Version May 2024
Hereditary angioedema (HAE), prophylaxis: Limited data available (Riedl 2017):
Adolescents ≥13 years:
<84 kg: IV: 50 units/kg twice weekly; maximum dose: 4,200 units/dose.
≥84 kg: IV: 4,200 units twice weekly.
Note: Dosing based on a small multinational phase II randomized double-blind placebo-controlled crossover trial in patients with frequent attacks (defined as a history of ≥4 HAE attacks per month for ≥3 consecutive months) and C1 inhibitor levels <50% of normal. Both weekly and twice-weekly administration of C1 inhibitor (recombinant) significantly reduced the number of HAE attacks after 4 weeks of therapy compared with placebo; however, the twice-weekly regimen resulted in more consistent achievement of ≥50% reduction in attacks (Riedl 2017). May reduce frequency of administration to once weekly, ensuring maintenance of symptom control; once-weekly dosing was shown to be more effective than placebo but with the potential for more frequent attacks compared with twice-weekly dosing (Reshef 2013; Riedl 2017).
Hereditary angioedema (HAE), treatment of acute attacks (non-laryngeal):
Children ≥5 years: Limited data available: IV: 50 units/kg as a single dose, maximum dose: 4,200 units/dose. Dosing based on a small open-label phase II multinational study (n=20 subjects accounting for 73 HAE attacks; age range: 5 to 14 years); approximately 96% (70/73) HAE attacks were treated with a single dose; time to beginning of symptom relief occurred in a median of 60 minutes and time to minimal symptoms occurred in a median of 122.5 minutes; instances of multiple doses included: 1 patient received a second dose during 1 attack and another received a second dose during 2 separate attacks for persistent symptoms; treatment was well-tolerated overall (Reshef 2019).
Adolescents: Note: Unlike human C1 inhibitors, efficacy not established in patients with laryngeal attacks due to a limited number of patients; in some trials, patients with laryngeal attacks were excluded (Valerieva 2018; manufacturer's labeling).
Initial dosing:
<84 kg: IV: 50 units/kg as a single dose, maximum dose: 4,200 units/dose.
≥84 kg: IV: 4,200 units as a single dose.
Redosing: If attack symptoms persist, 1 additional dose may be administered; no more than 2 doses may be administered per 24 hours. In trials, patients were administered a second dose 4 hours after the initial dose if relief not achieved; median time to minimal symptoms was about 5 hours (range: 4 to 12 hours) (Riedl 2014).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "C1 inhibitor, recombinant human: Drug information")
Hereditary angioedema attacks, treatment:
Note: To minimize morbidity and mortality, should be self-administered (or administered by a caregiver) at the onset of an attack whenever possible (US HAEA [Busse 2021]).
IV:
Weight <84 kg: 50 units/kg as a single dose; some experts recommend rounding up the dose to utilize a full vial (2,100 units/vial); maximum single dose: 4,200 units (Zuraw 2022; manufacturer's labeling).
Weight ≥84 kg: 4,200 units as a single dose (manufacturer's labeling).
Repeat dosing: A clinical response is usually observed within ~2 to 4 hours of the initial dose; after ~2 to 4 hours, a second dose may be given if symptoms worsen, but this is rarely needed; no more than 2 doses may be administered per 24 hours, maximum daily dose: 8,400 units/day (Zuraw 2010; Zuraw 2022; manufacturer's labeling).
Hereditary angioedema attacks, long-term prophylaxis (off-label use) (alternative agent): IV:
Weight <84 kg: 50 units/kg (maximum dose: 4,200 units) twice weekly (Riedl 2017).
Weight ≥84 kg: 4,200 units twice weekly (Riedl 2017).
Note: May reduce frequency of administration to once weekly, ensuring maintenance of symptom control; once-weekly dosing was shown to be more effective than placebo but with the potential for more frequent attacks compared with twice-weekly dosing (Reshef 2013, Riedl 2017). Dosing more than twice weekly has not been studied.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Immunologic: Antibody development (6% to ≤17%; anti-C1INH, anti-rhC1INH, and anti-host-related impurities)
1% to 10%:
Central nervous system: Headache (10%; includes procedural headache), vertigo (3%)
Dermatologic: Burning sensation of skin (2%), erythema (2%; marginatum)
Gastrointestinal: Diarrhea (≥2%), nausea (≥2%)
Hematologic & oncologic: C-reactive protein increased (2%), increased serum fibrinogen (fibrin D-dimer: 2%), lipoma (2%)
Hypersensitivity: Angioedema (3%)
Neuromuscular & skeletal: Back pain (3%)
Respiratory: Sneezing (2%)
<1%, postmarketing and/or case reports: Abdominal pain, anaphylaxis, skin rash
Life-threatening immediate hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations or any component of the formulation; allergy to rabbits or rabbit-derived products. Note: Patients with a clinical history of a rabbit allergy and/or cow's milk allergy who are negative on skin testing to C1 inhibitor (recombinant) have tolerated a subcutaneous challenge of C1 inhibitor (recombinant) (van den Elzen 2016).
Concerns related to adverse effects:
• Hypersensitivity: Severe hypersensitivity reactions (eg, urticaria, hives, tightness of the chest, wheezing, hypotension, anaphylaxis) may occur during or after administration. Signs/symptoms of hypersensitivity reactions may be similar to the attacks associated with hereditary angioedema, therefore, consideration should be given to treatment methods. In the event of acute hypersensitivity reactions to C1 inhibitor therapy, treatment should be discontinued and appropriate treatment should be instituted.
• Thrombotic events: Serious arterial and venous thromboembolic events have been reported at recommended doses in patients with risk factors (eg, presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, immobility). Closely monitor patients with preexisting risks for thrombotic events during and after administration.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Ruconest: 2100 units (1 ea) [contains rabbit protein]
No
Solution (reconstituted) (Ruconest Intravenous)
2100 unit (per each): $9,150.00
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Parenteral: IV: Administer through a separate infusion line as a slow IV injection over ~5 minutes. Appropriately trained patients may self-administer upon recognition of a hereditary angioedema (HAE) attack. In pediatric treatment trials for HAE, doses in children ≤12 years of age were administered over 5 minutes (Reshef 2019).
IV: Administer by a separate infusion line as a slow IV injection over ~5 minutes. Appropriately trained patients may self-administer upon recognition of an HAE attack.
Store intact vials at 2°C to 25°C (36°F to 77°F) for up to 48 months; do not freeze. Protect from light. Reconstituted solution may be stored at 2°C to 8°C (36°F to 46°F) for ≤8 hours; do not freeze. Discard unused portion.
Treatment of acute attacks of hereditary angioedema (HAE) (FDA approved in ages ≥13 years and adults). Note: Efficacy has not been established in HAE laryngeal attacks. Has also been used for prevention of HAE attacks.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: May enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Estrogen Derivatives: May enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Outcome data following maternal administration of C1 inhibitor (recombinant) for the treatment of hereditary angioedema (HAE) attacks during pregnancy are limited (Grivcheva-Panovska 2020; Hakl 2018; Moldovan 2019). In one case, treatment of the mother may have also resolved an attack in the fetus (Grivcheva-Panovska 2020).
C1 inhibitor (human) is preferred for the treatment and prophylaxis of HAE during pregnancy. Patients with HAE should be monitored closely during pregnancy and for at least 72 hours after delivery (WAO/EAACI [Maurer 2022]).
Monitor for signs/symptoms of hypersensitivity reactions and thrombotic events. Prior to initiation for long-term prophylaxis, test for immunoglobulin E (IgE) antibodies against rabbit antigens; repeat testing annually or after 10 treatments, whichever occurs first (Craig 2012).
C1 inhibitor, a serine protease inhibitor (serpin), regulates the activation of the complement and contact system pathways by irreversibly binding target proteases. Suppression of contact system activation by C1 inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate vascular permeability that leads to clinical manifestations of hereditary angioedema (HAE) attacks by preventing the generation of bradykinin.
Onset of action: Onset of symptom relief: Median: 90 minutes
Distribution: Vss: ~3 L
Half-life elimination: ~2.5 hours
Time to peak: ~0.3 hours
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