Firazyr 30 mg solution for injection in prefilled syringe

Each prefilled syringe of 3 ml contains icatibant acetate equivalent to 30 mg icatibant.

Each ml of the solution contains 10 mg of icatibant.

For a 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 subcutaneous administration preferably in the abdominal area.

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

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).

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

Each Firazyr syringe is intended for single use only.

Posology

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

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

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 dosage adjustment is required in patients with hepatic impairment.

Renal impairment

No dosage 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 pediatric data are available.

Hypersensitivity to the active substance or to any of the excipients.

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.

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.

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

Co-administration of Firazyr with 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).

Breastfeeding

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 immature animals repeated use of icatibant reversibly delayed sexual maturation (see section 5.3).

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

The safety of icatibant has been established in 1304 subjects treated with various doses, regimens and routes of administration during Phase IIII studies in various indications.

Sixty three (HAE) patients received icatibant in two Phase III trials for treatment of an attack in the controlled phase and 126 patients were treated in the open label phase.

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 in severity, transient, and resolved without further intervention.

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

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

Note: Due to the low number of patients, each of the uncommon events has only been reported in a single patient.

Table 1: Adverse reactions reported with icatibant in the phase III clinical trials.

* HAE attacks were reported as adverse reactions, however based on time of occurrence, the majority were recurrent attacks and not related to treatment with Firazyr.

Self-administration:

In an open-label study, the safety profile of the patients who self-administered Firazyr was similar to that administered by healthcare professionals.

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: cardiac therapy, other cardiac preparations, ATC code: C01EB19.

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 4fold.

Efficacy data were obtained from an initial openlabel Phase II study and from two randomised, double blind controlled multi centre Phase III studies (one with oral tranexamic acid as the comparator and one placebo controlled). The pivotal Phase III studies were otherwise identical in design. 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.

In the Phase III trials, the primary efficacy endpoint was time to onset of symptom relief using a visual analogue scale (VAS). In both studies, patients on icatibant had a faster median time to onset of symptom relief (2.0 and 2.5 hours, respectively) compared to tranexamic acid (12.0 hours) and placebo (4.6 hours). The treatment effect of icatibant was confirmed by secondary efficacy endpoints.

The following table shows the results for the two pivotal trials

126 patients were treated in the open label extension (OLE) phase 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 Study 2 and 89.8% in Study 1) in both studies required only a single dose of icatibant.

A total of 38 patients were treated for a total of 78 attacks of HAE affecting the larynx. The results were similar to patients with non-laryngeal attacks of HAE with a median time to start of regression of symptoms of 0.6 - 1.0 hours (controlled phase).

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.

Metabolism

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 eva luated. There are no pharmacokinetic data in children.

Repeated-dose studies of up to 3months duration have been conducted in rat and dog. Maximum daily exposures (AUC) at the No Observed Adverse Effect Levels in the 3month study in rat were 3.6 times and in the 4 week study in dog were 9.4 times the AUC in humans after a subcutaneous dose of 30 mg.

Long-term studies to determine the carcinogenic potential of icatibant have not been conducted to date.

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 immature rats and dogs, repeated use of icatibant reversibly delayed sexual maturation. The effects appeared to be secondary to icatibant-induced changes in gonadotrophin levels, and were reversible. Similar effects of icatibant on gonadotrophins also occurred in sexually mature dogs.

Icatibant had no effect on the fertility of male mice and rats.

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 prefilled 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 prefilled syringe with one needle or a multipack containing three prefilled 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.

Jerini AG

Invalidenstr. 130

D-10115 Berlin

Germany

EU/1/08/461/001

EU/1/08/461/002

11/07/2008

28/02/2011

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