Icatibant-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ICATIBANT-VISTA (ICATIBANT-VISTA)

Composition:

active substance: icatibant acetate;

1 pre-filled syringe (3 mL) contains icatibant acetate equivalent to icatibant
30 mg;

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

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: clear, colorless solution in a 3 mL glass syringe, free from visible particles.

Pharmacotherapeutic group. Other hematological agents, drugs for the treatment of hereditary angioedema. ATC code B06A C02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Hereditary angioedema (HAE) is an autosomal dominant disease caused by deficiency or dysfunction of C1 esterase inhibitor. HAE attacks are associated with increased bradykinin release, which is a key mediator in the development of clinical symptoms.

HAE is characterized by recurrent episodes of subcutaneous and/or submucosal swelling involving the upper respiratory tract, skin, and gastrointestinal tract. An attack typically lasts from 2 to 5 days.

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

Pharmacodynamic effects.

Icatibant was administered to healthy young volunteers at a dose of 0.8 mg/kg over 4 hours, or at 1.5 mg/kg/day or 0.15 mg/kg/day for 3 days, effectively preventing bradykinin-induced hypotension, vasodilation, and reflex tachycardia. Icatibant has been shown to act as a competitive antagonist even when bradykinin levels are increased fourfold.

Clinical efficacy and safety.

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

The phase III clinical trials (FAST-1 and FAST-2) were randomized, double-blind, controlled studies with identical designs, except for the comparator drug (one used oral tranexamic acid as the comparator, and the other was placebo-controlled). A total of 130 patients were randomized to receive either icatibant 30 mg (63 patients) or a comparator (tranexamic acid – 38 patients or placebo – 29 patients). Subsequent HAE episodes were treated in an open-label manner. Patients with symptoms of laryngeal angioedema received open-label icatibant therapy. The primary efficacy endpoint was time to onset of symptom relief assessed using a visual analogue scale (VAS). Efficacy results from these studies are shown in Table 1. FAST-3 was a randomized, placebo-controlled, parallel-group study involving 98 adult patients with a mean age of 36 years. Patients were randomized to receive either icatibant 30 mg or placebo via subcutaneous injection. Some patients in this study had acute HAE attacks while receiving androgens, antifibrinolytics, or C1 inhibitors. The primary endpoint was time to onset of symptom relief assessed using a composite 3-item visual analogue scale (VAS-3), consisting of assessments of skin swelling, skin pain, and abdominal pain. Efficacy results from FAST-3 are shown in Table 2.

In these studies, the median time to onset of symptom relief was shorter in patients receiving icatibant (2.0, 2.5, and 2.0 hours, respectively) compared to patients receiving tranexamic acid (12.0 hours) and placebo (4.6 and 19.8 hours). The therapeutic effect of icatibant was confirmed by secondary efficacy endpoints. In a pooled analysis of these phase III controlled trials, time to onset of symptom resolution and time to onset of resolution of primary symptoms were consistent regardless of age group, sex, race, body weight, or concomitant use of androgens or antifibrinolytics.

Response was also consistent across repeated attacks in the phase III controlled trials. Overall, 237 patients received 1386 doses of icatibant 30 mg for treatment of 1278 acute HAE attacks. In the first 15 patients experiencing attacks treated with icatibant (1114 doses for 1030 attacks), the median time to onset of symptom relief was similar across all attacks (ranging from 2.0 to 2.5 hours). 92.4% of these HAE attacks were treated with a single dose of icatibant.

Table 1

Efficacy results for FAST-1 and FAST-2

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Table 2

Efficacy results for FAST-3.

A total of 66 patients with laryngeal attacks of HAE were treated in these controlled Phase III clinical trials. The results were similar to those in patients with non-laryngeal HAE attacks regarding time to onset of symptom relief. Pediatric use.

An open-label, single-group study (HGT-FIR-086) was conducted in 32 patients. All patients received at least one dose of icatibant (0.4 mg/kg body weight up to a maximum dose of 30 mg), and most patients were followed for at least 6 months. Eleven patients were prepubertal, and 21 patients were either pubertal or postpubertal.

The efficacy population consisted of 22 patients who received icatibant (11 prepubertal and 11 pubertal/postpubertal) for an HAE attack.

The primary efficacy endpoint was time to onset of symptom relief (TOSR), measured using an investigator-reported combined symptom score. Time to symptom relief was defined as the duration of time (in hours) during which symptoms decreased by 20%. Overall, the median time to onset of symptom relief was 1.0 hour (95% CI, 1.0–1.1 hours). Approximately 50% and 90% of patients experienced symptom relief within 1 and 2 hours after treatment, respectively.

Overall, the median time to minimal symptoms (the earliest time after treatment when all symptoms were mild or absent) was 1.1 hours (95% CI, 1.0–2.0 hours).

Pharmacokinetics.

The pharmacokinetics of icatibant have been characterized in studies using both intravenous and subcutaneous administration in 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 reach maximum concentration is approximately 30 minutes.

Distribution.

The volume of distribution of icatibant (Vss) is approximately 20–25 L. Plasma protein binding is 44%.

Biotransformation.

Icatibant is extensively metabolized by proteolytic enzymes into inactive metabolites, which are primarily excreted in urine.

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

Icatibant is primarily eliminated via metabolism, with less than 10% of the dose excreted unchanged in urine. Clearance is approximately 15–20 L/h and is dose-independent. The terminal half-life in plasma is approximately 1–2 hours.

Special patient populations.

Elderly patients.

Data indicate an age-related decrease in clearance, resulting in approximately 50–60% higher exposure in elderly patients (75–80 years of age) compared to patients aged 40 years.

Gender.

Data indicate no difference in clearance between women and men after adjustment for body weight.

Hepatic and renal impairment.

Limited data suggest that the effect of icatibant is not influenced by hepatic or renal impairment.

Race.

Information on the effect across individual racial groups is limited. Available exposure data indicate no difference in clearance between non-white (n = 40) and white (n = 132) patients.

Use in children.

The pharmacokinetics of icatibant in pediatric patients with HAE were characterized in study HGT-FIR-086 (see section "Pharmacodynamics"). After a single subcutaneous dose (0.4 mg/kg up to a maximum dose of 30 mg), the time to maximum concentration is approximately 30 minutes, and the terminal half-life is approximately 2 hours. There are no observed differences in icatibant exposure between patients with HAE during and outside of an attack. Population pharmacokinetic modeling using data from both adult and pediatric patients showed that icatibant clearance is body weight-dependent, with lower clearance values observed in children with lower body weight. Based on body weight-based dosing modeling, the predicted icatibant exposure in pediatric patients with HAE (see section "Posology and method of administration") is lower than the exposure observed in clinical studies conducted in adult patients with HAE.

Clinical characteristics.

Indications.

Symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents, and children from 2 years of age (caused by C1 esterase inhibitor deficiency).

Contraindications.

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

Special precautions.

The solution should be clear, colorless, and free of visible particles.

Use in the pediatric population.

The appropriate dose for administration depends on body weight (see section "Method of administration and dosage").

If the required dose is less than 30 mg (3 mL), the following equipment is needed to obtain and administer the appropriate dose:

• adapter (proximal and/or distal Luer Lock connector);
• 3 mL (recommended) graduated syringe.

The pre-filled icatibant syringe and all other components are intended 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 discarded into a sharps container.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of icatibant with angiotensin-converting enzyme (ACE) inhibitors has not been studied. ACE inhibitors are contraindicated in patients with HAE due to the potential increase in bradykinin levels.

Use in children.

All drug interaction studies have been conducted only in adults.

Special precautions for use.

Laryngeal attacks.

Patients with laryngeal attacks should remain in an appropriate medical facility after injection until a physician considers discharge safe.

Ischemic heart disease.

Under conditions of ischemia, worsening of cardiac function and reduced coronary blood flow are theoretically possible due to antagonism of bradykinin type 2 receptors. Therefore, caution should be exercised when administering icatibant to patients with acute ischemic heart disease or unstable angina.

Stroke.

Although data exist supporting a positive effect of B2-receptor blockade immediately after stroke, there is a theoretical possibility that icatibant may attenuate the beneficial neuroprotective effects of bradykinin in the late phase. Accordingly, caution should be exercised when prescribing icatibant to patients within several weeks following a stroke.

Administration by a caregiver/patient self-injection.

For patients who have never previously used the medicinal product ICATIBANT-VISTA, the first treatment should be administered in a medical facility or under physician supervision.

If there is insufficient symptom relief or recurrence of symptoms after self-administration or administration by a caregiver, the patient or caregiver should contact a physician. For adults, subsequent doses required to control an attack should be administered in a medical facility (see section "Dosage and administration"). There are no data on administration of subsequent doses to control the same attack in adolescents or children. Patients who have experienced a laryngeal attack must seek medical attention and be monitored in a medical facility, including after having administered an injection at home.

Important information about excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per syringe and is therefore essentially sodium-free.

Use in children.

There is limited experience with treating more than one HAE attack with icatibant in children.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no clinical data on the effects of icatibant in pregnancy. Animal studies have shown effects on implantation of the fertilized egg and on labor; however, the potential risk in humans is unknown.

Icatibant should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus (e.g., for treatment of potentially life-threatening laryngeal attacks).

Breastfeeding period.

Icatibant is excreted in the milk of lactating rats at concentrations similar to those in maternal blood. No effect on postnatal development was observed in rats.

It is unknown whether icatibant is excreted in human breast milk; however, women who are breastfeeding and require treatment with icatibant are recommended to refrain from breastfeeding for 12 hours after treatment.

Fertility.

In both rats and dogs, repeated administration of icatibant resulted in effects on reproductive organs. Icatibant did not affect fertility in male mice and rats. In a study of 39 healthy adult men and women who received 30 mg of icatibant every 6 hours as 3 doses every 3 days (a total of 9 doses), no clinically significant changes were observed compared to baseline in basal and GnRH-stimulated reproductive hormone concentrations in either women or men. No significant effect of icatibant on progesterone concentration during the luteal phase, luteal function, or menstrual cycle duration was observed in women, and no significant effect on sperm count, motility, or morphology was observed in men. The dosing regimen used in this study is unlikely to be maintained under clinical conditions.

Ability to affect reaction speed when driving or operating machinery.

Icatibant has a minor influence on the ability to drive or operate machinery. Fatigue, lethargy, tiredness, somnolence, and dizziness have been reported after administration of icatibant. These symptoms may occur as a result of the HAE attack itself. Patients should not drive or operate machinery if they experience fatigue or dizziness.

Administration and Dosage.

The medicinal product ICATIBANT-VISTA is intended to be administered under the supervision of a healthcare professional.

Dosage.

Adults.

The recommended dose for adults is a single 30 mg subcutaneous injection of ICATIBANT-VISTA.

In most cases, one injection of ICATIBANT-VISTA is sufficient to control an attack. If symptoms are not adequately relieved or if symptoms recur, a second injection of ICATIBANT-VISTA may be administered 6 hours after the first injection. If symptoms are still not adequately relieved or if symptoms recur again, a third injection of ICATIBANT-VISTA may be given 6 hours after the second injection. No more than 3 injections of this medicinal product should be administered within 24 hours.

During clinical studies, no more than 8 injections of ICATIBANT-VISTA were administered per month.

Children.

The recommended dose of ICATIBANT-VISTA based on body weight for children and adolescents (aged 2 to 17 years) is presented in Table 3.

Table 3

Dosing regimen for children

During the clinical trial, no more than 1 injection of the medicinal product icatibant was administered per HAE attack.

Elderly patients

Information regarding patients aged 65 years and older is limited.

It has been demonstrated that elderly individuals exhibit increased systemic exposure to icatibant. The clinical significance of this exposure regarding icatibant safety is unknown (see section "Pharmacokinetics").

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Renal impairment

Dose adjustment is not required in patients with renal impairment.

Method of administration

The medicinal product ICATIBANT-VISTA is intended for subcutaneous administration, preferably in the abdominal area.

This medicinal product should be administered slowly, taking into account the volume to be injected. Each pre-filled syringe of ICATIBANT-VISTA is for single use only.

Caregiver / self-administration of the medicinal product

The decision on whether to designate a caregiver or allow self-administration of ICATIBANT-VISTA must be made solely by a physician experienced in the diagnosis and treatment of hereditary angioedema (see section "Special instructions").

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

Step-by-step instructions for administration of ICATIBANT-VISTA injection for:

• self-administration (adults);
• administration to adults, adolescents, or children aged 2 years and older (with body weight of at least 12 kg) by a caregiver or healthcare professional.

Children.

The medicinal product can be used in children aged 2 years and older. Dosage regimens cannot be recommended for children under 2 years of age or with body weight less than 12 kg, as safety and efficacy have not been established in this pediatric population.

Overdose.

Clinical data on overdose are lacking. A dose of 3.2 mg/kg intravenously (approximately 8 times higher than the therapeutic dose) caused transient erythema, pruritus, flushing, or arterial hypotension in healthy volunteers. No therapeutic intervention was required.

Adverse reactions

In clinical studies, a total of 999 attacks of HAE were treated with icatibant 30 mg administered subcutaneously by healthcare professionals. Icatibant 30 mg was administered subcutaneously by healthcare professionals to 129 healthy volunteers and 236 patients with HAE. Almost all patients who received subcutaneous icatibant during clinical trials experienced injection site reactions (characterized by skin irritation, swelling, pain, itching, erythema, and burning sensation). These reactions were generally mild or moderate in severity, transient, and resolved without further intervention. Adverse reactions (see Table 4)

The frequency categories of adverse reactions listed in Table 4 are defined according to the following criteria: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Table 4

Adverse reactions reported during the use of icatibant

Use in children.

A total of 32 pediatric patients (8 children aged 2 to 11 years and 24 adolescents aged 12 to 17 years) with HAE received treatment with icatibant during clinical trials. Thirty-one patients received a single dose of icatibant, and one patient (an adolescent) received icatibant for two HAE attacks (a total of two doses). Icatibant was administered subcutaneously at a dose of 0.4 mg/kg according to body weight, up to a maximum dose of 30 mg. Injection site reactions such as erythema, swelling, burning sensation, skin pain, and pruritus were observed in most pediatric patients receiving subcutaneous icatibant; these were mild or moderate in severity and consistent with reactions reported in adults. Injection site reactions considered severe occurred in two children and resolved completely within 6 hours. These reactions included erythema, swelling, burning, and warmth. No clinically significant changes in reproductive hormones were observed during clinical trials.

Description of selected adverse reactions.

Immunogenicity.

In controlled Phase III studies of repeated treatment in adults, transient positive antibody responses to icatibant were observed in isolated cases. Efficacy was maintained in all patients. One patient receiving icatibant tested positive for anti-icatibant antibodies both before and after administration of the drug. This patient was monitored for 5 months, and subsequent samples were negative for antibodies against icatibant. Hypersensitivity reactions or anaphylactic reactions have not been reported with icatibant use.

Reporting suspected adverse reactions.

Reporting of adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Packaging. 3 mL in a pre-filled syringe, 1 or 3 syringes per carton.

Prescription status. Prescription only.

Manufacturer. Nang Kuang Pharmaceutical Co., Ltd.

Manufacturer's address and location of business activity.

No. 1001, 1001-1, Zhongshan Rd., Xinhua Dist, Tainan City, Taiwan (R.O.C.).