revealing 75 minutes as the median time to the beginning of symptom relief and reporting no relapses in the 24 hours after the HAE episode with Ruconest administration (50 U/kg). This analysis not only supported the efficacy of Ruconest treatment, but it also reported a sustained response to the drug in the treatment of acute HAE attacks for at least 3 days.12 A different phase 3 trial was conducted to confirm the efficacy, safety, and immunogenicity of the recombinant C1-INH in acute HAE when administered at 50 U/kg (NCT01188564).13

In an open-label extension of the European, Israeli, and Argentinean study, the efficacy and safety of the recombinant C1-INH as A first-line therapy in HAE and its effect on subsequent attacks were evaluated.3 In this study, patients were administered a single vial of Ruconest (2100 U), followed by up to 2 additional vials. Fifty-seven patients were treated in this extension study. Data showed that the treatment was well tolerated, with no immunogenicity triggered, and that a sustained relief of symptoms was reached within 4 hours following treatment in 87% of the patients. A high rate of therapeutic response was also maintained in the following episodes of HAE.3


1. Ruconest. Prescribing information. Pharming Healthcare Inc; 2020. Accessed June 10, 2022.

2. Ruconest. European Medicines Agency. Updated March 11, 2021. Accessed June 10, 2022.

3. Moldovan D, Reshef A, Fabiani J, et al. Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. Clin Exp Allergy. 2012;42(6):929-935. doi:10.1111/j.1365-2222.2012.03984.x

4. Plosker GL. Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema. BioDrugs. 2012;26(5):315-323. doi:10.2165/11206880-000000000-00000

5. A phase 2 HAE prophylaxis study with recombinant human C1 inhibitor. September 25, 2014. Updated December 8, 2017. Accessed June 10, 2022.

6. Riedl MA, Grivcheva-Panovska V, Moldovan D, et al. Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial. Lancet. 2017;390(10102):1595-1602. doi:10.1016/S0140-6736(17)31963-3

7. Safety of Ruconest in 2-13 year old hereditary angioedema (HAE) patients. May 25, 2011. Updated July 18, 2018. Accessed June 10, 2022.

8. Pharming receives European Commission approval for treatment of acute hereditary angioedema attacks in children with Ruconest®. News release. Pharming Group N.V.; April 30, 2020.

9. Recombinant human C1 inhibitor for the treatment of acute attacks in patients with hereditary angioedema (NCT00225147). September 23, 2005. Updated February 22, 2013. Accessed June 10, 2022.

10. Recombinant human C1 inhibitor for the treatment of acute attacks in patients with hereditary angioedema (NCT00262301). December 6, 2005. Updated October 2, 2012. Accessed June 10, 2022.

11. Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010;126(4):821-827.e14. doi:10.1016/j.jaci.2010.07.021

12. Bernstein JA, Relan A, Harper JR, Riedl M. Sustained response of recombinant human C1 esterase inhibitor for acute treatment of hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2017;118(4):452-455. doi:10.1016/j.anai.2017.01.029

13. Efficacy, safety and immunogenicity study of recombinant human C1 inhibitor for the treatment of acute HAE attacks. August 25, 2010. Updated August 7, 2015. Accessed June 10, 2022.

Reviewed by Kyle Habet, MD, on 6/26/2022.