HAE long-term prophylaxis (LTP) & on-demand agent selection
FDA-approved long-term prophylaxis and on-demand agents for hereditary angioedema type I/II, with mechanism, dosing, and positioning by attack frequency and patient factors.
Evidence tier: Guideline-derived.
| Agent (class) | Indication & approval | Dose & key clinical notes |
|---|---|---|
| Lanadelumab (Takhzyro), anti-plasma kallikrein mAb [LTP] | Long-term prophylaxis (LTP) for HAE type I/II, age ≥2 y (FDA); adults and adolescents (EMA). First-choice LTP agent, superior attack reduction vs placebo (HELP trial: 87% reduction in attack rate). | 300 mg SC q2w; may extend to q4w if well-controlled at ≥6 months. SC self-injection, no IV access needed. Onset of prophylactic effect within 1-2 weeks. Inject-site reactions common (28%). Keep on-demand therapy available, LTP is not 100% protective. |
| Berotralstat (Orladeyo), oral plasma kallikrein inhibitor [LTP] | LTP for HAE type I/II. Age ≥12 y for the 150 mg capsule; FDA approved ORAL PELLETS in Dec 2025 extending use down to age 2. First oral LTP agent, eliminates injection burden. Phase 3 (APeX-2): 44% reduction in attack rate vs placebo at 150 mg. | 150 mg PO QD with food. Moderate renal or hepatic impairment: 110 mg QD. Drug interactions (CYP3A4 inhibitor/substrate). Less attack reduction than lanadelumab but oral, preferred for patients who prioritize oral therapy or have injection reluctance. |
| Subcutaneous C1-INH (pdC1-INH), Haegarda [LTP] | LTP for HAE type I/II, age ≥6 y (FDA). Phase 3 (COMPACT): 90% reduction in attack rate at 60 IU/kg q3-4d. | 60 IU/kg SC twice weekly. High volume injection (up to 10 mL per dose), injection burden and injection-site reactions. Blood product, not suitable for patients who refuse blood products. Well-tolerated long-term safety record. |
| Donidalorsen (Dawnzera), prekallikrein-directed antisense oligonucleotide [LTP] | LTP for HAE, FDA-approved 21 Aug 2025, age ≥12 y. A ligand-conjugated antisense oligonucleotide that reduces hepatic PREKALLIKREIN synthesis, it is not a kallikrein inhibitor and is unrelated to icatibant. Phase 3 OASIS-HAE: 81% reduction in monthly attack rate vs placebo. | 80 mg SC every 4 weeks by autoinjector; the interval may be extended to every 8 weeks in patients with good control. Subcutaneous, NOT oral. Flexible dosing interval is its main practical advantage. |
| Garadacimab (Andembry), anti-factor XIIa monoclonal antibody [LTP] | LTP for HAE, FDA-approved 16 Jun 2025, age ≥12 y. The only prophylactic agent targeting activated factor XIIa, upstream of kallikrein and bradykinin generation. Phase 3 VANGUARD: >99% median reduction in attack rate, with 62% of patients attack-free over the trial period. | 400 mg SC loading dose, then 200 mg SC once monthly by autoinjector. Once-monthly maintenance from the outset, which is the simplest schedule among the injectable LTP agents. |
| Icatibant (Firazyr), bradykinin B2-receptor antagonist [On-demand] | On-demand treatment of acute HAE attacks, age ≥2 y. First-choice self-injectable on-demand agent for most adults. | 30 mg SC q6h (max 3 doses/24 h). SC injection, can be given without IV access. Non-blood-product. Onset 1-2 h. The preferred self-injectable on-demand agent for adults who can self-inject. Pediatric weight-based dosing for age <18 y. |
| Sebetralstat (Ekterly), oral plasma kallikrein inhibitor [On-demand] | On-demand treatment of acute HAE attacks, age ≥12 y. First oral on-demand agent (FDA-approved 2025). | 600 mg PO at onset; repeat 600 mg at 3 h (max 1200 mg/24 h). First oral on-demand therapy, eliminates injection barrier that causes treatment delay. Onset similar to icatibant in KONFIDENT trial. Cannot be used if active swallowing compromise from throat swelling. |
| pdC1-INH (Berinert), C1-esterase inhibitor concentrate [On-demand] | On-demand treatment of acute HAE attacks, age ≥2 y. Preferred for pediatric, pregnant, or breastfeeding patients. Preferred in ER/hospital when IV access is established. | 20 IU/kg IV; may repeat if attack worsens. Blood product. Longest on-demand safety record. First-line in laryngeal attacks in ER settings (IV already established). First-choice in children and during pregnancy. |
| rhC1-INH (Ruconest), recombinant C1-esterase inhibitor [On-demand] | On-demand treatment of acute HAE attacks, adults. Avoid in rabbit allergy. | 50 IU/kg IV (max 4200 U); max 2 doses/24 h. Recombinant (rabbit-derived), same mechanism as pdC1-INH without blood product risks. Avoid if known rabbit allergy. |
| Ecallantide (Kalbitor), plasma kallikrein inhibitor [On-demand] | On-demand treatment of acute HAE attacks, age ≥12 y. Must be administered by a healthcare professional, not self-administered. | 30 mg SC (3 × 10 mg); max 2 doses/24 h. ~2% anaphylaxis risk (boxed warning), requires HCP administration. Appropriate in clinic/ER settings. |
| Fresh frozen plasma (FFP), last resort [On-demand] | On-demand: only when no approved agent is available. Can worsen HAE by supplying bradykinin-generating substrate. | ~2 units IV; prefer SD plasma. Secure the airway first in laryngeal attacks. Last resort, not a standard treatment option. |
| Anabolic androgens (danazol, stanozolol), obsolete LTP | Historical LTP, now rarely used due to significant long-term toxicity. Superseded by lanadelumab, berotralstat, pdC1-INH SC. | Danazol 50-200 mg QD (titrate to minimum effective dose). Avoid in children, pregnancy, hepatic disease. Risks: virilization, hepatotoxicity, hepatocellular adenoma, dyslipidemia. Consider only if newer LTP agents are inaccessible. |
Notes
- Lanadelumab is a reasonable first choice for many adults with HAE type I/II, with convenient SC q2w or q4w dosing, but note there are NO head-to-head trials among the first-line LTP agents. Comparisons across HELP, COMPACT, APeX-2, OASIS-HAE and VANGUARD are cross-trial and indirect, and WAO/EAACI treats the first-line LTP options as co-equal choices rather than ranking them.
- Berotralstat is the preferred LTP for patients with injection reluctance or phobia, the oral route removes the primary barrier to consistent prophylaxis.
- Every patient on LTP must also have ≥2 doses of self-injectable on-demand medication (icatibant or sebetralstat), LTP reduces but does not eliminate breakthrough attacks.
- Distinguish HAE type I/II (C1-INH deficiency/dysfunction, bradykinin-mediated) from histaminergic angioedema, antihistamines and corticosteroids are ineffective for HAE.
- HAE with normal C1-INH (formerly HAE type III), associated with F12 mutation (estrogen-sensitive): lanadelumab, icatibant, and C1-INH concentrates appear effective but evidence is more limited. Avoid estrogen-containing contraceptives.
- Pregnancy: pdC1-INH IV is the preferred on-demand agent and LTP option. Lanadelumab is not yet routinely recommended during pregnancy (limited data). Avoid androgens absolutely.
Evidence & citations
- Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema, The 2021 revision and update. Allergy. 2022;77(7):1961-1990. PMID 35006617
- Longhurst H, Cicardi M, Craig T, et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med. 2017;376(12):1131-1140. PMID 28328347
- Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021;148(1):164-172. PMID 33098856
- Riedl MA, Aygören-Pürsün E, Bernstein JA, et al. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks (KONFIDENT). N Engl J Med. 2024;391(1):32-43. PMID 38819658
- Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150. PMID 32898710
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