FIRAZYR Solution for injection Ref.[10973] Active ingredients: Icatibant

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.

Sodium content

This medicinal product contains less than 1 mmol (23 milligrams) of sodium per syringe, so it is essentially 'sodium-free.'

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.

Paediatric population

Interaction studies have only been performed in adults.

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 are italicised.

Table 2. Adverse reactions reported with icatibant:

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

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 antiicatibant 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.

Not applicable.