Icatibant

Firazyr (Shire Australia)
pre-filled syringe containing 30 mg/3 mL solution
Approved indication: hereditary angioedema
Australian Medicines Handbook Appendix A

Hereditary angioedema is a rare condition which is characterised by attacks of swelling that can occur anywhere in the body including face, larynx, gut or limbs. It can be painful, particularly with gastrointestinal attacks, and if the larynx is affected asphyxiation and death can occur. Most untreated patients will experience at least one acute attack a month which typically lasts for a few days.

The condition is caused by the absence or dysfunction of the C1 esterase inhibitor. This is thought to lead to increased vascular permeability due to unregulated bradykinin activation.

Icatibant, a synthetic decapeptide, has a similar structure to bradykinin and acts as a competitive antagonist blocking the receptors that bradykinin normally attaches to. Inhibiting bradykinin during an acute attack reduces ongoing inflammatory processes. Treatments for histamine-induced angioedema, such as corticosteroids, antihistamines or adrenaline, have no effect in patients with hereditary angioedema.

In a pilot study of 15 patients with hereditary angioedema, icatibant, given intravenously or subcutaneously, reduced recovery time from acute attacks compared to historical data from untreated attacks.¹ Based on these findings, randomised controlled trials were conducted.

In a head-to-head trial, subcutaneous icatibant (30 mg) was compared to oral tranexamic acid, another treatment for hereditary angioedema (FAST-2 trial). The median time to onset of symptom relief was shorter for icatibant than tranexamic acid (2 hours vs 12 hours) in the 74 patients.²

Icatibant also brought more rapid symptom relief from attacks compared to placebo (2.5 hours vs 4.6 hours) in another study trial of 56 patients (FAST-1 trial). However, this difference was not statistically significant. Not all patients in the controlled trials responded to icatibant immediately - four hours after the start of treatment, 20-33% of patients had not responded.²

Icatibant is given as a 3 mL subcutaneous injection in the abdomen so it is not surprising that the most common adverse events are injection-site reactions. These include erythema, swelling, burning, itching and pain. Recurrent angioedema attacks have been reported as serious adverse events with icatibant, but the relationship of these to treatment is unclear.

After injection, icatibant is rapidly absorbed with maximum concentrations being reached after about 30 minutes. It has a terminal half-life of 1-2 hours and its metabolites are mainly excreted in the urine. Cytochrome P450 enzymes are not involved in the metabolism of icatibant and dose adjustments are not needed in renal and hepatic impairment.

Bradykinin has been implicated in the protection of the myocardium during ischaemia. Icatibant could potentially antagonise this protective effect so it should be used with caution in people with acute ischaemic heart disease, unstable angina pectoris or who have recently had a stroke. Icatibant is not indicated for children.

It is not known if neutralising antibodies develop to icatibant. So far, no signs of increasing hypersensitivity have been observed in patients who have received repeated doses. With adequate training, patients can self-administer icatibant if the doctor thinks it is appropriate. However, if the symptoms are not resolving after two hours, or if the face, lips or pharyngeal area are affected, patients should seek immediate medical help.

Icatibant appears to be an effective treatment for hereditary angioedema, more so than tranexamic acid. It is not known how icatibant will compare to human C1 esterase inhibitor, another recently approved treatment for hereditary angioedema (Aust Prescr 2010;33:89-95).

Manufacturer provided the clinical evaluation

The Transparency Score is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.