e therapeutic dose for HAE) caused erythema, itching and hypotension in healthy subjects. No therapeutic intervention was necessary.
11 DESCRIPTION
FIRAZYR (icatibant) is a synthetic decapeptide with five non-proteinogenic amino acids. The chemical structure of icatibant acetate is presented in Figure 1.
Figure 1 Chemical Structure
Chemical name: D-Arginyl-L-arginyl-L-prolyl-L[(4R)-4-hydroxyprolyl]-glycyl-L[3-(2-thienyl)alanyl]-L-seryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L[(3aS,7aS)-octahydroindol-2-ylcarbonyl]-L-arginine, acetate salt
FIRAZYR is provided as a sterile, isotonic, and buffered solution of icatibant acetate in a single-use, prefilled syringe for subcutaneous administration. Each mL of the solution contains 10 mg of icatibant (free base). Each prefilled syringe delivers 3 mL of solution equivalent to a 30 mg icatibant dose. The solution is clear and colorless.
The solution also contains sodium chloride, glacial acetic acid, sodium hydroxide and water for injection with a pH of approximately 5.5. The solution does not contain preservatives.
Pharmacological class: Icatibant is a bradykinin B2 receptor antagonist.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 Pharmacodynamics
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 eva luated 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.
12.3 Pharmacokinetics
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 simil
