healthcare provider or pharmacist how to throw away used syringes and needles. See Figure O.

Figure                                                     O

This Patient Package Insert and Instructions for Use have been approved by the

U.S. Food and Drug Administration.

Manufactured for:

Shire Orphan Therapies, Inc. 300 Shire Way

Lexington, MA 02421

August 2011

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Firazyr 30 mg solution for injection in pre-filled syringe

Each pre-filled syringe of 3 ml contains icatibant acetate equivalent to 30 mg icatibant. Each ml of the solution contains 10 mg of icatibant.

For the full list of excipients, see section 6.1.

Solution for injection.

The solution is a clear and colourless liquid.

4.1 Therapeutic indications

Firazyr is indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older, with C1-esterase-inhibitor deficiency.

Firazyr is intended for use under the guidance of a healthcare professional. Posology

Adults

The recommended dose for adults is a single subcutaneous injection of Firazyr 30 mg.

In the majority of cases a single injection of Firazyr is sufficient to treat an attack. In case of insufficient relief or recurrence of symptoms, a second injection of Firazyr can be administered after 6 hours. If the second injection produces insufficient relief or a recurrence of symptoms is observed, a third injection of Firazyr can be administered after a further 6 hours. No more than 3 injections of Firazyr should be administered in a 24 hour period.

In the clinical trials, not more than 8 injections of Firazyr per month have been administered.

Paediatric population

The recommended dose of Firazyr based on body weight in children and adolescents (aged 2 to 17 years) is provided in table 1 below.

In the clinical trial, not more than 1 injection of Firazyr per HAE attack has been administered.

No dosage regimen for children aged less than 2 years or weighing less than 12 kg can be recommended as the safety and efficacy in this paediatric group has not been established.

Elderly

Limited information is available on patients older than 65 years of age.

Elderly people have been shown to have increased systemic exposure to icatibant. The relevance of this to the safety of Firazyr is unknown (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

Renal impairment

No dose adjustment is required in patients with renal impairment. Method of administration

Firazyr is intended for subcutaneous administration preferably in the abdominal area.

Firazyr solution for injection should be injected slowly due to the volume to be administered. Each Firazyr syringe is intended for single use only.

Refer to the patient information leaflet for instructions for use.

Caregiver/self-administration

The decision on initiating caregiver or self-administration of Firazyr should only be taken by a physician experienced in the diagnosis and treatment of hereditary angioedema (see section 4.4).

Adults

Firazyr may be self-administered or administered by a caregiver only after training in subcutaneous injection technique by a healthcare professional.

Children and adolescents aged 2-17 years

Firazyr may be administered by a caregiver only after training in subcutaneous injection technique by a healthcare professional.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Laryngeal attacks

Patients with laryngeal attacks should be managed in an appropriate medical institution after injection until the physician considers discharge to be safe.

Ischemic heart disease

Under ischemic conditions, a deterioration of cardiac function and a decrease in coronary blood flow could theoretically arise from antagonism of bradykinin receptor type 2. Caution should therefore be observed in the administration of Firazyr to patients with acute ischemic heart disease or unstable angina pectoris (see section 5.3).

Stroke

Although there is evidence to support a beneficial effect of B2 receptor blockade immediately following a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phase neuroprotective effects of bradykinin. Accordingly, caution should be observed in the administration of icatibant to patients in the weeks following a stroke.

Caregiver/self-administration

For patients who have never received Firazyr previously, the first treatment should be given in a medical institution or under the guidance of a physician.

In case of insufficient relief or recurrence of symptoms after self-treatment or administration by a caregiver, it is recommended that the patient or caregiver should seek medical advice. For adults, subsequent doses that may be required for the same attack should be administered within a medical institution (see section 4.2). There are no data on administering subsequent doses for the same attack in adolescents or children.

Patients experiencing a laryngeal attack should always seek medical advice and be observed in a medical institution also after having taken the injection at home.

Paediatric population

There is limited experience with treatment of more than one HAE attack with Firazyr in the paediatric population.

Pharmacokinetic drug interactions involving CYP450 are not expected (see section 5.2).

Co-administration of Firazyr with angiotensin-converting-enzyme (ACE) inhibitors has not been studied. ACE inhibitors are contraindicated in HAE patients due to possible enhancement of bradykinin levels.

Pregnancy

For icatibant, no clinical data on exposed pregnancies are available. Animal studies showed effects on uterine implantation and parturition (see section 5.3), but the potential risk for humans is unknown.

Firazyr should be used during pregnancy only, if the potential benefit justifies the potential risk for the foetus, (e.g for treatment of potentially life threatening laryngeal attacks).

Breast-feeding

Icatibant is excreted in the milk of lactating rats at concentrations similar to those in maternal blood. No effects were detected in the post-natal development of rat pups.

It is unknown whether icatibant is excreted in human breast milk but it is recommended that breastfeeding women, who wish to take Firazyr, should not breastfeed for 12 hours after treatment.

Fertility

In both rats and dogs, repeated use of icatibant resulted in effects on reproductive organs. Icatibant had no effect on the fertility of male mice and rats (see section 5.3). In a study of 39 healthy adult men and women treated with 30 mg every 6 hours for 3 doses every 3 days for a total of 9 doses, there were no clinically significant changes from baseline in basal and GnRH-stimulated concentration of reproductive hormones in either females or males. There were no significant effects of icatibant on the concentration of luteal phase progesterone and luteal function, or on menstrual cycle length in females and there were no significant effects of icatibant on sperm count, motility and morphology in males.

The dosing regimen used for this study is unlikely to be sustained in the clinical setting.

Firazyr has minor influence on the ability to drive and use machines. Fatigue, lethargy, tiredness, somnolence, and dizziness have been reported following the use of Firazyr. These symptoms may occur as a result of an attack of HAE. Patients should be advised not to drive and use machines if they feel tired or dizzy.

Summary of the safety profile

In clinical studies used for registration, a total of 999 HAE attacks have been treated with 30 mg Firazyr administered subcutaneously by a healthcare professional. Firazyr 30 mg SC has been administered by a healthcare professional to 129 healthy subjects and 236 patients with HAE.

Almost all subjects who were treated with subcutaneous icatibant in clinical trials developed reactions at the site of injection (characterised by skin irritation, swelling, pain, itchiness, erythema, burning sensation). These reactions were generally mild to moderate in severity, transient, and resolved without further intervention.

Tabulated list of adverse reactions

The frequency of adverse reactions listed in Table 1 is defined using the following convention:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

All adverse reactions from post-marketing experience areitalicised.

Paediatric Population

A total of 32 paediatric patients (8 children aged 2 to 11 years and 24 adolescents aged 12 to 17 years) with HAE were exposed to treatment with icatibant during clinical studies. Thirty-one patients received a single dose of icatibant and 1 patient (an adolescent) received icatibant for two HAE attacks (in total, two doses). Firazyr was administered by subcutaneous injection at a dose of 0.4 mg/kg based on body weight to a maximum dose of 30 mg.

The majority of paediatric patients who were treated with subcutaneous icatibant experienced injection site reactions such as erythema, swelling, burning sensation, skin pain and itching/pruritus; these were found to be mild to moderate in severity and consistent with reactions that have been reported in adults. Two paediatric patients experienced injection site reactions which were assessed as severe and which were completely resolved within 6 hours. These reactions were erythema, swelling, burning and warm sensation.

No clinically significant changes in reproductive hormones were observed during clinical studies. Description of selected adverse reactions

Immunogenicity

Across repeated treatment in adults in the controlled phase III trials, transient positivity to anti- icatibant antibodies was observed in rare cases. All patients maintained efficacy. One Firazyr-treated patient tested positive for anti-icatibant antibodies before and after treatment with Firazyr. This patient was followed for 5 months and further samples were negative for anti-icatibant antibodies. No hypersensitivity or anaphylactic reactions were reported with Firazyr.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

No clinical information on overdose is available.

A dose of 3.2 mg/kg intravenously (approximately 8 times the therapeutic dose) caused transient erythema, itching, flushing or hypotension in healthy subjects. No therapeutic intervention was necessary.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other haematological agents, drugs used to treat hereditary angioedema; ATC code: B06AC02.

Mechanism of action

HAE (an autosomal dominant disease) is caused by an absence or dysfunction of C1-esterase- inhibitor. HAE attacks are accompanied by an increased release of bradykinin, which is the key mediator in the development of the clinical symptoms.

HAE manifests as intermittent attacks of subcutaneous and/or sub mucosal oedema involving the upper respiratory tract, the skin and the gastrointestinal tract. An attack usually lasts between 2 to 5 days.

Icatibant is a selective competitive antagonist at the bradykinin type 2 (B2) receptor. It is a synthetic decapeptide with a structure similar to bradykinin, but with 5 non-proteinogenic amino acids. In HAE increased bradykinin concentrations are the key mediator in the development of the clinical symptoms.

Pharmacodynamic effects

In healthy young subjects, icatibant administered in doses of 0.8 mg/kg over 4 hours; 1.5 mg/kg/day or

0.15 mg/kg/day for 3 days, development of bradykinin-induced hypotension, vasodilatation and reflex tachycardia was prevented. Icatibant was shown to be a competitive antagonist when the bradykinin challenge dose was increased 4-fold.

Clinical efficacy and safety

Efficacy data were obtained from an initial open-label Phase II study and from three controlled Phase III studies.

Phase III clinical studies (FAST-1 and FAST-2) were randomized, double-blind, controlled trials and had identical designs except for the comparator (one with oral tranexamic acid as the comparator and one placebo controlled). A total of 130 patients were randomized to receive either a 30 mg dose of icatibant (63 patients) or comparator (either tranexamic acid, - 38 or placebo - 29 patients).

Subsequent episodes of HAE were treated in an open label extension. Patients with symptoms of laryngeal angioedema received open label treatment with icatibant. The primary efficacy endpoint was the time to onset of symptom relief using a visual analogue scale (VAS). Table 3 shows the efficacy results for these studies.

FAST-3 was a randomized, placebo-controlled, parallel-group study of 98 adult patients with a median age of 36 years. Patients were randomized to receive either icatibant 30 mg or placebo by subcutaneous injection. A subset of patients in this study experienced acute HAE attacks while receiving androgens, antifibrinolytic agents or Cl inhibitors. The primary endpoint was time to onset of symptom relief assessed using a 3-item composite visual analog score (VAS-3) consisting of assessments of skin swelling, skin pain, and abdominal pain. Table 4 shows the efficacy results for FAST-3.

In these studies, patients on icatibant had a faster median time to onset of symptom relief (2.0, 2.5 and

2.0 hours, respectively) compared to tranexamic acid (12.0 hours) and placebo (4.6 and 19.8 hours). The treatment effect of icatibant was confirmed by secondary efficacy endpoints.

In an integrated analysis of these controlled Phase III studies, the time to onset of symptom relief and time to onset of primary symptom relief were similar regardless of age group, sex, race, weight or whether or not the patient used androgens or antifibrinolytic agents.

Response was also consistent across repeated attacks in the controlled Phase III trials. A total of 237 patients were treated with 1,386 doses of 30 mg icatibant for 1,278 attacks of acute HAE. In the first 15 Firazyr treated attacks (1,114 doses for 1,030 attacks), the median times to onset of symptom relief were similar across attacks (2.0 to 2.5 hours). 92.4% of these attacks of HAE were treated with a single dose of Firazyr.

Table 4. Efficacy results for FAST-3

A total of 66 patients with attacks of HAE affecting the larynx were treated in these controlled Phase III clinical trials. The results were similar to patients with non-laryngeal attacks of HAE with respect to time to onset of symptom relief.

Paediatric population

An open label, non-randomised single-arm study (HGT-FIR-086) was performed with a total of 32 patients. All patients received at least one dose of icatibant (0.4mg/kg body weight up to a maximum dose of 30 mg) and the majority of patients were followed up for a minimum of 6 months. Eleven patients were of prepubertal status and 21 patients were either pubertal or postpubertal.

The efficacy population consisted of 22 patients who had been treated with icatibant (11 prepubertal and 11 pubertal/postpubertal) for HAE attack.

The primary efficacy endpoint was the time to onset of symptom relief (TOSR) measured using a composite investigator-reported symptom score. Time to symptom relief was defined as the duration of time (in hours) taken for improvement of symptoms to occur by a magnitude of 20%.

Overall the median time to onset of symptom relief was 1.0 hour (95% confidence interval, 1.0-1.1 hours). At 1 and 2 hours post treatment, approximately 50% and 90% of patients experienced onset of symptom relief, respectively.

Overall, the median time to minimal symptoms (earliest time post treatment when all symptoms were either mild or absent) was 1.1 hours (95% confidence interval, 1.0-2.0 hours).

The pharmacokinetics of icatibant has been characterized by studies using both intravenous and subcutaneous administration to healthy volunteers and patients. The pharmacokinetic profile of icatibant in patients with HAE is similar to that in healthy volunteers.

Absorption

Following subcutaneous administration, the absolute bioavailability of icatibant is 97%. The time to maximum concentration is approximately 30 minutes.

Distribution

Icatibant volume of distribution (Vss) is about 20-25 L. Plasma protein binding is 44%.

Elimination

Icatibant is mainly eliminated by metabolism with less than 10% of the dose eliminated in the urine as unchanged drug. Clearance is about 15-20 l/h and independent of dose. The terminal plasma half-life is about 1-2 hours.

Biotransformation

Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine.

In vitrostudies have confirmed that icatibant is not degraded by oxidative metabolic pathways and is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4.

Special populations

Elderly

Data suggest an age-related decline in clearance resulting in about 50-60% higher exposure in older people (75-80 years) compared to patients aged 40 years.

Gender

Data suggest that there is no difference in the clearance between females and males after correcting for body weight.

Hepatic and Renal Impairment

Limited data suggest that icatibant exposure is not influenced by hepatic or renal impairment.

Race

Information on individual race effect is limited. Available exposure data suggest no difference in the clearance between non-White (n=40) and White (n=132) subjects.

Paediatric population

The pharmacokinetics of icatibant were characterized in paediatric HAE patients in study HGT-FIR- 086 (see section 5.1). Following a single subcutaneous administration (0.4 mg/kg up to a maximum of 30 mg), the time to maximum concentration is approximately 30 minutes and the terminal half-life is about 2 hours. There are no observed differences in the exposure to icatibant between HAE patients with and without an attack. Population pharmacokinetic modelling using both adult and paediatric data showed that clearance of icatibant is related to body weight with lower clearance values noted for lower body weights in the paediatric HAE population. Based on modelling for weight banded dosing, the predicted exposure to icatibant in the paediatric HAE population (see section 4.2) is lower than the observed exposure in studies conducted with adult HAE patients.

Repeated-dose studies of up to 6-months duration in rats and 9-months duration in dogs have been conducted. In both rats and dogs, there was a dose-related reduction in circulating sex hormone levels and the repeated use of icatibant reversibly delayed sexual maturation.

Maximum daily exposures defined by area under the curve (AUC) at the No Observed Adverse Effect Levels (NOAEL) in the 9-month study in dog were 2.3 times the AUC in adult humans after a subcutaneous dose of 30 mg. A NOAEL was not measurable in the rat study, however, all of the findings from that study showed either completely or partially reversible effects in treated rats.

Adrenal gland hypertrophy was observed at all doses tested in rats. Adrenal gland hypertrophy was

seen to reverse after cessation of icatibant treatment. The clinical relevance of the adrenal gland findings is unknown.

Icatibant had no effect on the fertility of male mice (top dose 80.8 mg/kg/day) and rats (top dose 10 mg/kg/day).

In a 2 year study to evaluate the carcinogenic potential of icatibant in rats, daily doses giving exposure levels up to approximately 2-fold that achieved after a therapeutic dose in humans had no effect on the incidence or morphology of tumours. Results do not indicate a carcinogenic potential for icatibant.

In a standard battery ofin vitroandin vivotests icatibant was not genotoxic.

Icatibant was not teratogenic when administered by SC injection during early embryonic and fetal development in rat (top dose 25 mg/kg/day) and rabbit (top dose 10 mg/kg/day). Icatibant is a potent antagonist of bradykinin and therefore, at high dose levels, treatment can have effects on the uterine implantation process and subsequent uterine stability in early pregnancy. These uterine effects also manifest in late stage pregnancy where icatibant exhibits a tocolytic effect resulting in delayed parturition in the rat, with increased fetal distress and perinatal death at high doses (10 mg/kg/day).

A 2-week subcutaneous dose range finding study in juvenile rats identified 25 mg/kg/day as a maximally tolerated dose. In the pivotal juvenile toxicity study in which sexually immature rats were treated daily with 3 mg/kg/day for 7 weeks, atrophy of testes and epididymides were observed; the observed microscopic findings were partially reversible. Similar effects of icatibant on reproductive tissue were seen in sexually mature rats and dogs. These tissue findings were consistent with reported effects on gonadotrophins and during the subsequent treatment-free period appear to be reversible.

Icatibant did not elicit any cardiac conduction changein vitro(hERG channel) orin vivoin normal dogs or in various dog models (ventricular pacing, physical exertion and coronary ligation) where no associated hemodynamic changes were observed. Icatibant has been shown to aggravate induced cardiac ischemia in several non-clinical models, although a detrimental effect has not consistently been shown in acute ischemia.

6.1 List of excipients

Sodium chloride

Acetic acid, glacial (for pH adjustment) Sodium hydroxide (for pH adjustment) Water for injections

Not applicable.

18 months.

Do not store above 25○C.

Do not freeze.

3 ml of solution in a 3 ml pre-filled syringe (type I glass) with plunger stopper (bromobutyl coated with fluorocarbon polymer). A hypodermic needle (25 G; 16 mm) is included in the pack.

Pack size of one pre-filled syringe with one needle or a multipack containing three pre-filled syringes with three needles.

Not all pack sizes may be marketed.

The solution should be clear and colourless and free from visible particles. Paediatric use

The appropriate dose to be administered is based on body weight (see section 4.2).

Where the required dose is less than 30 mg (3 ml), the following equipment is required to extract and administer the appropriate dose:

· Adapter (proximal and/or distal female luer lock connector/coupler)

· 3 ml (recommended) graduated syringe

The pre-filled icatibant syringe and all other components are for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements. All needles and syringes should be disposed of in a sharps container.

Shire Pharmaceuticals Ireland Limited Block 2 & 3 Miesian Plaza

50 – 58 Baggot Street Lower

Dublin 2 Ireland

EU/1/08/461/001 EU/1/08/461/002

Date of first authorisation: 11 July 2008 Date of latest renewal: 13 March 2013

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

A MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Shire Pharmaceuticals Ireland Limited Block 2 & 3 Miesian Plaza

50 – 58 Baggot Street Lower

Dublin 2 Ireland.

Medicinal product subject to medical prescription.

· Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

· Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

· At the request of the European Medicines Agency;

· Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

LABELLING AND PACKAGE LEAFLET

A. LABELLING

Firazyr 30 mg solution for injection in pre-filled syringe Icatibant

Each 3 ml pre-filled syringe contains icatibant acetate equivalent to 30 mg icatibant. Each ml of the solution contains 10 mg of icatibant.

Contains: acetic acid glacial, sodium hydroxide, sodium chloride, water for injections.

Solution for injection One pre-filled syringe One 25G needle

Subcutaneous use

Read the package leaflet before use For single use only

Keep out of the sight and reach of children.

EXP

Do not store above 25ºC. Do not freeze.

Shire Pharmaceuticals Ireland Limited Dublin 2

Ireland

EU/1/08/461/001

Lot

Medicinal product subject to medical prescription.

Firazyr 30 mg

2D barcode carrying the unique identifier included.

PC:

SN:

NN:

Firazyr 30 mg solution for injection in pre-filled syringe Icatibant

Each 3 ml pre-filled syringe contains icatibant acetate equivalent to 30 mg icatibant. Each ml of the solution contains 10 mg of icatibant.

Contains: acetic acid glacial, sodium hydroxide, sodium chloride, water for injections.

Solution for injection

Multipack containing three pre-filled syringes and three 25G needles

Subcutaneous use

Read the package leaflet before use For single use only

Keep out of the sight and reach of children.

EXP

Do not store above 25ºC. Do not freeze.

Shire Pharmaceuticals Ireland Limited Dublin 2

Ireland

EU/1/08/461/002

Lot

Medicinal product subject to medical prescription.

Firazyr 30 mg

2D barcode carrying the unique identifier included.

PC:

SN:

NN:

Firazyr 30 mg solution for injection in pre-filled syringe Icatibant

Each 3 ml pre-filled syringe contains icatibant acetate equivalent to 30 mg icatibant. Each ml of the solution contains 10 mg of icatibant.

Contains: acetic acid glacial, sodium hydroxide, sodium chloride, water for injections.

Solution for injection

One pre-filled syringe and one 25G needle. Component of a multipack, can’t be sold separately.

Subcutaneous use

Read the package leaflet before use For single use only

Keep out of the sight and reach of children.

EXP

Do not store above 25ºC. Do not freeze.

Shire Pharmaceuticals Ireland Limited Dublin 2

Ireland

EU/1/08/461/002

Lot

Medicinal product subject to medical prescription.

Firazyr 30 mg

2D barcode carrying the unique identifier included.

PC:

SN:

NN:

Firazyr 30 mg solution for injection in pre-filled syringe Icatibant

Shire Pharmaceuticals Ireland Limited

EXP

Lot

Subcutaneous use

Firazyr 30 mg Icatibant

sc

EXP

Lot

30 mg/3 ml

Shire Pharmaceuticals Ireland Limited

Package Leaflet: Information for the user

Firazyr 30 mg solution for injection pre-filled syringe

Icatibant

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

- If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

1. What Firazyr is and what it is used for

2. What you need to know before you use Firazyr

3. How to use Firazyr

4. Possible side effects

5. How to store Firazyr

6. Contents of the pack and other information

Firazyr contains the active substance icatibant.

Firazyr is used for treating the symptoms of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older.

In HAE levels of a substance in your bloodstream called bradykinin are increased and this leads to symptoms like swelling, pain, nausea, and diarrhoea.

Firazyr blocks the activity of bradykinin and therefore ends the further progression of the symptoms.

- If you are allergic to icatibant, or any of the other ingredients of this medicine (listed in section 6).

Talk to your doctor before taking Firazyr:

- if you are suffering from angina (reduced blood flow to the heart muscle)

- if you have recently suffered a stroke

Some of the side effects connected with Firazyr are similar to the symptoms of your disease. Tell your doctor immediately if you notice that your symptoms of the attack get worse after you received Firazyr

In addition:

- You or your caregiver must be trained on subcutaneous (under the skin) injection technique before you self-inject or your caregiver injects you with Firazyr.

- Immediately after you self-inject Firazyr or your caregiver injects you with Firazyr while you are experiencing a laryngeal attack (obstruction of the upper airway), you must seek medical care in a medical institution.

- If your symptoms are not resolved following one self- or caregiver administered injection of Firazyr, you should seek medical advice regarding additional injections of Firazyr. For adult patients, up to 2 additional injections may be given within 24 hours.

Firazyr is not recommended for use in children under 2 years of age or weighing less than 12 kg because it has not been studied in these patients.

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Firazyr is not known to interact with other medicines. If you are taking a medicine known as an Angiotensin Converting Enzyme (ACE) inhibitor (for example: captopril, enalapril, ramipril, quinapril, lisinopril) which is used to lower your blood pressure or for any other reason, you should inform your doctor before receiving Firazyr.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor before starting to use Firazyr.

If you are breast-feeding you should not breast-feed for 12 hours after you have last received Firazyr.

Do not drive or use machines if you feel tired or dizzy as a result of your HAE attack or after using Firazyr.

The injection solution contains less than 1 mmol (23 milligrams) of sodium, so it is essentially ‘sodium-free’.

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

If you have never received Firazyr previously, your first dose of Firazyr will always be injected by your doctor or nurse. Your doctor will tell you when it is safe for you to go home. After discussion with your doctor or nurse and after training in subcutaneous (under the skin) injection technique, you may be able to inject yourself with Firazyr or your caregiver may inject Firazyr for you when you have an HAE attack. It is important that Firazyr is injected subcutaneously (under the skin) as soon as you notice an attack of angioedema. Your healthcare provider will teach you and your caregiver how to safely inject Firazyr by following the instructions in the Package Leaflet.

Your doctor has determined the exact dose of Firazyr and will tell you how often it should be used.

- The recommended dose of Firazyr is one injection (3 ml, 30 mg) injected subcutaneously (under the skin) as soon as you notice the attack of angioedema (for example increased skin swelling, particularly affecting the face and neck, or increasing tummy pain).

- If you experience no relief of symptoms after 6 hours, you should seek medical advice regarding additional injections of Firazyr. For adults, up to 2 additional injections may be given within 24 hours.

Children and adolescents aged 2 to 17 years

- The recommended dose of Firazyr is one injection of 1 ml up to a maximum of 3 ml based on body weight injected subcutaneously (under the skin) as soon as you develop symptoms of an angioedema attack (for example increased skin swelling, particularly affecting the face and neck, increasing tummy pain).

- See section on instructions for use for the dose to inject.

- If you are not sure which dose to inject, ask your doctor, pharmacist or nurse.

How should Firazyr be administered?

Firazyr is intended for subcutaneous injection (under the skin). Each syringe should only be used once.

Firazyr is injected with a short needle into the fatty tissue under the skin in the abdomen (tummy). If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

- self-administration (adults)

- administration by a caregiver or healthcare professional to adults, adolescents or children aged over 2 years (weighing at least 12 kg).

The instructions include the following main steps:

1) General Information

2a) Preparing the syringe for children and adolescents (2-17 years) weighing 65 kg or less 2b) Preparing the syringe and needle for injection (all patients)

3) Preparing the injection site

4) Injecting the solution

5) Disposal of the injection material

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Almost all patients receiving Firazyr will experience a reaction at the site of the injection (such as skin irritation, swelling, pain, itchiness, redness of the skin and burning sensation). These effects are usually mild and clear up without the need for any additional treatment.

Very common (may affect more than 1 in 10 people) :

Additional injection site reactions (pressure sensation, bruising, reduced sensation and/or numbness, raised itchy skin rash and warmth).

Common (may affect up to 1 in 10 people) : Feeling sick

Headache Dizziness Fever Itching Rash

Skin redness

Abnormal liver function test

Not known (frequency cannot be estimated from the available data) : Hives (urticaria)

Tell your doctor immediately if you notice that the symptoms of your attack get worse after you received Firazyr.

If you get any side effects talk to your doctor. This includes any possible side effects not listed in this leaflet.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the label after ‘EXP’. The expiry date refers to the last day of that month.

Do not store above 25○C. Do not freeze.

Do not use this medicine if you notice that the syringe or needle packaging is damaged or if there are any visible signs of deterioration, for example if the solution is cloudy, if it has floating particles, or if the colour of the solution has changed.

Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.