Off-label Firazyr Use Found Safe in Small Study, but Biomarkers May Help

Firazyr (icatibant), when used off-label to treat acute non-hereditary angioedema, can elicit different treatment responses, and its use — and best use — needs to be better understood by doctors treating attacks in this patient group, a real-world study from Australia reports.

Biomarkers that could more easily distinguish histamine-mediated angioedema from attacks triggered by the overproduction of bradykinin, a pro-inflammatory peptide, are also needed, its researchers wrote. Bradykinin is the cause of all forms of hereditary angioedema and some non-hereditary forms.

Data also highlighted the overuse of adrenaline in these patients, which is effective only against angioedema caused by histamine, a molecule involved in allergic reactions.

The study, “Real‐world off‐label use of icatibant for acute management of non‐hereditary angioedema,” was published in the Internal Medicine Journal.  

Firazyr, a medication that blocks bradykinin activity, is approved by the U.S. Food and Drug Administration (FDA) to treat acute attacks of hereditary angioedema (HAE) in adults. In Australia, it is approved to treat acute HAE attacks in patients ages 2 and older with C1-esterase-inhibitor deficiency.

The treatment, administered as a subcutaneous (under-the-skin) injection, can also be used off-label to treat patients with bradykinin-mediated non-hereditary angioedema.

Researchers analyzed such off-label use in non-hereditary, or acquired, angioedema patients in South Australia, based on pharmacy records between January 2012 and August 2018.

A total of 18 patients (eight men and 10 women) with a median age of 62 (range 18–95) were given Firazyr to manage acute angioedema. Eleven patients (61%) also had high blood pressure (hypertension).

Most of these patients (78%) were treated with Firazyr in the emergency department of a hospital or after admission, and seven (39%) were prescribed the treatment by an immunologist. One patient, a 56-year-old man, had recurrent attacks that required multiple treatments with Firazyr.

No treatment-related adverse events were reported, but differences in its use were highlighted by researchers.

All 18 patients experienced angioedema in the face, lips, tongue, or upper airway, with four (22%) also having swelling of the larynx or hypopharynx (lower throat). 

“Three of 18 of patients were given icatibant for AE [adverse event] only involving lip or anterior tongue, where arguably it is not indicated,” the researchers wrote. “The same number received icatibant more than 24 h[ours] after symptom onset, even though early treatment with icatibant is more likely to be efficacious.”

In all but four cases, angioedema was triggered by medication, including angiotensin converting enzyme (ACE) inhibitors in seven patients (32%), and angiotensin receptor blockers (ARBs) and tissue plasminogen activators in three patients each (17%). Of note, ACE inhibitors and ARBs are commonly used to lower blood pressure, while tissue plasminogen activators are used to dissolve blood clots, such as those that can follow a stroke.

Two patients (11%) had acquired C1 inhibitor deficiency associated with non-Hodgkin lymphoma, a type of blood cancer, and two cases were idiopathic (without a known cause).

Patients generally responded well to Firazyr treatment. The median time to symptom resolution after treatment was 18 hours across the whole group, and nine hours among those with ACE inhibitors. In previous reports, the median post-treatment resolution time was eight hours for ACE inhibitor-induced angioedema and 8.5 to 10 hours for HAE. 

The time to initial response to treatment was four hours, compared with one to two hours in previous reports. The median time between symptom onset and treatment was 6.5 hours, but this varied widely (1–83 hours).

Patients stayed at a hospital for a median of 36 hours, excluding the patient admitted for a stroke that was complicated by angioedema.

Prior to Firazyr, 83% of these patients had received adrenaline, and two had been intubated as it was given during surgery. After Firazyr’s use, there were no reports of adrenaline or intubation need.

“While … a rapidly available biomarker might help to differentiate between histaminergic and non-histaminergic [angioedema], a clinical algorithm incorporating patient medication use, background medical conditions, [angioedema] location, absence of allergic triggers and lack of response to anaphylaxis treatments might help to avoid overuse of adrenaline and facilitate the timely and appropriate administration of icatibant,” the researchers concluded.

They acknowledged their study was limited by its small size, lack of a comparison group, and retrospective nature, which may have affected the estimations given factors such as response to treatment time.