FIRAZYR 30mg 10mg / ml solution for injection in pre-filled syringe medication leaflet

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.

Firazyr is indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) inadults, 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.

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 ofinsufficient relief or recurrence of symptoms, a second injection of Firazyr can be administered after6 hours. If the second injection produces insufficient relief or a recurrence of symptoms is observed, athird 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.

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

Table 1: Dosage regimen for paediatric patients

Body Weight Dose (Injection Volume)12 kg to 25 kg 10 mg (1.0 ml)26 kg to 40 kg 15 mg (1.5 ml)41 kg to 50 kg 20 mg (2.0 ml)51 kg to 65 kg 25 mg (2.5 ml)>65 kg 30 mg (3.0 ml)

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 berecommended as the safety and efficacy in this paediatric group has not been established.

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 ofthis to the safety of Firazyr is unknown (see section 5.2).

No dose adjustment is required in patients with hepatic impairment.

No dose adjustment is required in patients with renal impairment.

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 aphysician experienced in the diagnosis and treatment of hereditary angioedema (see section 4.4).

Firazyr may be self-administered or administered by a caregiver only after training in subcutaneousinjection 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 bya 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 injectionuntil the physician considers discharge to be safe.

Ischemic heart disease

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

Stroke

Although there is evidence to support a beneficial effect of B2 receptor blockade immediatelyfollowing a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phaseneuroprotective effects of bradykinin. Accordingly, caution should be observed in the administrationof 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 amedical institution or under the guidance of a physician.

In case of insufficient relief or recurrence of symptoms after self-treatment or administration by acaregiver, 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 medicalinstitution (see section 4.2). There are no data on administering subsequent doses for the same attackin adolescents or children.

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

This medicinal product contains less than 1 mmol (23 milligrams) of sodium per syringe, so it isessentially ‘sodium-free.’

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

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

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

Interaction studies have only been performed in adults.

For icatibant, no clinical data on exposed pregnancies are available. Animal studies showed effects onuterine 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 thefoetus, (e.g for treatment of potentially life threatening laryngeal attacks).

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 thatbreastfeeding women, who wish to take Firazyr, should not breastfeed for 12 hours after treatment.

In both rats and dogs, repeated use of icatibant resulted in effects on reproductive organs. Icatibant hadno effect on the fertility of male mice and rats (see section 5.3). In a study of 39 healthy adult men andwomen treated with 30 mg every 6 hours for 3 doses every 3 days for a total of 9 doses, there were noclinically significant changes from baseline in basal and GnRH-stimulated concentration ofreproductive hormones in either females or males. There were no significant effects of icatibant on theconcentration of luteal phase progesterone and luteal function, or on menstrual cycle length in femalesand 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 mayoccur as a result of an attack of HAE. Patients should be advised not to drive and use machines if theyfeel tired or dizzy.

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 beenadministered 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 reactionsat the site of injection (characterised by skin irritation, swelling, pain, itchiness, erythema, burningsensation). These reactions were generally mild to moderate in severity, transient, and resolvedwithout further intervention.

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 000to <1/1 000); very rare (<1/10 000).

All adverse reactions from post-marketing experience are italicised.

Table 2: Adverse reactions reported with icatibant

System Organ Class Preferred Term(incidence category)

Nervous system disorders(Common, ≥1/100 to <1/10) Dizziness

Gastrointestinal disorders(Common, ≥1/100 to <1/10) Nausea

Skin and subcutaneous tissue disorders(Common, ≥1/100 to <1/10) Rash

Erythema

Pruritus(Unknown) Urticaria

General disorders and administration siteconditions(Very Common, ≥1/10) Injection site reactions*(Common, ≥1/100 to <1/10) Pyrexia

Investigations(Common, ≥1/100 to <1/10) Transaminases increased

* Injection site bruising, Injection site hematoma, Injection site burning, Injection site erythema, Injectionsite 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.

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 patientsreceived 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 basedon body weight to a maximum dose of 30 mg.

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

No clinically significant changes in reproductive hormones were observed during clinical studies.

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-treatedpatient tested positive for anti-icatibant antibodies before and after treatment with Firazyr. This patientwas followed for 5 months and further samples were negative for anti-icatibant antibodies. Nohypersensitivity or anaphylactic reactions were reported with Firazyr.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted 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 transienterythema, itching, flushing or hypotension in healthy subjects. No therapeutic intervention wasnecessary.

Pharmacotherapeutic group: Other haematological agents, drugs used to treat hereditary angioedema;

ATC code: B06AC02.

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 keymediator in the development of the clinical symptoms.

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

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

In healthy young subjects, icatibant administered in doses of 0.8 mg/kg over 4 hours; 1.5 mg/kg/day or0.15 mg/kg/day for 3 days, development of bradykinin-induced hypotension, vasodilatation and reflextachycardia was prevented. Icatibant was shown to be a competitive antagonist when the bradykininchallenge dose was increased 4-fold.

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 andhad identical designs except for the comparator (one with oral tranexamic acid as the comparator andone placebo controlled). A total of 130 patients were randomized to receive either a 30 mg dose oficatibant (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 oflaryngeal angioedema received open label treatment with icatibant. The primary efficacy endpoint wasthe time to onset of symptom relief using a visual analogue scale (VAS). Table 3 shows the efficacyresults for these studies.

FAST-3 was a randomized, placebo-controlled, parallel-group study of 98 adult patients with a medianage of 36 years. Patients were randomized to receive either icatibant 30 mg or placebo bysubcutaneous injection. A subset of patients in this study experienced acute HAE attacks whilereceiving androgens, antifibrinolytic agents or Cl inhibitors. The primary endpoint was time to onsetof symptom relief assessed using a 3-item composite visual analog score (VAS-3) consisting ofassessments 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 and2.0 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 andtime to onset of primary symptom relief were similar regardless of age group, sex, race, weight orwhether 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 237patients were treated with 1,386 doses of 30 mg icatibant for 1,278 attacks of acute HAE. In the first15 Firazyr treated attacks (1,114 doses for 1,030 attacks), the median times to onset of symptom reliefwere similar across attacks (2.0 to 2.5 hours). 92.4% of these attacks of HAE were treated with asingle dose of Firazyr.

Table 3. Efficacy results for FAST-1 and FAST-2

Controlled Clinical Study of FIRAZYR vs Tranexamic acid or Placebo: Efficacy Results

FAST-2 FAST-1

Tranexamicicatibant icatibant Placeboacid

Number of subjects Number of subjects36 38 27 29in ITT Population in ITT Population

Controlled Clinical Study of FIRAZYR vs Tranexamic acid or Placebo: Efficacy Results

FAST-2 FAST-1

Tranexamicicatibant icatibant Placeboacid

Baseline Baseline63.7 61.5 69.3 67.7

VAS(mm) VAS(mm)

Change from Change from

- 41.6 -14.6 -44.8 -23.5baseline to 4 hours baseline to 4 hours

Difference Differencebetween treatments -27.8 (-39.4, -16.2) p < 0.001 between treatments -23.3 (-37.1, -9.4) p = 0.002(95% CI, p-value) (95% CI, p-value)

Change from Change frombaseline to -54.0 -30.3 baseline to -54.2 -42.412 hours 12 hours

Difference Differencebetween treatments -24.1 (-33.6, -14.6) p < 0.001 between treatments -15.2 (-28.6, -1.7) p = 0.028(95% CI, p-value) (95% CI, p-value)

Median time to Median time toonset of symptom onset of symptomrelief (hours) relief (hours)

All episodes All episodes2.0 12.0 2.5 4.6(N = 74) (N = 56)

Response rate Response rate(%, CI) at 4 hours (%, CI) at 4 hoursafter start of after start oftreatment treatment

All episodes 80.0 30.6 All episodes 66.7 46.4(N = 74) (63.1, 91.6) (16.3, 48.1) (N = 56) (46.0, 83.5) (27.5, 66.1)

Median time to Median time toonset of symptom onset of symptomrelief: all relief: allsymptoms (hours): symptoms (hours):

Abdominal pain 1.6 3.5 Abdominal pain 2.0 3.3

Skin swelling 2.6 18.1 Skin swelling 3.1 10.2

Skin pain 1.5 12.0 Skin pain 1.6 9.0

Median time to Median time toalmost complete almost completesymptom relief symptom relief(hours) (hours)

All episodes All episodes10.0 51.0 8.5 19.4(N = 74) (N = 56)

Median time to Median time toregression of regression ofsymptoms, by symptoms, bypatient (hours) patient (hours)

All episodes All episodes0.8 7.9 0.8 16.9(N = 74) (N = 56)

Median time to Median time tooverall patient overall patientimprovement, by improvement, byphysician (hours) physician (hours)

All episodes All episodes1.5 6.9 1.0 5.7(N = 74) (N = 56)

Table 4. Efficacy results for FAST-3

Efficacy Results: FAST-3; Controlled Phase -- ITT population

Endpoint Statistic Firazyr Placebo p-value(n = 43) (n=45)

Primary Endpoint

Time to Onset of Symptom Median 2.0 19.8 <0.001

Relief-- Composite VAS (hrs)

Other Endpoints

Time to Onset of Primary Median 1.5 18.5 < 0.001

Symptom Relief (hrs)

Change in Composite VAS Mean -19.74 -7.49 < 0.001

Score at 2 hrs after treatment

Change in Composite Mean -0.53 -0.22 < 0.001

Subject-Assessed Symptom

Score at 2 hours

Change in Composite Mean -0.44 -0.19 < 0.001

Investigator-Assessed

Symptom Score at 2 hours

Time to Almost Complete Median 8.0 36.0 0.012

Symptom Relief (hrs)

Time to Subject-Assessed Median 0.8 3.5 < 0.001

Initial Symptom

Improvement (hrs)

Time to Investigator- Median 0.8 3.4 < 0.001

Assessed Initial Visual

Symptom Improvement (hrs)

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 respectto time to onset of symptom relief.

An open label, non-randomised single-arm study (HGT-FIR-086) was performed with a total of 32patients. All patients received at least one dose of icatibant (0.4mg/kg body weight up to a maximumdose of 30 mg) and the majority of patients were followed up for a minimum of 6 months. Elevenpatients 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 prepubertaland 11 pubertal/postpubertal) for HAE attack.

The primary efficacy endpoint was the time to onset of symptom relief (TOSR) measured using acomposite investigator-reported symptom score. Time to symptom relief was defined as the durationof 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, 1.0-1.1hours). At 1 and 2 hours post treatment, approximately 50% and 90% of patients experienced onset ofsymptom relief, respectively.

Overall, the median time to minimal symptoms (earliest time post treatment when all symptoms wereeither 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 andsubcutaneous administration to healthy volunteers and patients. The pharmacokinetic profile oficatibant in patients with HAE is similar to that in healthy volunteers.

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

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

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

In vitro studies have confirmed that icatibant is not degraded by oxidative metabolic pathways and isnot 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.

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

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

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

Hepatic and Renal Impairment

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

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

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 of30 mg), the time to maximum concentration is approximately 30 minutes and the terminal half-life isabout 2 hours. There are no observed differences in the exposure to icatibant between HAE patientswith and without an attack. Population pharmacokinetic modelling using both adult and paediatric datashowed that clearance of icatibant is related to body weight with lower clearance values noted forlower 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 theobserved 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 beenconducted. In both rats and dogs, there was a dose-related reduction in circulating sex hormone levelsand 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 asubcutaneous dose of 30 mg. A NOAEL was not measurable in the rat study, however, all of thefindings 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 wasseen to reverse after cessation of icatibant treatment. The clinical relevance of the adrenal glandfindings is unknown.

Icatibant had no effect on the fertility of male mice (top dose 80.8 mg/kg/day) and rats (top dose10 mg/kg/day).

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

In a standard battery of in vitro and in vivo tests icatibant was not genotoxic.

Icatibant was not teratogenic when administered by SC injection during early embryonic and fetaldevelopment in rat (top dose 25 mg/kg/day) and rabbit (top dose 10 mg/kg/day). Icatibant is a potentantagonist of bradykinin and therefore, at high dose levels, treatment can have effects on the uterineimplantation process and subsequent uterine stability in early pregnancy. These uterine effects alsomanifest in late stage pregnancy where icatibant exhibits a tocolytic effect resulting in delayedparturition 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 amaximally tolerated dose. In the pivotal juvenile toxicity study in which sexually immature rats weretreated daily with 3 mg/kg/day for 7 weeks, atrophy of testes and epididymides were observed; theobserved microscopic findings were partially reversible. Similar effects of icatibant on reproductivetissue were seen in sexually mature rats and dogs. These tissue findings were consistent with reportedeffects on gonadotrophins and during the subsequent treatment-free period appear to be reversible.

Icatibant did not elicit any cardiac conduction change in vitro (hERG channel) or in vivo in normaldogs or in various dog models (ventricular pacing, physical exertion and coronary ligation) where noassociated hemodynamic changes were observed. Icatibant has been shown to aggravate inducedcardiac ischemia in several non-clinical models, although a detrimental effect has not consistentlybeen shown in acute ischemia.

Sodium chloride

Acetic acid, glacial (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

Not applicable.

2 years.

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 coatedwith 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 syringeswith three needles.

Not all pack sizes may be marketed.

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

Use in the paediatric population

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 andadminister 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.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

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 Agencyhttp://www.ema.europa.eu.