INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFFECTO (AFETTO)

Composition:

Active substance: bilastine;

One tablet contains 20 mg of bilastine;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, oval-shaped, with a biconvex surface and a score line.

Pharmacotherapeutic group. Antihistamines for systemic use. Other antihistamines for systemic use. Bilastine. ATC code R06AX29.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Bilastine is a non-sedating, long-acting histamine antagonist and a highly selective blocker of peripheral H1-receptors, which does not bind to muscarinic receptors.

After single administration, bilastine suppresses histamine-induced skin reactions (wheals and erythema) for up to 24 hours.

Clinical efficacy and safety

In clinical studies involving adults and adolescents with allergic rhinoconjunctivitis (seasonal and perennial), administration of 20 mg bilastine once daily for 14–28 days was effective in alleviating symptoms such as sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus, lacrimation, and ocular redness. Symptoms were effectively controlled for 24 hours.

In two clinical studies involving patients with chronic idiopathic urticaria, administration of 20 mg bilastine once daily for 28 days was effective in reducing the intensity of itching, as well as the number and size of wheals, and urticaria-related discomfort. Patients showed improvement in sleep and quality of life.

In clinical studies, bilastine did not cause clinically significant QTc interval prolongation or any other cardiovascular effects, even when administered at a dose of 200 mg daily (10 times the clinical dose) for 7 days in 9 participants, or when co-administered with P-glycoprotein (P-gp) inhibitors such as ketoconazole (24 participants) and erythromycin (24 participants). Additionally, a thorough QT study was conducted in 30 volunteers.

In controlled clinical trials, at the recommended dose of 20 mg once daily, the central nervous system (CNS) safety profile of bilastine was similar to that of placebo, and the incidence of somnolence with bilastine was not statistically different from placebo. Bilastine at doses up to 40 mg daily did not affect psychomotor performance in clinical studies or the ability to drive in a standard driving test.

In elderly patients (≥ 65 years of age) participating in Phase II and III studies, efficacy and safety were not different from those observed in younger patients.

In a post-marketing study involving 146 elderly patients, no differences in safety profile were observed compared to other adult participants.

Children

Adolescents (aged 12–17 years) were included in the clinical development program. Of these, 128 adolescents received bilastine during clinical trials (81 in double-blind allergic rhinoconjunctivitis studies), while the remaining 116 adolescents were randomized to receive active comparator drugs or placebo. No differences in efficacy or safety between adults and adolescents were observed.

According to current guidelines, proven efficacy in adults and adolescents may be considered acceptable for children, given that systemic exposure to 10 mg bilastine in children aged 6 to 11 years with body weight ≥ 20 kg corresponds to exposure in adults receiving 20 mg bilastine (see section "Pharmacokinetics"). Extrapolation of data obtained in adults and adolescents is considered justified for this medicinal product, as the pathophysiology of allergic rhinoconjunctivitis and urticaria is the same across all age groups.

In a 12-week controlled clinical trial in children aged 2 to 11 years (total of 509 children, of whom 260 received 10 mg bilastine [58 aged 2 to < 6 years, 105 aged 6 to < 9 years, and 97 aged 9 to < 12 years], and 249 received placebo [58 aged 2 to < 6 years, 95 aged 6 to < 9 years, and 96 aged 9 to < 12 years]), the safety profile of bilastine (n = 260) at the recommended pediatric dose of 10 mg once daily was similar to that of placebo (n = 249), with adverse reactions reported in 5.8% and 8.0% of patients receiving 10 mg bilastine and placebo, respectively. Both 10 mg bilastine and placebo slightly reduced somnolence and sedative effects as assessed by the pediatric sleep quality questionnaire, with no statistically significant difference between treatment groups. In children aged 2 to 11 years, administration of 10 mg bilastine daily showed no significant difference in QTc compared to placebo. A specific pediatric quality-of-life questionnaire in children with allergic rhinoconjunctivitis or chronic urticaria demonstrated overall improvement over 12 weeks, with no statistically significant difference between bilastine and placebo groups. A total of 509 children participated in the study, including 479 with allergic rhinoconjunctivitis and 30 with diagnosed chronic urticaria. Of the 260 children receiving bilastine, 252 (96.9%) were treated for allergic rhinoconjunctivitis and 8 (3.1%) for chronic urticaria. Similarly, of the 249 children receiving placebo, 227 (91.2%) were treated for allergic rhinoconjunctivitis and 22 (8.8%) for chronic urticaria.

The European Medicines Agency has waived the obligation to submit results of bilastine studies in all pediatric populations under 2 years of age (see section "Posology and method of administration").

Pharmacokinetics

Absorption

After oral administration, bilastine is rapidly absorbed, with peak plasma concentration reached approximately 1.3 hours post-dose. No accumulation was observed. The mean bioavailability of bilastine after oral administration is 61%.

Distribution

In vitro and in vivo studies have shown that bilastine is a substrate of P-gp (see section "Interaction with other medicinal products and other forms of interaction" for interactions with ketoconazole, erythromycin, and diltiazem) and OATP (see section "Interaction with other medicinal products and other forms of interaction" for interaction with grapefruit juice). Bilastine does not appear to be a substrate of the BCRP or renal transporters OST2, OAT1, and OAT3. In vitro data do not suggest that bilastine inhibits the activity of transporter proteins such as P-gp, MRP2, BCRP, BSEP, OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and NTCP in systemic circulation, as its inhibitory capacity for P-gp, OATP2B1, and OCT1 is negligible, with IC50 values ≥ 300 µM, significantly exceeding the predicted maximum plasma concentration (Cmax) following clinical use of bilastine. Thus, such interactions are not expected to be clinically relevant. However, these results suggest that inhibition of transporter proteins in the intestinal mucosa (e.g., P-gp) by bilastine cannot be excluded. At therapeutic doses, 84–90% of bilastine is plasma protein-bound.

Biotransformation

In vitro studies showed that bilastine does not induce or inhibit the activity of CYP450 isoenzymes.

Elimination

In a mass balance study conducted in healthy adult volunteers, after a single 20 mg dose of 14C-bilastine, nearly 95% of the administered dose was recovered in urine and feces (28.3% and 66.5%, respectively) as unchanged bilastine, indicating minimal metabolism of bilastine in humans. The mean elimination half-life of bilastine in healthy volunteers is 14.5 hours.

Linearity

Within the investigated dose range (5 to 220 mg), bilastine exhibits linear pharmacokinetics with low inter-subject variability.

Renal impairment

Studies in patients with varying degrees of renal function showed that with normal renal function (GFR [glomerular filtration rate]: > 80 mL/min/1.73 m²), mean AUC0–∞ (± SD) was 737.4 (± 260.8) ng·h/mL; with mild renal impairment (GFR: 50–80 mL/min/1.73 m²), it was 967.4 (± 140.2) ng·h/mL; with moderate impairment (GFR: 30 to < 50 mL/min/1.73 m²), 1384.2 (± 263.23) ng·h/mL; and with severe impairment (GFR: < 30 mL/min/1.73 m²), 1708.5 (± 699.0) ng·h/mL.

In patients with normal renal function, mean (± SD) elimination half-life of bilastine was 9.3 hours (± 2.8); in patients with mild impairment, 15.1 hours (± 7.7); moderate impairment, 10.5 hours (± 2.3); and severe impairment, 18.4 hours (± 11.4). Bilastine was undetectable in urine in nearly all patients within 48–72 hours after administration. Such pharmacokinetic changes are not expected to be clinically significant or affect the safety of bilastine, as plasma concentrations in patients with renal impairment remain within safe limits.

Hepatic impairment

Pharmacokinetic data in patients with hepatic impairment are not available. Bilastine is not metabolized in humans. Studies in patients with renal impairment indicate that bilastine is primarily eliminated via the kidneys, with only minimal biliary excretion likely. Hepatic function changes are not expected to have a clinically significant impact on bilastine pharmacokinetics.

Elderly patients

Pharmacokinetic data in patients over 65 years of age are limited. Pharmacokinetic parameters of bilastine in patients over 65 years and those aged 18–35 years do not differ significantly.

Children

Pharmacokinetic data in adolescents (12–17 years) are not available, as extrapolation of adult data is considered appropriate for this medicinal product.

Pharmacokinetic data in children were obtained from a Phase II pharmacokinetic study in which 31 children aged 4 to 11 years with allergic rhinoconjunctivitis or chronic urticaria received one 10 mg orally disintegrating tablet of bilastine once daily. Pharmacokinetic analysis of plasma bilastine concentrations showed that after administration of the recommended pediatric dose of 10 mg once daily, systemic exposure corresponds to that observed in adults and adolescents receiving 20 mg. The mean AUC value in children aged 6 to 11 years was 1014 ng·h/mL. These results were generally below the maximum safe level established based on data from administration of 80 mg bilastine once daily in adults, according to the drug's safety profile. This confirms that a 10 mg oral dose of bilastine once daily is a justified therapeutic dose for pediatric patients aged 6 to 11 years with body weight ≥ 20 kg.

Clinical characteristics

Indications. For symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria.

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

Interaction with other medicinal products and other forms of interaction

Interaction studies have been conducted only in adults.

Interaction with food. Food reduces oral bioavailability of bilastine by 30%.

Interaction with grapefruit juice. When bilastine 20 mg is taken concomitantly with grapefruit juice, the bioavailability of bilastine is reduced by 30%. A similar effect may also occur with other fruit juices. The extent of reduced bioavailability may vary depending on the juice manufacturer and fruit type. The mechanism of this interaction involves inhibition of the OATP1A2 transporter protein, for which bilastine is a substrate (see section "Pharmacokinetics"). Medicinal products that are substrates or inhibitors of OATP1A2 (e.g. ritonavir or rifampicin) may also reduce plasma concentrations of bilastine.

Interaction with ketoconazole or erythromycin. When 20 mg of bilastine once daily is taken concomitantly with 400 mg of ketoconazole once daily or 500 mg of erythromycin three times daily, the AUC of bilastine increases twofold and the Cmax increases two- to threefold. These changes can be explained by interactions at the level of transporter proteins responsible for drug efflux from intestinal cells, since bilastine is a substrate for P-glycoprotein and is not metabolized (see section "Pharmacokinetics"). These changes are unlikely to affect the safety profile of bilastine on one hand, and ketoconazole or erythromycin on the other. Other medicinal products that are substrates or inhibitors of P-gp (e.g. cyclosporine) may also increase plasma concentrations of bilastine.

Interaction with diltiazem. When 20 mg of bilastine once daily is taken concomitantly with 60 mg of diltiazem once daily, the Cmax of bilastine increases by 50%. This effect can be explained by interactions at the level of transporter proteins responsible for drug efflux from intestinal cells (see section "Pharmacokinetics"); this effect is unlikely to affect the safety profile of bilastine.

Interaction with ethanol. After concomitant administration of alcohol and bilastine 20 mg once daily, psychomotor functions remained at the same level as after concomitant administration of alcohol and placebo.

Interaction with lorazepam. When bilastine 20 mg once daily was administered concomitantly with lorazepam 3 mg once daily for 8 days, no enhancement of the CNS depressant effect of lorazepam was observed.

Paediatric population. Interaction studies with other medicinal products have been conducted only in adults. Due to the lack of clinical experience regarding interactions of bilastine with other medicinal products, food, or fruit juices in children, when prescribing bilastine to paediatric patients, the interaction data obtained in adults should currently be taken into account. There are no clinical data available to determine whether interaction-induced changes in AUC or Cmax affect the safety profile of bilastine in children.

Special precautions for use

Children. The efficacy and safety of bilastine in children under 2 years of age have not been established, and clinical experience in children aged 2 to 5 years is limited. Therefore, bilastine should not be prescribed to these age groups.

In patients with moderate or severe renal impairment, concomitant use of bilastine with P-glycoprotein inhibitors (e.g., ketoconazole, erythromycin, cyclosporine, ritonavir, or diltiazem) may lead to increased plasma levels of bilastine, increasing the risk of its adverse effects. Therefore, concomitant use of bilastine and P-glycoprotein inhibitors should be avoided in patients with moderate or severe renal impairment.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Cases of QT interval prolongation on electrocardiogram have been reported in patients treated with bilastine (see sections "Adverse reactions", "Overdose", and "Pharmacological properties"). Medicinal products that cause QT/QTc prolongation may potentially increase the risk of torsades de pointes.

Therefore, bilastine should be used with caution in patients who have an increased risk of QT/QTc interval prolongation. This includes patients with a history of cardiac arrhythmias; patients with hypokalemia, hypomagnesemia, or hypocalcemia; patients with confirmed QT interval prolongation or marked bradycardia; and patients receiving concomitant medications known to prolong QT/QTc.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of bilastine in pregnant women are lacking or limited.

Animal studies have not shown any direct or indirect harmful effects on reproductive performance, labor, or postnatal development. For safety reasons, it is advisable to avoid use of the medicinal product Afetto during pregnancy.

Breastfeeding. Studies on the excretion of bilastine into human breast milk have not been conducted. Available pharmacokinetic data have shown that bilastine is excreted into milk in animals. A decision on whether to continue/stop breastfeeding or to continue/abstain from treatment with Afetto should be made, taking into account the benefit of breastfeeding for the child and the benefit of bilastine therapy for the mother.

Fertility. Clinical data are limited or unavailable. Animal studies in rats showed no negative effect on fertility.

Ability to affect reaction speed when driving or operating machinery

In a study evaluating the effect of bilastine on driving ability in adults, treatment with bilastine at a dose of 20 mg did not impair the ability to drive. However, since individual response to the medicinal product may vary, patients should be advised to refrain from driving or operating machinery until they know how they respond to bilastine.

Dosage and Administration

Dosage

Adults and children aged 12 years and older: 20 mg of bilastine (1 tablet) once daily to relieve symptoms of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria.

The tablet should be taken 1 hour before or 2 hours after a meal or fruit juice (see section "Interaction with other medicinal products and other forms of interaction").

Duration of treatment: Patients with allergic rhinoconjunctivitis should use the medicinal product only during periods of allergen exposure. For patients with seasonal allergic rhinitis, treatment may be discontinued once symptoms subside and resumed upon their recurrence. For patients with perennial allergic rhinitis, the medicinal product may be used continuously throughout the period of allergen exposure. In cases of urticaria, the duration of treatment depends on the nature, duration, and course of symptoms.

Special patient groups

Elderly patients: Dose adjustment is not required in elderly patients (see sections "Pharmacodynamics" and "Pharmacokinetics").

Renal impairment: Studies conducted in high-risk groups (adults with impaired renal function) have shown that dose adjustment of bilastine in adults is not necessary (see section "Pharmacokinetics").

Hepatic impairment: There is no clinical experience with bilastine in adults with impaired liver function. However, since bilastine is not metabolized and is excreted unchanged in urine and feces, hepatic impairment is not expected to lead to an increase in systemic exposure to dangerous levels in adult patients. Therefore, dose adjustment is not required in adult patients with hepatic impairment (see section "Pharmacokinetics").

Children

Children aged 6 to 11 years weighing at least 20 kg: Bilastine orodispersible tablets 10 mg or bilastine oral solution 2.5 mg/mL may be prescribed for this patient group.

Children under 6 years of age weighing less than 20 kg: Current data are provided in sections ***"***Special precautions for use", "Side effects", "Pharmacodynamics", and "Pharmacokinetics", but dosage recommendations cannot be established. Therefore, bilastine should not be used in this age group.

The safety and efficacy of bilastine in children with renal or hepatic impairment have not been established.

Administration

For oral use.

Tablets should be taken with water. The daily dose should be taken as a single dose.

Children. The medicinal product (with a bilastine dosage of 20 mg) is intended for use in children aged 12 years and older.

Overdose

Information on acute overdose with bilastine was collected based on data from clinical trials and post-marketing surveillance. In clinical studies, after administration of bilastine at doses 10–11 times higher than the therapeutic dose (220 mg as a single dose or 200 mg daily for 7 days) to 26 healthy adult volunteers, the incidence of adverse reactions was twice as high compared to placebo. The most common adverse reactions were dizziness, headache, and nausea. No reports of serious adverse reactions or significant prolongation of the QTC interval were observed. Information collected during post-marketing surveillance is consistent with data obtained during clinical trials.

In a thorough QT/QTC interval crossover study involving 30 healthy adult volunteers, critical assessment of the effect of multiple doses of bilastine (100 mg × 4 days) on ventricular repolarization did not reveal significant prolongation of the QTC interval.

Data on overdose in children are lacking. In case of overdose, symptomatic and supportive treatment is recommended.

There is no specific antidote for bilastine.

Adverse Reactions

General safety profile in adult and adolescent patients. During clinical studies in adult and adolescent patients suffering from allergic rhinoconjunctivitis or chronic idiopathic urticaria, adverse reactions with bilastine 20 mg occurred at approximately the same frequency as with placebo (12.7% vs. 12.8%). Phase II and III clinical trials conducted during clinical development included 2,525 adult and adolescent patients treated with various doses of bilastine, of whom 1,697 received bilastine 20 mg. In these studies, 1,362 patients received placebo. The most commonly reported adverse reactions in patients receiving bilastine 20 mg for allergic rhinoconjunctivitis or chronic idiopathic urticaria were headache, somnolence, dizziness, and fatigue. These adverse reactions occurred at a frequency comparable to that observed in patients receiving placebo.

Table of adverse reactions in adult and adolescent patients. The table below lists adverse reactions that were likely related to bilastine and observed in more than 0.1% of patients who received bilastine 20 mg during clinical development (N = 1,697).

The frequency of adverse reactions is defined as follows: 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); not known (cannot be estimated from the available data).

Reactions occurring rarely and very rarely, as well as those for which the frequency is unknown, were not included in Table 1.

Table 1

* In the post-marketing period, cases of QT interval prolongation on electrocardiogram have also been reported.

During the post-marketing period, the following were observed: palpitations, tachycardia, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnea, rash, localized/local swelling, erythema), and vomiting. The frequency of these adverse reactions is unknown (cannot be estimated based on available data).

Description of individual adverse reactions in adult and adolescent patients. Somnolence, headache, dizziness, and fatigue were observed both in patients receiving bilastine at a dose of 20 mg and in those receiving placebo. The frequency of these reactions was: 3.06% vs. 2.86% for somnolence; 4.01% vs. 3.38% for headache; 0.83% vs. 0.59% for dizziness; 0.83% vs. 1.32% for fatigue.

Data collected during post-marketing surveillance confirmed the safety profile observed during clinical development.

Overall safety profile in children. During clinical development, the frequency, type, and severity of adverse reactions in adolescents (12–17 years) were similar to those in adults. Data collected in this group (adolescents) during post-marketing surveillance were consistent with the results of clinical trials.

The percentage of children (2–11 years) who experienced adverse reactions after treatment of allergic rhinoconjunctivitis or chronic idiopathic urticaria with bilastine 10 mg in a 12-week controlled clinical study was comparable to that of patients receiving placebo (68.5% vs. 67.5%).

Among the reported adverse reactions most commonly observed in children aged 2–11 years receiving bilastine (in the form of orally disintegrating tablets) during clinical trials (total of 291 children: 260 children received the medicinal product in the safety clinical study, 31 children in the pharmacokinetic study), were: headache, allergic conjunctivitis, rhinitis, and abdominal pain. These same adverse reactions occurred at a comparable frequency in 249 patients receiving placebo.

Table of adverse reactions in children. The table below lists adverse reactions that were likely related to bilastine and occurred in more than 0.1% of children (2–11 years) receiving bilastine during clinical development.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Reactions occurring rarely and very rarely, as well as those for which frequency is not known, were not included in Table 2.

Table 2

260 children received the medicinal product during safety clinical trials, 31 children received the medicinal product during pharmacokinetic studies

Description of individual adverse reactions in children. Headache, abdominal pain, allergic conjunctivitis, and rhinitis were observed both in children treated with bilastine at a dose of 10 mg and in children who received placebo. The reported frequencies were: 2.1% vs 1.2% for headache; 1.0% vs 1.2% for abdominal pain; 1.4% vs 2.0% for allergic conjunctivitis; and 1.0% vs 1.2% for rhinitis.

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

Shelf life. 2.5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets per blister; 1, 2, or 3 blisters per carton.

Dispensing category. Over-the-counter.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of operations. 139 Saksaganskoho Street, Kyiv, 01032, Ukraine.