Data from FDA - Curated by Marshall Pearce - Last updated 07 December 2017

Indication(s)

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)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions

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 Shire Human Genetic Therapies at 1-800-828-2088 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 can not 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 trialsEvents 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 Similar adverse reactions have been observed in postmarketing use as compared to the clinical trials.

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.

Usage information

Dosing and administration

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)].

Use in special populations

8 USE IN SPECIFIC POPULATIONS Elderly patients demonstrate increased systemic exposure to icatibant.

Differences in efficacy and safety between elderly and younger patients have not been identified.

(8.5) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women.

Icatibant was not teratogenic in rats or rabbits; however, it caused delayed parturition, fetal death, and pre-implantation loss in rats and premature birth, abortion, fetal death, and pre-implantation loss in rabbits.

FIRAZYR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Delayed parturition and fetal death in rats occurred at 0.5 and 2-fold, respectively, the maximum recommended human dose (MRHD) (on an AUC basis at maternal doses of 1 and 3 mg/kg, respectively).

Increased pre-implantation loss in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

In rabbits, premature birth and abortion rates increased at a dose that was less than 1/40th the MRHD (on a mg/ m2 basis at a maternal dose of 0.1 mg/kg).

Studies in rabbits also indicated that pre-implantation loss and increased fetal deaths occurred at 13-fold greater than the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

Nonteratogenic effects: Impairment of pup air-righting reflex and decreased pup hair growth in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

8.2 Labor and Delivery There are no human studies that have investigated the effects of FIRAZYR on preterm labor or labor at term; 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 0.5-fold times the MRHD (on an AUC basis at a maternal dose of 1 mg/kg).

8.3 Nursing Mothers Because many drugs are excreted in human milk, caution should be exercised when FIRAZYR is administered to a nursing woman.

Icatibant is excreted into the milk of lactating rats.

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Juvenile Toxicity Data Subcutaneous daily administration of icatibant to young rats during the juvenile period of development (postnatal days 22-70) delayed the sexual maturation of male reproductive tissues (atrophy of testes and epididymides) at exposures approximating one-third or greater the MRHD on a mg/ m2 basis.

Impaired fertility and reproductive performance were also observed in male rats at the end of the postnatal treatment period at exposures approximating the MRHD or greater on a mg/ m2 basis.

No effects were observed in females at exposures approximating 3-fold the MRHD on a mg/ m2 basis.

The observed tissue findings in males were consistent with those seen in sexually mature rats and dogs and are attributed to antagonism of the bradykinin B2 receptor and subsequent effects on gonadotropins.

The observed effects may be a consequence of daily icatibant administration.

Toxicity to the testis did not occur in dogs treated twice a week for 9 months [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

8.5 Geriatric Use Clinical studies of FIRAZYR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elderly patients are likely to have increased systemic exposure to FIRAZYR compared to younger (18-45 years) patients [see Clinical Pharmacology (12.3)].

Since other reported clinical experience has not identified differences in efficacy and safety between elderly and younger patients, no dose adjustment is recommended.

8.6 Hepatic Impairment FIRAZYR was studied in patients with mild to moderate (Child Pugh scores of 5 to 8) hepatic impairment.

No change in systemic exposure is noted in these patient populations.

No dose adjustment is required in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment Although a formal renal impairment study has not been conducted, 10 of 37 patients treated with FIRAZYR had hepatorenal syndrome with glomerular filtration rate (GFR) below 60 mL/min.

FIRAZYR is cleared non-renally and hence it is not expected to show any change in systemic exposure in patients with impaired renal function.

No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Pregnancy and lactation
8.3 Nursing Mothers Because many drugs are excreted in human milk, caution should be exercised when FIRAZYR is administered to a nursing woman. Icatibant is excreted into the milk of lactating rats.

Interactions

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

More information

Category Value
Authorisation number NDA022150
Orphan designation No
Product NDC 54092-702
Date Last Revised 09-12-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 1148141
Storage and handling 16.2 Storage and Handling Keep out of the reach of children. Store between 2 - 25° C (36 - 77° F). Do not freeze. Store in carton until time of administration.
Marketing authorisation holder Shire US Manufacturing Inc.