ICATIBANT ZENTIVA 30 mg

1 INDICATIONS AND USAGE FIRAZYR ® (icatibant) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. FIRAZYR 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 )

2 DOSAGE AND ADMINISTRATION 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 FIRAZYR 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 FIRAZYR 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 FIRAZYR by subcutaneous injection over at least 30 seconds. Patients may self-administer FIRAZYR upon recognition of symptoms of an HAE attack after training under the guidance of a healthcare professional [see Patient Counseling Information (17) ] .

5 WARNINGS AND PRECAUTIONS Laryngeal attacks: Following treatment of laryngeal attacks with FIRAZYR, advise patients to seek immediate medical attention. ( 5.1 ) 5.1 Laryngeal Attacks Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in an appropriate healthcare facility immediately in addition to treatment with FIRAZYR.

6 ADVERSE REACTIONS 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 Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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 FIRAZYR 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 FIRAZYR 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 FIRAZYR 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 FIRAZYR versus placebo in the placebo-controlled trials Events occurring within 14 days of study drug administration FIRAZYR (N =77) Placebo (N = 75) System Organ Class Preferred Term Subjects (%) Subjects (%) General disorders and administration site conditions Injection site reaction 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 75 (97) 25 (33) Pyrexia 3 (4) 0 Investigations Transaminase increased 3 (4) 0 Nervous system disorders Dizziness 2 (3) 1 (1) The third trial was active-controlled and was comprised of 35 patients who received FIRAZYR 30 mg and 38 patients who received the comparator. Adverse reactions for FIRAZYR 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 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. 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 FIRAZYR. 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 FIRAZYR in patients who self-administered FIRAZYR 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 FIRAZYR. 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 FIRAZYR: 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.