INDICATIONS & USAGE SECTION

Highlight: 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)

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.

DOSAGE & ADMINISTRATION SECTION

Highlight: * 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 DOSAGE AND ADMINISTRATION

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)].

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection: 10 mg per mL (3)

3 DOSAGE FORMS AND STRENGTHS

FIRAZYR injection is supplied in a prefilled syringe delivering 30 mg icatibant. Each syringe delivers 3 mL solution with a concentration of 10 mg per mL.

CONTRAINDICATIONS SECTION

Highlight: None (4)

4 CONTRAINDICATIONS

None.

DRUG INTERACTIONS SECTION

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.

USE IN SPECIFIC POPULATIONS SECTION

Highlight: 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published literature and the pharmacovigilance database with Firazyr (icatibant) use in pregnant women have not identified a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, icatibant, administered by the subcutaneous route during the period of organogenesis, did not cause structural abnormalities in rats or rabbits; however, premature birth and abortion were observed in rabbits at doses approximately 0.025 times the maximum recommended human dose (MRHD) and higher. Decreased embryofetal survival was observed in rabbits at a subcutaneous dose that was 13 times the MRHD. In a pre- and post-natal development study in rats, delayed parturition was observed at subcutaneous doses 0.5 times the MRHD and higher, which resulted in deaths of dams at doses 2 times the MRHD and higher. Fetal death and early pup deaths were observed with doses 2 times the MRHD (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study with rats that received icatibant from gestation days 7 to 18, there was no evidence of any treatment-related structural abnormalities or effects on embryo-fetal survival with maternal doses up to 2.7 times the MRHD (on a mg/m2 basis with maternal subcutaneous doses up to 25 mg/kg/day). In a fertility and early embryonic development study with rats, icatibant increased pre-implantation loss at a dose that was 7 times the MRHD (on an AUC basis at a maternal dose of 10 mg/kg/day).

In an embryo-fetal development study with rabbits that received icatibant from gestation days 7 to 18, premature birth and abortion rates increased at doses approximately 0.025 times the MRHD and higher (on a mg/m2 basis at maternal subcutaneous doses of 0.1 mg/kg and higher). Icatibant treatment resulted in dose-related decreases of total implantations and total number of live fetuses as well as dose-related increases of percent pre-implantation loss at a dose that was 13 times the MRHD (on an AUC basis with a maternal subcutaneous dose of 10 mg/kg/day). There was no evidence of any treatment-related structural abnormalities with maternal doses up to 13 times the MRHD (on an AUC basis with maternal subcutaneous doses up to 10 mg/kg/day).

In a pre- and post-natal development study in the rat, dams received icatibant by the subcutaneous route at doses of 1, 3, and 10 mg/kg/day from gestation day 6 to post-partum (PPD) day 20. Delayed parturition was observed at doses 0.5 times the MRHD and higher (on an AUC basis with maternal subcutaneous doses of 1 mg/kg/day and higher), which resulted in deaths of dams at doses 2 times the MRHD and higher (on an AUC basis with maternal subcutaneous doses of 3 mg/kg/day and higher). Fetal death and increased pup deaths through PPD 4 were observed with doses 2 times the MRHD (on an AUC with a maternal subcutaneous dose of 3 mg/kg/day and higher). Impairment of pup righting reflex and decreased pup hair growth were also observed at 7 times the MRHD (on an AUC basis with a maternal dose of 10 mg/kg). Icatibant and the M2 metabolite were found in maternal milk following subcutaneous administration of icatibant. The no effect dose for F1 pups was identified at a dose 0.5 times the MRHD (on an AUC basis with a maternal subcutaneous dose of 1 mg/kg/day). A no effect dose was not identified for F0 maternal toxicity.

8.2 Lactation

Risk Summary

There are no data on the presence of icatibant in human milk, the effects on the breastfed infant, or the effects on milk production. Icatibant and the M2 metabolite were found in rat milk following subcutaneous administration of icatibant (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. However, systemic absorption of icatibant in infants is not expected after oral exposure through breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FIRAZYR and any potential adverse effects on the breastfed child from FIRAZYR or from the underlying maternal condition.

Data

Animal Data

Icatibant is excreted into the milk of lactating rats at concentrations that sometimes slightly exceeded those measured in the maternal plasma.

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)].

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

The efficacy and safety of FIRAZYR for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Among the 223 patients in these studies, the mean age was 38 years, 64% were female, and 95% were white. Approximately 57% of patients reported use of attenuated androgens, antifibrinolytic agents, or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling.

Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients with a median age of 36 years. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either FIRAZYR 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label FIRAZYR 30 mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-item VAS score (Figure 2). The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with FIRAZYR (n=43) compared to placebo (n=45) was 2.0 hours [95% CI 1.5, 3.0] versus 19.8 hours [95% CI 6.1, 26.3], respectively (p<0.001).

Figure 2 Time to 50% reduction from baseline in 3-item VAS score.

Other evaluated endpoints included time to almost complete symptom relief (VAS<10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8.0 versus 36.0 hours for FIRAZYR and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with FIRAZYR used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo.

In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received FIRAZYR 30 mg for the treatment of an acute HAE attack. Across the three trials, FIRAZYR had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours.

Recurrent attacks

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 in these trials. In an assessment of the first 5 FIRAZYR-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-itemVAS score were similar across attacks (2.0, 2.0, 2.4, 2.0, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of FIRAZYR.

Laryngeal attacks

A total of 60 patients with laryngeal attacks were treated with FIRAZYR in the controlled trials. Efficacy results were similar to those observed for non- laryngeal (cutaneous and abdominal) sites of attack.

Self-administration

Self-administration of FIRAZYR by 56 patients was assessed in an open label trial. Patients who administered FIRAZYR during an acute attack of HAE had a median time to 50% reduction from the pretreatment composite 3-itemVAS score of 2.6 hours.

OVERDOSAGE SECTION

10 OVERDOSAGE

In a clinical study evaluating a 90 mg dose (30 mg in each of 3 subcutaneous sites), the adverse event profile was similar to that seen with 30 mg administered in a single subcutaneous site.

In another clinical study, a dose of 3.2 mg/kg administered intravenously (approximately 8 times the therapeutic dose for HAE) caused erythema, itching and hypotension in healthy subjects. No therapeutic intervention was necessary.

SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION
FIRAZYR (FIR-a-zeer)
(icatibant) Injection, for subcutaneous use

Please read this Patient Information before you use FIRAZYR and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is FIRAZYR?

FIRAZYR is a medicine used to treat acute attacks of hereditary angioedema (HAE) in adults 18 years and older.
It is not known if FIRAZYR is safe or effective for children under 18 years of age.

What should I tell my healthcare provider before using FIRAZYR?

Before you use FIRAZYR, tell your healthcare provider about all your medical conditions including if you:

are pregnant or plan to become pregnant. It is not known if FIRAZYR will harm your unborn baby. You and your healthcare provider will decide if FIRAZYR is right for you.
are breastfeeding or plan to breastfeed. It is not known if FIRAZYR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use FIRAZYR.

**Tell your healthcare provider about all the medicines you take,**including prescription and over the counter medicines, vitamins, and herbal supplements.

How should I use FIRAZYR?

Read the Instructions for Use at the end of this Patient Information leaflet for detailed instructions about the right way to use FIRAZYR.
Use FIRAZYR exactly as your healthcare provider tells you to use it.
Your healthcare provider will prescribe the right dose of FIRAZYR for you and tell you when to use it.
Your healthcare provider will teach you or a caregiver how to give FIRAZYR injections.
If your symptoms continue or come back, you may repeat your FIRAZYR injection at least six hours apart.
Do not use more than 3 doses in 24 hours. *If you have a laryngeal attack, inject FIRAZYR and then go to the nearest hospital emergency room right away.

What should I avoid while using FIRAZYR?

Tiredness, drowsiness, and dizziness can happen in people who take FIRAZYR. If this happens, do not drive a car, use machinery, or do anything that needs you to be alert.

What are the possible side effects of FIRAZYR?

The most common side effects of FIRAZYR include:

redness, bruising, swelling, warmth, burning, itching, irritation, hives, numbness, pressure, or pain at the injection site
fever
too much of an enzyme called transaminase in your blood
dizziness
nausea
headache
rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of FIRAZYR. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store FIRAZYR?

Store FIRAZYR between 36°F to 77°F (2°C to 25°C).
Do not freeze.
Store FIRAZYR in the original carton until you are ready to use it.

Keep FIRAZYR and all medicines out of the reach of children.

General information about the safe and effective use of FIRAZYR

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use FIRAZYR for a condition for which it was not prescribed. Do not give FIRAZYR to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about FIRAZYR. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about FIRAZYR that is written for health professionals.

For more information, go to www.FIRAZYR.com or call 1-800-828-2088.

What are the ingredients in FIRAZYR?

Active ingredient: icatibant acetate

**Inactive Ingredients:**sodium chloride (isotonicity reagent), glacial acetic acid (pH adjuster), sodium hydroxide (pH adjuster), and water

INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE

FIRAZYR (FIR-a-zeer)
(icatibant)
Injection, for subcutaneous use

Step 1. Preparing your dose of FIRAZYR

Wash your hands with soap and water.
You will need the following supplies:
- Your FIRAZYR carton that includes 1 single-dose FIRAZYR prefilled syringe and 1 needle.
- 1 alcohol wipe
- The medicine inside your FIRAZYR prefilled syringe should be clear and colorless. Do not use your FIRAZYR prefilled syringe if the solution contains particles, is cloudy, or has an unusual color.

Figure A

Figure A

Step 2. Remove the prefilled syringe and needle from the carton. See Figure B.

Figure B

** Figure B**

Step 3. Twist the needle cap lid to break the seal (the needle should remain inside the protective needle cap until ready to use).SeeFigure C.

Figure C

** Figure C**

Step 4. Remove the protective cap from the end of the pre-filled syringe by unscrewing the cap. Hold the syringe firmly. Carefully attach the needle to the prefilled syringe containing the colorless FIRAZYR solution.See Figure D.

Figure D

** Figure D**

Step 5. Firmly screw the needle on the prefilled syringe. Be careful not to remove the needle from the needle cap. SeeFigure E.

Figure E

** Figure E**

Preparing the Injection Site

**Step 6. Choose the injection site.**The injection site should be a fold of skin on your stomach, about 2 to 4 inches (5 to 10 cm) below your belly button on either side.SeeFigure F.

The area you choose for injection should be at least 2 inches (5 cm) away from any scars. Do not choose an area that is bruised, swollen, or painful.

Figure F

** Figure F**

Step 7. Clean your FIRAZYR injection site with an alcohol wipe and allow it to dry. See****Figure G.

Figure G

** Figure G**

Injecting your FIRAZYR

Step 8. Remove the needle from the needle cap by holding the needle cap and carefully pulling the syringe.Do not pull up on the plunger. See Figure H.

Figure H

** Figure H**

Step 9. Hold the FIRAZYR prefilled syringe in 1 hand, between your fingers and thumb. SeeFigure I.

Figure I

** Figure I**

Step 10. Use your other hand to gently pinch the fold of skin you cleaned with the alcohol wipe between your thumb and fingers for your injection. See Figure J.

Figure J

** Figure J**

Step 11. Hold the syringe between a 45-to-90 degree angle to your skin with the needle facing the fold of skin you are holding. SeeFigure K.

Figure K

** Figure K**

Step 12. Hold the fold of skin. Bring the syringe to the skin and quickly insert the needle into the skin fold. SeeFigure L.

Figure L

** Figure L**

Step 13. Push the plunger, at the top of the syringe, for at least 30 seconds until no FIRAZYR is in the syringe. SeeFigure M.

Figure M

** Figure M**

Step 14. Release the skin fold and gently pull the needle out. See Figure N.

Figure N

** Figure N**

Disposal of your used FIRAZYR prefilled syringe

Step 15. Place your used FIRAZYR syringe, with the needle attached, in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.

If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:

made of a heavy-duty plastic,
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
upright and stable during use,
leak-resistant, and
properly labeled to warn of hazardous waste inside the container.

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.

Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this.Do not recycle your used sharps disposal container.

Figure O

** Figure O**

Distributed by:
Takeda Pharmaceuticals America, Inc.
Lexington, MA 02421

FIRAZYR® and the FIRAZYR Logo® are registered trademarks of Shire Orphan Therapies GmbH. TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Revised: January 2024

SPL UNCLASSIFIED SECTION