Hereditary Angioedema

What is hereditary angioedema?

HAE is a rare genetic disorder characterized by recurrent bouts of swelling in the absence of itching or hives.^1-3 HAE-related swelling usually affects the face, extremities, gastrointestinal tract, genitals, and upper airway (e.g., larynx).¹ Swelling is due to fluid third-spacing, and can be so severe that hypotension develops.⁴

HAE-related swelling of the hands and feet is painful, and may limit activities of daily life.³

Abdominal attacks can cause severe pain, nausea, vomiting, diarrhea, and significant bloating of the abdominal wall.³

Swelling may be life-threatening when the airway is involved.¹ Respiratory tract attacks are the most dangerous, and carry a 30% mortality rate when left untreated. Up to half of all patients with HAE will have at least one laryngeal attack, making this an important concern.³ Attacks involving the upper airway must be treated emergently.¹

Most HAE episodes last about three to four days when untreated.¹²

What is the pathophysiology of hereditary angioedema?

There are three different types of HAE: HAE-1 (C1-INH deficiency), HAE-2 (defective C1-INH), and HAE with normal C1-INH, which is very rare.² The swelling of HAE1/2 has been linked to excessive bradykinin levels.² The pathophysiology of HAE with normal C1-INH has not been well-characterized, but may also involve bradykinin, particularly in patients with a mutation of factor XII.²

Bradykinin is a potent vasodilatory peptide that promotes vascular permeability.¹ C1 esterase inhibitor normally hinders kallikrein- and activated factor XII-mediated bradykinin production.⁵

What are some important concepts in hereditary angioedema treatment?

Current HAE medications provide C1 esterase inhibitor enzyme, inhibit kallikrein inhibition, or block bradykinin receptors to reduce bradykinin levels and/or activity.¹ The chart below provides an overview of these medications.

HAE management includes treatment of acute attacks, pre-procedural prophylaxis (especially for procedures near the upper airway, such as dental procedures or intubation) and long-term prophylaxis.²

Long-term prophylaxis is used to reduce the frequency and/or severity of attacks, thus minimizing the impact of HAE on quality of life.¹ The decision to use long-term prophylaxis should be individualized, based on frequency and severity of attacks, impact on quality of life, the patient’s access to acute medical care, and the patient’s ability to self-administer acute treatment.¹ All patients must have a plan for treating acute attacks (i.e., prophylaxis does not prevent 100% of attacks).¹

Acute treatment should be available during and after procedures, even if preprocedural prophylaxis was given.¹

Antihistamines, epinephrine, and corticosteroids are not effective HAE treatments.¹

Acute treatments reduce duration and severity of attacks.² Treatments that can be caregiver- or self-administered are preferred because treatment is more effective the earlier it is started.¹

• Symptoms usually start responding to treatment within 30 to 120 minutes of administration.⁹

Analgesics and antiemetics may be used to treat nausea, vomiting, diarrhea, and pain. Aggressive hydration may be needed.⁴

What medications have been associated with hereditary angioedema flares?

HEA attacks in some patients may be triggered by:¹

• angiotensin-converting enzyme (ACE) inhibitors
• estrogen-containing contraceptives
• estrogen-replacement therapy
• dipeptidyl peptidase IV inhibitors (i.e., “gliptins” for diabetes)
• neprilysin inhibitors (sacubitril; one of the medications found in Entresto)

What are some practical considerations for hospitals that care for hereditary angioedema patients?

Continue patients’ long-term prophylaxis in the hospital to prevent flare-ups during hospitalizations. Consider allowing patients to bring their own medication from home.

Medication reconciliation should address the most recent administration date to ensure correct timing for the next dose.

Keep at least one HAE medication on formulary for treatment of acute attacks. Involve your allergists in formulary decisions. Look into consignment-based stocking to reduce cost.

PROPHYLAXIS

Cinryze
(C1 esterase inhibitor, human)

Adults and adolescents (U.S., age ≥12 years): 1,000 units IV twice weekly (every 3 to 4 days). Infuse over 10 minutes.

Ages 6 to 11 years (U.S): 500 units IV twice weekly (every 3 to 4 days). Infuse over 5 minutes.

Pre-procedure prophylaxis, ages ≥2 years of age (off-label): 1,000 units IV within 24 hours before the procedure (500 units if 10 to 25 kg).¹

The most common side effects are headache, nausea, vomiting, rash, and fever. May pose risk of viral transmission. Rare thromboembolic events have been reported with C1 esterase inhibitors.

Berinert
(C1 esterase inhibitor, human)

Pre-procedure prophylaxis (off-label): 1,000 units (adults) IV; 15 to 30 units/kg IV (pediatrics) within six hours before the procedure. Ensure at least two additional doses are available.¹

The most common side effect is altered taste. May pose risk of viral transmission. Rare thromboembolic events have been reported with C1 esterase inhibitors.

Haegarda
(C1 esterase inhibitor, human)

Adults and adolescents (U.S., age ≥12 years): 60 units/kg SC twice weekly (every 3 to 4 days).

The most common side effects are injection site reaction, hypersensitivity, nasopharyngitis, and dizziness. May pose risk of viral transmission. Rare thromboembolic events have been reported with C1 esterase inhibitors. Preferred over intravenous options for long-term prophylaxis.

Takhzyro
(lanadelumab)

Age ≥12 years: 300 mg SC every two weeks. May reduce frequency to once every four weeks if the patient has been well controlled (e.g., no attacks) for >6 months.

The most common side effects are injection site reactions, myalgia, dizziness, diarrhea, upper respiratory infections, headache, and rash.

Danazol

Pre-procedure prophylaxis (adult): 2.5 to 10 mg/kg/day (max 600 mg/day), starting five days pre-procedure and continuing for two to three days post-procedure.¹

Long-term prophylaxis (adult): 200 mg three times a day. Based on response, the dose can be increased to a total daily dose of 800 mg, or reduced by 50% every one to three months to the minimum effective dose.⁷ To minimize side effects, attempt to reduce the dose to ≤200 mg/day.¹

Not first-line due to side effects and inferior efficacy.¹

Androgenic side effects and weight gain are common.⁷ Liver enzymes should be monitored.⁷ Muscle pain and depression have also been reported.⁷ Not for use during pregnancy or breastfeeding, or in children.^1,6

Tranexamic acid

Pre-procedure prophylaxis: 25 mg/kg two to three times daily (max 3 to 6 g/day) starting five days before and continuing for two to five days afterward.¹

Long-term prophylaxis: 30 to 50 mg/kg/day (max 6 g), in two or three divided doses.¹

Not first-line due to side effects and inferior efficacy.¹

Take with food due to gastrointestinal upset. May cause myalgia and creatine kinase elevation. Poses theoretical thrombosis risk.²

Fresh frozen plasma (FFP)

Pre-procedure prophylaxis: 2 units in adults or 10 mL/kg for children given one to two hours pre-procedure.¹

Reserve for emergent situations when first-line HAE medications are not available.^1,2 Poses risk of infusion reactions, lung injury, and viral transmission.⁸ Theoretically, could worsen HAE; contains bradykinin precursors.¹

TREATMENT

Berinert
(C1 esterase inhibitor, human)

20 units/kg IV x one dose. Infuse at 4 mL/minute.

The most common side effect is altered taste. May increase HAE-associated pain. May pose risk of viral transmission. Rare thromboembolic events have been reported with C1 esterase inhibitors. Can be used to treat HAE with normal C1-INH.¹

Cinryze
(C1 esterase inhibitor, human)

Off-label: 1,000 units IV within 24 hours before the procedure (500 units if <25 kg).¹

The most common side effects are headache, nausea, vomiting, rash, and fever. Poses risk of viral transmission. Rare thromboembolic events have been reported with C1 esterase inhibitors.

Firazyr
(icatibant)

Adult: 30 mg SC x one dose. May be repeated every 6 hours x two more doses. Max dose: 3 injections in 24 hrs.

Ages 2 to 17 years (Canada):

• 12 to 25 kg: 10 mg
• 26 to 40 kg: 15 mg
• 41 to 50 kg: 20 mg
• 51 to 65 kg: 25 mg
• >65 kg: 30 mg

In clinical trials, only one dose per attack was given.

Injection site reactions occur in almost all patients. Patients can self-inject, but advise them to also seek medical treatment for laryngeal involvement.

Can be used to treat HAE with normal C1-INH.¹

Kalbitor (U.S.)
(ecallantide)

Three SC injections of 10 mg/L, for a total dose of 30 mg x one dose. May repeat (30 mg) one time per 24 hours for a resistant attack.

Anaphylactic reactions have been reported; must be administered by a healthcare professional where anaphylaxis can be handled. The most common side effects are headache, nausea, diarrhea, fever, injection site reactions, and nasopharyngitis.

Ruconest (U.S.)
(C1 esterase inhibitor, recombinant)

50 units/kg x one dose (max 4,200 units)

Derived from a rabbit protein; may cause allergic reactions in patients with rabbit allergy. The most common side effects are headache, nausea, and diarrhea.

Fresh frozen plasma (FFP)

2 units IV (adults) or 10 mL/kg (children), given every 2 to 4 hours until clinical improvement is achieved.^10,11

Reserve for emergent situations when first-line HAE medications are not available.^1,2 Poses risk of infusion reactions, lung injury, and viral transmission.⁸ In theory could worsen HAE because it contains bradykinin precursors.¹