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) in adults (with C1-esterase-inhibitor deficiency).

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

Posology

The recommended dose 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.

Special populations

Elderly patients

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

Elderly patients 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.

Paediatric population

The safety and efficacy of Firazyr in children aged 0-18 years has not been established.

No data are available.

Method of administration

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

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

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

Each Firazyr syringe is intended for single use only.

Firazyr solution for injection should be injected slowly due to the volume to be administered (3 ml).

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.

Self-administration

For patients who 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, it is recommended that the patient should seek medical advice and that subsequent doses are given in a medical institution (see section 4.2).

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.

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 or 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).

Table 1: Adverse reactions reported with icatibant

Description of selected adverse reactions

Immunogenicity

Across repeated treatment 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

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 or hypotension in healthy subjects. No therapeutic intervention was necessary.

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 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.

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.

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 2 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 30mg 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 3 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 225 patients were treated with 1,076 doses of 30mg icatibant for 987 attacks of acute HAE. In an assessment of the first 5 icatibant-treated attacks (621 doses for 582 attacks) the time to onset of symptom relief was similar across attacks. 92.9 % of these attacks were treated with a single dose of icatibant.

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

Table 3. Efficacy results for FAST-3

126 patients were treated in the open label extension (OLE) phase FAST-1 and FAST-2 for a total of 714 separate attacks. The efficacy results were similar to those seen in the controlled phase of the studies. The majority of attacks (88.2% in FAST-1 and 89.8% in FAST-2) required only a single dose of icatibant.

A total of 60 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.

The pharmacokinetics of icatibant has been extensively 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 vitro studies 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

Data suggest an age-related decline in clearance resulting in about 50-60% higher exposure in the elderly (75-80 years) compared to patients aged 40 years. Data suggests that gender and weight do not have a significant influence on icatibant pharmacokinetics.

Limited data suggest that icatibant exposure is not influenced by hepatic or renal impairment. The influence of race on icatibant pharmacokinetics has not been evaluated. There are no pharmacokinetic data in children.

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 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 of in vitro and in vivo tests icatibant was not genotoxic.

Icatibant was not teratogenic when administered by s.c. 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).

In a juvenile toxicity study in which sexually immature rats were treated daily with 3 mg/kg for 7 weeks, atrophy of testes and epididymides were observed. 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 change in vitro (hERG channel) or in vivo in 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.

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 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. For single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

Shire Orphan Therapies GmbH

Friedrichstrasse 149

D-10117 Berlin

Germany

EU/1/08/461/001

EU/1/08/461/002

Date of first authorisation: 11 July 2008

Date of latest renewal: March 2013

March 2013

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