Niksar

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIXAR® (NIXAR®)

Composition:

Active substance: bilastine;

1 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: oval, biconvex white tablets with a score line for breaking (length 10 mm, width 5 mm), without lines or cracks on the surface. The score line is intended solely to facilitate tablet splitting for ease of swallowing and not for dividing the tablet into equal doses.

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 a single dose, bilastine suppresses histamine-induced skin reactions, such as 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, tearing, and eye redness. Symptoms were effectively controlled by bilastine 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 pruritus and the number and size of wheals, as well as urticaria-related discomfort. Patients experienced improved sleep and quality of life.

In clinical studies of bilastine, no clinically significant QTc interval prolongation or other cardiovascular effects were observed, 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, the central nervous system (CNS) safety profile of bilastine at the recommended dose of 20 mg once daily 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, the efficacy and safety of the drug did not differ 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 active comparator or placebo groups. No differences in efficacy or safety were observed between adults and adolescents.

According to 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 at the recommended pediatric dose of 10 mg once daily (n = 260) was similar to that of placebo (n = 249). Adverse reactions occurred in 5.8% and 8.0% of patients receiving 10 mg bilastine and placebo, respectively. Both 10 mg bilastine and placebo resulted in a slight reduction in sleepiness and sedative effect as assessed by the Pediatric Sleep Questionnaire, with no statistically significant difference between treatment groups. In children aged 2 to 11 years, administration of 10 mg bilastine daily did not result in a significant difference in QTc compared to placebo. A specific quality-of-life questionnaire for children with allergic rhinoconjunctivitis or chronic urticaria demonstrated overall improvement in scores over 12 weeks, with no statistically significant difference between the 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 "Dosage and administration").

Pharmacokinetics

Absorption. After oral administration, bilastine is rapidly absorbed, with peak plasma concentration reached in approximately 1.3 hours. Accumulation is not observed. The average 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 ketoconazole, erythromycin, and diltiazem") and OATP (see section "Interaction with grapefruit juice"). Bilastine does not appear to be a substrate of the BCRP transporter 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 calculated maximum plasma concentration (Cmax) following clinical use of bilastine. Thus, such interactions are not expected to have clinical relevance. However, these results suggest that inhibition of transporters located in the intestinal mucosa (e.g., P-gp) by bilastine cannot be ruled out. At therapeutic doses, 84–90% of bilastine is bound to plasma proteins.

Biotransformation. In vitro studies indicate 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. Over the studied dose range (5 to 220 mg), bilastine exhibits linear pharmacokinetics with low inter-individual variability.

Renal impairment. A study in patients with varying degrees of renal function showed that with normal renal function (eGFR: >80 mL/min/1.73 m²), the mean AUC0–∞ (± SD) was 737.4 (± 260.8) ng•h/mL; with mild renal impairment (eGFR: 50–80 mL/min/1.73 m²), it was 967.4 (± 140.2) ng•h/mL; with moderate impairment (eGFR: 30–<50 mL/min/1.73 m²), 1384.2 (± 263.23) ng•h/mL; and with severe impairment (eGFR: <30 mL/min/1.73 m²), 1708.5 (± 699.0) ng•h/mL.

In patients with normal renal function, the mean (± SD) elimination half-life of bilastine was 9.3 hours (± 2.8); in patients with mild impairment, 15.1 hours (± 7.7); with moderate impairment, 10.5 hours (± 2.3); and with severe impairment, 18.4 hours (± 11.4). In nearly all patients, bilastine was no longer detectable in urine within 48–72 hours after administration. Such pharmacokinetic changes are not expected to have clinical significance or impact on 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 lacking. Bilastine is not metabolized in humans. Results from a study in patients with renal impairment indicate that bilastine is primarily eliminated via the kidneys, with only minimal biliary excretion likely. Hepatic function changes do not have a clinically significant impact on the pharmacokinetics of bilastine.

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 data from adults is considered appropriate for this medicinal product.

Pharmacokinetic data in children were obtained from a Phase II pharmacokinetic study involving 31 children aged 4 to 11 years with allergic rhinoconjunctivitis or chronic urticaria who 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, with a mean AUC in children aged 6 to 11 years of 1014 ng•h/mL. These results were generally below the maximum safe level established based on data from adult use of 80 mg bilastine once daily, according to the drug's safety profile. These findings confirm 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.

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 and are presented below.

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

Interaction with grapefruit juice. When bilastine 20 mg and grapefruit juice are administered concomitantly, 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 source. 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 bilastine plasma concentrations.

Interaction with ketoconazole or erythromycin. When 20 mg of bilastine once daily and 400 mg of ketoconazole once daily or 500 mg of erythromycin three times daily are administered concomitantly, the AUC of bilastine increases twofold and Cmax by 2–3 times. 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 (P-gp) 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 bilastine plasma concentrations.

Interaction with diltiazem. When 20 mg of bilastine once daily and 60 mg of diltiazem once daily are administered concomitantly, 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 performance 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 conclude 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 administered 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, etc.) may lead to increased plasma levels of bilastine and, consequently, to an increased risk of its adverse effects. Therefore, patients with moderate or severe renal impairment should avoid concomitant use of bilastine and P-glycoprotein inhibitors.

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

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 function, parturition, or postnatal development. As a precautionary measure, it is advisable to avoid the use of the medicinal product Nixar® during pregnancy.

Breastfeeding. Studies on the excretion of bilastine into human breast milk have not been conducted. Available pharmacokinetic data indicate that bilastine passes into breast milk in animals. The decision on whether to continue/withhold breastfeeding or to continue/abstain from treatment with Nixar® should be made after considering the benefit of breastfeeding for the child and the benefit of bilastine therapy for the mother.

Fertility. Clinical data are limited or unavailable. Studies in rats did not reveal any negative effect on fertility.

Ability to influence the reaction rate while driving or operating machinery.

Studies on the effect of bilastine on the ability to drive vehicles demonstrated that in adults, treatment with bilastine at a dose of 20 mg did not affect the ability to drive. However, since individual response to the medicinal product may vary, patients should be advised to refrain from driving vehicles or operating machinery until they have determined their individual response to bilastine.

Administration and Dosage.

Dosage.

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

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

Duration of treatment: Patients with allergic rhinoconjunctivitis should take the medication only during exposure to allergens. For patients with seasonal allergic rhinitis, treatment may be discontinued after symptom relief and resumed upon symptom recurrence. For patients with perennial allergic rhinitis, the drug may be administered continuously throughout the period of allergen exposure. In cases of urticaria, the duration of treatment depends on the nature, duration, and dynamics 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: Clinical experience with bilastine in adults with hepatic impairment is limited. 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 a dangerous level 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 with body weight ≥20 kg.

This patient group may be prescribed bilastine dispersible tablets 10 mg, as well as bilastine oral solution 2.5 mg/mL.

• Children under 6 years of age with body weight below 20 kg.

Available data are described in sections ***"***Special precautions for use", "Adverse reactions", "Pharmacodynamics", and "Pharmacokinetics", but dosage recommendations cannot be provided. 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 method.

For oral use.

Tablets should be taken with water. The daily dose should be taken at one time.

Children.

The medicinal product containing 20 mg of the active substance bilastine is intended for use in children aged 12 years and older.

Overdose.

Information regarding acute overdose of bilastine was obtained from clinical trials conducted during drug development and post-marketing surveillance. In clinical studies, 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 resulted in a twofold increase in the incidence of adverse reactions compared to placebo. The most commonly reported adverse reactions included dizziness, headache, and nausea. No reports of serious adverse reactions or significant QTc interval prolongation were recorded. Post-marketing surveillance data are consistent with findings from clinical trials.

In a thorough QT/QTC 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 QTc interval prolongation.

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

There is no known specific antidote for bilastine.

Adverse reactions.

General safety profile in adult and adolescent patients. In clinical studies conducted 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 2525 adult and adolescent patients treated with various doses of bilastine, of whom 1697 received bilastine 20 mg. In these studies, 1362 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 = 1697).

Frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); 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 the table.

Frequency unknown (cannot be estimated based on available data): tachycardia, palpitations, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnea, rash, localized or local swelling, and erythema), and vomiting have been reported in the post-marketing period.

Description of individual adverse reactions in adult and adolescent patients. Somnolence, headache, dizziness, and fatigue were observed both in patients receiving bilastine 20 mg and in those receiving placebo. The reported frequencies were 3.06% vs. 2.86% for somnolence; 4.01% vs. 3.38% for headache; 0.83% vs. 0.59% for dizziness; and 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 findings from clinical trials.

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

The most commonly reported adverse reactions in 291 children (2–11 years) treated with bilastine (in the form of orally disintegrating tablets) in clinical trials (#260 children received the drug in a safety study, 31 children in a pharmacokinetic study) included headache, allergic conjunctivitis, rhinitis, and abdominal pain. These same adverse reactions occurred at comparable frequencies in 249 patients receiving placebo.

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

The frequency of adverse reactions is categorized 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); unknown (cannot be estimated from available data).

Reactions occurring rarely and very rarely, as well as those with unknown frequency, were not included in the table.

#260 children received the drug during safety clinical trials, 31 children received the drug 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 drug registration is important. It enables continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua or through the company's website https://www.berlin-chemie.ua.

Shelf life. 5 years.

Do not use the drug after the expiry date stated on the packaging.

Storage conditions.

Special storage conditions are not required. Keep out of reach of children.

Packaging.

10 tablets per blister; 1, 2, 3, or 5 blisters per cardboard box.

Dispensing category.

Over-the-counter.

Manufacturer.

Menarini - von Heyden GmbH.

Manufacturer's location and address of business activity.

Leipziger Strasse 7-13, 01097 Dresden, Germany.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's location and address of business activity.

Via Campo di Pile, 67100 L'Aquila (AQ), Italy.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.