Icatibant (Firazyr) is a selective bradykinin B2 receptor antagonist used subcutaneously to treat acute attacks of hereditary angioedema (HAE) in adults. HAE is a rare, genetic syndrome that causes subcutaneous and submucosal edema that can affect the upper airways, face, extremities, genitals, and gastrointestinal tract. If an HAE attack involves the larynx or oropharynx, the attack can be life-threatening. Icatibant is administered upon recognition of an HAE attack. If symptoms persist or relapse after at least 6 hours following the initial icatibant dose, additional doses may be administered (up to 3 doses in 24 hours). Unlike ecallantide, icatibant may be administered by the patient after appropriate training by a healthcare professional. The FDA approved icatibant in August 2011.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
NOTE: Patients may self-administer icatibant upon recognition of acute hereditary angioedema (HAE) attack, after appropriate training under the guidance of a healthcare professional.
-For subcutaneous injection only.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Icatibant should be clear and colorless.
Subcutaneous Administration
-Supplied as a prefilled 30 mg syringe (10 mg/mL).
-Remove the prefilled syringe and 25-gauge needle from the carton. Attach the needle to the syringe hub; do not use a different needle. Do not remove needle cap until immediately before administration.
-Choose a site on the abdomen roughly 2 to 4 inches (5 to 10 cm) below the umbilicus on either side. The injection site should be at least 2 inches (5 cm) from any scars. Do not choose an area that is bruised, swollen, or painful.
-Disinfect injection site (abdominal area) and allow to dry.
-Uncap the needle. Hold prefilled syringe between fingers and thumb.
-Gently pinch the fold of disinfected skin. Hold the syringe at a 45 to 90 angle to the skin.
-Bring syringe toward skin and quickly insert the needle into the skin fold. Push the plunger, administer over at least 30 seconds, and until no medication remains in the syringe.
-Release skin and gently pull needle out. Dispose of the used syringe and needle in sharps disposal container immediately after use.
-May repeat at intervals of at least 6 hours if response is inadequate or symptoms recur. Do not administer more than 90 mg (3 doses) in 24 hours.
In clinical trials, adverse reactions reported in patients who received up to 3 doses of icatibant 30 mg administered at least 6 hours apart were consistent with that reported in patients receiving a single dose. In addition, the safety profile of icatibant in patients who self-administered their dose was similar to that of patients whose therapy was administered by healthcare professionals.
An injection site reaction occurred in almost all patients (97%) during clinical trials of icatibant. Reactions included local injection site bruising (ecchymosis), hematoma, burning, erythema, skin irritation, numbness, edema, pain, pressure sensation, pruritus, urticaria, and warmth. Rash also was reported during clinical trials in more than 1% of patients. Urticaria has been reported with postmarketing use of icatibant.
Dizziness was reported in 3% of patients during clinical trials of icatibant. Headache also was reported (incidence unknown).
Elevated hepatic enzymes (transaminase elevations) were reported in 4% of patients during icatibant clinical trials.
Fever was reported in 4% of patients during icatibant clinical trials. Nausea also was reported (incidence unknown).
During clinical trials, 4 patients tested positive for anti-icatibant antibodies (antibody formation), and 3 of these patients had negative subsequent tests. No hypersensitivity or anaphylactic reactions were reported, and no association between anti-icatibant antibodies and efficacy was observed.
Due to the potential for airway obstruction during an acute laryngeal HAE attack, patients should seek immediate medical attention in an appropriate health care facility in addition to icatibant treatment.
Available data from published literature and the pharmacovigilance database on icatibant use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Icatibant displayed no teratogenic effects in rats or rabbits at maternal doses up to 2.7 times and 13 times the maximum recommended human doses (MHRD). In embryo-fetal development studies involving rabbits that received subcutaneous icatibant on gestation days 7 to 18 and at doses approximately 0.025 times the MHRD and higher, the rates of premature birth and abortion were increased. Dose-related increases of percent pre-implantation loss, as well as, dose-related decreases of total implantations and in total number of live fetuses were observed when pregnant rabbits received icatibant doses up to 13 times the MRHD. In pre- and post-natal development studies in rats that received subcutaneous icatibant from gestation day 6 to post-partum day 20, delayed parturition and resulting deaths of dams were observed at doses 0.5 times the MRHD and higher and 2 times the MRHD and higher, respectively. At doses 2 times MRHD, fetal death and increased pup deaths were observed through post-partum day 4. Decreased pup hair growth and pup righting reflex impairment were observed with doses of 7 times the MRHD. Use icatibant during pregnancy only if the benefit outweighs the potential risk to the fetus. The effects of icatibant on labor or obstetric delivery have not been investigated; however, animal studies showed that icatibant causes delayed parturition and associated fetal death in rats and premature birth and abortion in rabbits. Delayed parturition occurred in rats at half the maximum recommended human dose.
There are no data on the presence of icatibant in human milk, the effects on the breastfed infant, or the effects on milk production. The manufacturer states that systemic absorption in infants following oral exposure of icatibant through breast milk is not expected. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Tiredness, drowsiness, and dizziness have been reported following the use of icatibant. Patients should be advised against driving or operating machinery if they feel tired or dizzy.
For the treatment of acute attacks of hereditary angioedema (HAE):
NOTE: Given the potential for airway obstruction during acute laryngeal HAE attacks, advise patients to seek immediate medical attention in an appropriate health care facility in addition to icatibant treatment.
Subcutaneous dosage:
Adults: 30 mg subcutaneously once. If response is inadequate or symptoms recur, may repeat dose at intervals of at least 6 hours. Max: 90 mg/24 hours.
For the treatment of ACE-inhibitor induced angioedema*:
Subcutaneous dosage:
Adults: 30 mg subcutaneously once.
Maximum Dosage Limits:
-Adults
30 mg/dose subcutaneously. May repeat at intervals of 6 hours; no more than 90 mg/24 hours subcutaneously.
-Geriatric
30 mg/dose subcutaneously. May repeat at intervals of 6 hours; no more than 90 mg/24 hours subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustments are needed.
*non-FDA-approved indication
Amlodipine; Benazepril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Angiotensin-converting enzyme inhibitors: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Benazepril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Captopril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Captopril; Hydrochlorothiazide, HCTZ: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Enalapril, Enalaprilat: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Fosinopril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Lisinopril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Lisinopril; Hydrochlorothiazide, HCTZ: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Moexipril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Perindopril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Perindopril; Amlodipine: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Quinapril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Quinapril; Hydrochlorothiazide, HCTZ: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Ramipril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Trandolapril: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Trandolapril; Verapamil: (Minor) Although clinical data are lacking, icatibant is a bradykinin B2 receptor antagonist and may theoretically potentiate the antihypertensive effect of ACE inhibitors.
Icatibant is a competitive inhibitor of the bradykinin B2 receptor. Hereditary angioedema (HAE) is caused by a deficiency of C1 esterase inhibitor. A deficiency of C1 esterase inhibitor may result in an increase in plasma bradykinin concentrations. The characteristic symptoms of HAE, localized swelling, inflammation, and pain, are thought to be caused by an excessive production of bradykinin. Icatibant inhibits bradykinin from binding to the B2 receptor, thus treating the symptoms of an acute HAE attack.
Icatibant is administered subcutaneously. Vd at steady state is 29 +/- 8.7 L. Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine. Less than 10% of the dose is eliminated as unchanged drug. Plasma clearance is 245 +/- 58 mL/minute, and mean half-life is 1.4 +/- 0.4 hours.
Intravenous icatibant (0.4 and 0.8 mg/kg over 4 hours) caused dose and time-dependent inhibition in the development of bradykinin-induced vasodilation, hypotension, and reflex tachycardia in healthy young subjects for 6 to 8 hours. Based on exposure-response analysis, a subcutaneous dose of 30 mg is predicted to be effective against bradykinin challenge for at least 6 hours.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
After a 30 mg subcutaneous dose, icatibant has an absolute bioavailability of 97%. The mean Cmax of 974 +/- 280 ng/mL is seen after 0.75 hours. The mean AUC is 2,165 +/- 568 ng x hour/mL, and there is no evidence of accumulation following three 30-mg doses administered 6 hours apart.
-Special Populations
Hepatic Impairment
No change in systemic exposure was seen in patients with mild to moderate hepatic impairment (Child Pugh scores of 5 to 8) compared to healthy patients.
Renal Impairment
The elimination of icatibant via the renal route is minor; therefore, renal impairment is not expected to affect the pharmacokinetics of icatibant.
Geriatric
Older patients exhibit lower clearance and higher systemic exposure of icatibant compared to younger patients. After a single 30 mg dose of icatibant, elderly patients showed an approximate 2-fold higher AUC compared to younger patients. However, only a minor difference (12% to 14%) in Cmax was seen between gender-matched elderly and younger patients. No differences in safety and efficacy between elderly patients and younger adults have been identified.
Gender Differences
There is a significant correlation between icatibant and body weight with reduced clearance seen with lower body weights. Therefore, females who typically weigh less than males exhibit lower clearance of icatibant, resulting in approximately 2-fold higher systemic exposure (AUC and Cmax) compared to males. Differences in efficacy between male and female patients have not been identified; dose adjustments are not needed.