ICATIBANT

Icatibant injection (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]-L­seryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L[(3aS,7aS) octahydroindol-2-ylcarbonyl]-L­ arginine, acetate salt Icatibant injection is provided as a sterile, isotonic, and buffered solution of icatibant acetate in a single-dose, prefilled syringe for subcutaneous administration. Each mL of the solution contains 10 mg of icatibant (free base) which is equivalent to 11.38 mg of icatibant acetate. 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 (isotonicity reagent), glacial acetic acid (buffering agent), sodium hydroxide (pH adjuster) 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. icatibant-structure

Icatibant injection is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. Icatibant injection is a bradykinin B2 receptor antagonist indicated for treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. ( 1 )

30 mg injected subcutaneously in the abdominal area. ( 2.1 ) If response is inadequate or symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 hours. ( 2.1 ) Do not administer more than 3 injections in 24 hours. ( 2.1 ) Patients may self-administer upon recognition of an HAE attack. ( 2.2 ) 2.1 Recommended Dosing The recommended dose of Icatibant injection is 30 mg administered by subcutaneous (SC) injection in the abdominal area. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses may be administered in any 24 hour period. 2.2 Administration Instructions Icatibant injection should be inspected visually for particulate matter and discoloration prior to administration. The drug solution should be clear and colorless. Do not administer if the product contains particulates or is discolored. Attach the provided 25 gauge needle to the syringe hub and screw on securely. Do not use a different needle. Disinfect the injection site and administer Icatibant injection by subcutaneous injection over at least 30 seconds. Discard unused portion. Patients may self-administer Icatibant injection upon recognition of symptoms of an HAE attack after training under the guidance of a healthcare professional [see Patient Counseling Information ( 17 )].

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The most commonly reported adverse reactions were injection site reactions, which occurred in almost all patients (97%) in clinical trials. Other common adverse reactions occurring in greater than 1% of patients included pyrexia, transaminase increase, dizziness, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The safety of icatibant was evaluated in three controlled trials that included 223 patients who received Icatibant injection 30 mg (n=113), placebo (n=75), or comparator (n=38). The mean age at study entry was 38 years (range 18 to 83 years), 64% were female, and 95% were white. The data described below represent adverse reactions observed from the two placebo-controlled trials, consisting of 77 patients who received Icatibant injection at a dose of 30 mg SC, and 75 who received placebo. The most frequently reported adverse reactions (occurring in greater than 1% of patients and at a higher rate with Icatibant injection versus placebo) are shown in Table 1. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 Adverse reactions observed in >1% of patients with acute attacks of HAE and at a higher rate with Icatibant injection versus placebo in the placebo-controlled trials a ICATIBANT INJECTION (N =77) Placebo (N = 75) System Organ Class Preferred Term Subjects (%) Subjects (%) General disorders and administration site conditions Injection site reaction b Pyrexia 75 (97) 3 (4) 25 (33) 0 Investigations Transaminase increased 3 (4) 0 Nervous system disorders Dizziness 2 (3) 1 (1) a Events occurring within 14 days of study drug administration b Injection site bruising, Injection site hematoma, Injection site burning, Injection site erythema, Injection site hypoesthesia, Injection site irritation, Injection site numbness, Injection site edema, Injection site pain, Injection site pressure sensation, Injection site pruritus, Injection site swelling, Injection site urticaria, and Injection site warmth The third trial was active-controlled and was comprised of 35 patients who received Icatibant injection 30 mg and 38 patients who received the comparator. Adverse reactions for Icatibant injection were similar in nature and frequency to those reported in Table 1. In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with Icatibant injection 30 mg and could receive up to 3 doses of Icatibant injection 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 Icatibant injection for 987 attacks of acute HAE. Adverse reactions similar in nature and frequency were observed to those seen in the controlled phase of the trials. Other adverse reactions reported included rash, nausea, and headache in patients exposed to Icatibant injection. The safety of self-administration was evaluated in a separate, open-label trial in 56 patients with HAE. In this trial, the safety profile of Icatibant injection in patients who self-administered Icatibant injection was similar in nature and frequency to that of patients whose therapy was administered by healthcare professionals. 6.2 Immunogenicity Across repeated treatment in the controlled trials, 4 patients tested positive for anti-icatibant antibodies. Three of these patients had subsequent tests which were negative. No hypersensitivity or anaphylactic reactions were reported with Icatibant injection. No association between anti-icatibant antibodies and efficacy was observed. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of Icatibant injection: urticaria. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.1 ACE Inhibitors Icatibant injection is a bradykinin B2 receptor antagonist and thereby has the potential to have a pharmacodynamic interaction with ACE inhibitors where Icatibant injection may attenuate the antihypertensive effect of ACE inhibitors. Clinical trials to date have excluded subjects taking ACE inhibitors.