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Mechanism of Action

Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE.


Following bradykinin challenge, intravenous administration of FIRAZYR caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. FIRAZYR intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion. Based on exposure-response analysis, a subcutaneous dose of 30 mg FIRAZYR is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown.

The effect of FIRAZYR 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 90 mg is adequate to represent the high exposure clinical scenario.


The pharmacokinetics of FIRAZYR has been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of FIRAZYR in patients with HAE is similar to that in healthy subjects.

The absolute bioavailability of FIRAZYR following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of FIRAZYR to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng·hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart. Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 29.0 ± 8.7 L.

Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug. Icatibant is not degraded by oxidative metabolic pathways, is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4.

Special populations

Hepatic Impairment

The pharmacokinetic parameters of FIRAZYR were found to be generally comparable between healthy subjects (n=8) and mild to moderate (Child Pugh scores of 5 to 8) hepatic impaired patients (n=8) following a dose of 0.15 mg/kg/day as continuous intravenous infusion over 3 days. In a separate study, FIRAZYR clearance in subjects with a wide range of hepatic impairment (Child-Pugh scores of 7 to 15) was similar to that in healthy subjects. No dose adjustment is necessary for patients with impairment of hepatic function [See Use In Specific Populations].

Renal Impairment

Since renal clearance of icatibant is a minor eliminating pathway, renal impairment is not expected to affect the pharmacokinetics of FIRAZYR and hence a formal renal impairment study was not conducted for FIRAZYR. In 10 patients with hepatorenal syndrome (GFR 30-60 mL/min), clearance of FIRAZYR was not dependent on renal function and therefore, did not show any observable differences in the plasma levels of icatibant or its metabolites compared to subjects with normal renal function. No dose adjustment is necessary for patients with impairment of renal function [See Use In Specific Populations].

Age and Gender

Three 30 mg subcutaneous doses of FIRAZYR administered every 6 hours were studied in young (18 to 45 years of age) and elderly (over 65 years of age) healthy male and female subjects. Following single-dose administration of 30 mg subcutaneous FIRAZYR, elderly males and females showed approximately 2-fold higher AUC compared to young males and females, respectively. However, only minor differences (~12-14%) between Cmax of gender–matched elderly and young subjects were observed. Older subjects tend to exhibit lower clearance compared to younger subjects and therefore higher systemic exposure. Gender effect on FIRAZYR pharmacokinetics was also observed in addition to age effect. Clearance of FIRAZYR is significantly correlated with bodyweight with lower clearance values noted for lower bodyweights. Hence, females with typically lower body weights compared to males exhibit lower clearance values, resulting in approximately 2-fold higher systemic exposure (both AUC and Cmax) compared to males. Differences in efficacy and safety between elderly and younger patients and male and female patients have not been identified. Dose adjustment based on age and gender is not warranted.

Drug Interactions

Formal drug-drug interaction studies were not conducted with FIRAZYR. Icatibant metabolism is not mediated by CYP450 enzymes. In vitro study did not show any significant inhibition and/or induction of drug metabolizing CYP450 enzymes; therefore, metabolic drug interactions between FIRAZYR and CYP450 substrates, inhibitors and inducers are not expected.

Animal Toxicology and/or Pharmacology

The B2 receptor has been implicated in the cardioprotective effects of bradykinin and antagonism of this receptor could potentially have negative cardiovascular effects during reperfusion after acute ischemia. Icatibant decreased coronary blood flow in the isolated guinea pig heart and aggravated the duration of post-ischemic reperfusion arrhythmias in the isolated rat heart. Intracoronary infusion of icatibant in an anesthetized myocardial infarction dog model increased mortality rate 2-fold over saline ischemia. There is limited human experience in acute ischemia. FIRAZYR should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient.

Clinical Studies

The efficacy and safety of FIRAZYR for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Among the 223 patients in these studies, the mean age was 38 years, 64% were female, and 95% were white. Approximately 57% of patients reported use of attenuated androgens, antifibrinolytic agents, or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling.

Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients with a median age of 36 years. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either FIRAZYR 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label FIRAZYR 30 mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-itemVAS score (Figure 2). The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with FIRAZYR (n=43) compared to placebo (n=45) was 2.0 hours [95% CI 1.5, 3.0] versus 19.8 hours [95% CI 6.1, 26.3], respectively (p < 0.001).

Figure 2 : Time to 50% reduction from baseline in 3-item VAS score.

Time to 50% reduction from baseline in 3-item VAS score - Illustration

Other evaluated endpoints included time to almost complete symptom relief (VAS < 10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8.0 versus 36.0 hours for FIRAZYR and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with FIRAZYR used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo.

In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received FIRAZYR 30 mg for the treatment of an acute HAE attack. Across the three trials, FIRAZYR had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours.

Recurrent attacks

In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg FIRAZYR for 987 attacks of acute HAE in these trials. In an assessment of the first 5 FIRAZYR-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-itemVAS score were similar across attacks (2.0, 2.0, 2.4, 2.0, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of FIRAZYR.

Laryngeal attacks

A total of 60 patients with laryngeal attacks were treated with FIRAZYR in the controlled trials. Efficacy results were similar to those observed for non-laryngeal (cutaneous and abdominal) sites of attack.


Self-administration of FIRAZYR by 56 patients was assessed in an open label trial. Patients who administered FIRAZYR during an acute attack of HAE had a median time to 50% reduction from the pretreatment composite 3-itemVAS score of 2.6 hours.

Last reviewed on RxList: 9/1/2011
This monograph has been modified to include the generic and brand name in many instances.


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