Nixar® 2.5 mg/ml

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIXAR® 2.5 MG/ML (NIXAR® 2.5 MG/ML)

Composition:

Active substance: bilastine;

1 ml of oral solution contains 2.5 mg of bilastine;

Excipients: betadex; hydroxyethylcellulose; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); sucralose (E 955); raspberry flavoring (main components: ethanol, triacetin, water, ethyl butyrate, linalyl acetate); diluted hydrochloric acid (10%) (for pH adjustment); sodium hydroxide (for pH adjustment); purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, slightly viscous aqueous solution with pH 3.0–4.0, free from sediment.

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 antihistamine that selectively binds to peripheral H1 receptors and does not bind to muscarinic receptors.

After a single dose of bilastine, skin reactions induced by histamine—namely wheals and erythema—are suppressed for up to 24 hours.

Clinical efficacy. The efficacy of bilastine has been studied in adults and adolescents. According to guidelines, the demonstrated efficacy in adults and adolescents can be considered acceptable for children, given that systemic exposure to 10 mg of bilastine in children aged 6 to 11 years with body weight of at least 20 kg corresponds to systemic exposure observed after administration of 20 mg of bilastine in adults (see section "Pharmacokinetics"). Extrapolation of data obtained in adults and adolescents is considered acceptable for this medicinal product, as the pathophysiology of allergic rhinoconjunctivitis and urticaria is the same across all age groups.

In clinical trials involving adults and adolescents with allergic rhinoconjunctivitis (seasonal and perennial), treatment with bilastine 20 mg once daily for 14–28 days resulted in improvement of disease symptoms such as sneezing, nasal discharge, nasal itching, nasal congestion, eye itching, tearing, and eye redness. Symptom control under the influence of bilastine was effectively maintained for 24 hours.

In two clinical trials involving patients with chronic idiopathic urticaria, treatment with bilastine 20 mg once daily for 28 days resulted in reduced intensity of itching and decreased number and size of wheals; in addition, patients experienced less discomfort due to urticaria. Patients also reported improved sleep and quality of life.

No clinically significant QTc interval prolongation or other cardiovascular adverse effects were observed during clinical trials with bilastine, even at a dose of 200 mg daily (10 times the clinical dose) administered to 9 participants for 7 days, or when bilastine was co-administered with P-gp inhibitors such as ketoconazole (24 participants) and erythromycin (24 participants). Furthermore, 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 did not differ statistically. In clinical trials, bilastine at doses up to 40 mg once daily did not affect psychomotor performance or ability to drive in a standard driving test.

In elderly patients (≥65 years) included in phase II and III studies, no differences in efficacy or safety were demonstrated compared to younger patients.

Clinical safety. In a 12-week controlled clinical trial involving children aged 2 to 11 years (total of 509 children, 260 receiving bilastine 10 mg: 58 aged 2 to <6 years, 105 aged 6 to <9 years, and 97 aged 9 to <12 years; 249 children receiving 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 observed in 5.8% and 8.0% of patients receiving bilastine 10 mg and placebo, respectively. Administration of bilastine 10 mg and placebo resulted in a slight reduction in sleepiness and sedative effect as assessed by a pediatric sleep questionnaire during this study; however, there was no statistically significant difference between treatment groups. In children aged 2 to 11 years receiving bilastine 10 mg daily, no significant difference in QTc interval was observed compared to those receiving placebo. Pediatric quality-of-life questionnaires specific to allergic rhinoconjunctivitis or chronic urticaria showed overall improvement in scores 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.

Pediatric population. The European Medicines Agency has waived the obligation to submit results of bilastine studies in all pediatric subpopulations under 2 years of age (see section "Dosage and administration" for information on use in children).

Pharmacokinetics.

Absorption. After oral administration, bilastine is rapidly absorbed, with peak plasma concentration reached approximately 1.3 hours after intake. No accumulation of the drug in the body was observed. The mean oral bioavailability of bilastine is 61%.

Distribution. In vitro and in vivo studies have demonstrated that bilastine is a substrate of P-gp (see section "Interaction with other medicinal products and other forms of interaction": "Interaction with ketoconazole or erythromycin" and "Interaction with diltiazem") and OATP (see section "Interaction with other medicinal products and other forms of interaction": "Interaction with grapefruit juice").

At therapeutic doses, bilastine is 84–90% bound to plasma proteins.

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

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

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

Renal impairment. The effect of bilastine in patients with renal impairment has been studied in adult patients.

In a study of patients with renal impairment, AUC0–∞ (AUC) increased from 737.4 (±260.8) ng•h/mL in patients with normal renal function (GFR: >80 mL/min/1.73 m²) to 967.4 (±140.2) ng•h/mL in patients with mild renal impairment (GFR: 50–80 mL/min/1.73 m²), 1384.2 (±263.23) ng•h/mL in patients with moderate renal impairment (GFR: 30–<50 mL/min/1.73 m²), and 1708.5 (±699.0) ng•h/mL in patients with severe renal impairment (GFR: <30 mL/min/1.73 m²). The elimination half-life of bilastine was 9.3 hours (±2.8) in patients without impairment, 15.1 hours (±7.7) in mild impairment, 10.5 hours (±2.3) in moderate impairment, and 18.4 hours (±11.4) in severe impairment. In all patients, bilastine excretion in urine was mostly complete within 48–72 hours. These pharmacokinetic changes are not expected to have a clinically significant impact on the safety of bilastine, as plasma concentration levels 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. Since studies in patients with renal impairment have shown that bilastine is primarily eliminated via the kidneys, biliary excretion is expected to play a minor role in its elimination. Changes in liver function are not expected to have a clinically significant effect on the pharmacokinetics of bilastine.

Pediatric population. 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 10 mg bilastine as orally disintegrating tablets, one tablet once daily. This dosage form was shown to be bioequivalent to the oral solution of bilastine 2.5 mg/mL. Pharmacokinetic analysis of bilastine plasma concentrations showed that after administration of the pediatric dose of 10 mg once daily, systemic exposure corresponds to that observed in adults and adolescents receiving 20 mg, with a mean AUC of 1014 ng•h/mL in children aged 6 to 11 years. 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. These findings support the selection of a bilastine dose of 10 mg once daily as a justified therapeutic dose for pediatric patients aged 6 to 11 years with body weight of at least 20 kg.

Preclinical safety data.

Preclinical data on bilastine, based on general safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies, showed no specific risk for humans.

In reproductive toxicity studies, effects of bilastine on the fetus (pre- and post-implantation fetal loss in rats, incomplete ossification of skull bones, sternebrae, and limbs in rabbits) were observed only at doses that were toxic to the mother.

When bilastine was administered to animals at doses without observed adverse effects (NOAEL), systemic exposure was significantly higher (>30 times) than systemic exposure in humans after administration of the recommended therapeutic dose.

In a lactation study, bilastine was detected in the milk of nursing rats after a single oral dose (20 mg/kg). The concentration of bilastine in milk was approximately half that in maternal plasma. The significance of these findings for humans is unknown.

In a fertility study in rats, bilastine was administered orally at doses up to 1000 mg/kg/day, with no effects observed on male or female reproductive organs. Mating, fertility, and pregnancy indices were unaffected.

According to a tissue distribution study in rats using autoradiography to determine drug concentrations in various tissues, bilastine does not accumulate in the CNS.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria. Nixar® is indicated for children aged 6 to 11 years with body weight of at least 20 kg.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Interaction with food. Food significantly reduces the oral bioavailability of bilastine administered at a dose of 20 mg in tablet form (by 30%) and 2.5 mg/mL in oral solution form (by 20%).

Interaction with grapefruit juice. When bilastine 20 mg was administered concomitantly with grapefruit juice, the bioavailability of bilastine decreased by 30%. A similar effect may occur with other fruit juices. The extent of reduced bioavailability may vary depending on the juice manufacturer and fruit type. This interaction is attributed to the ability of fruit components to inhibit OATP1A2, for which bilastine is a substrate (see section "Pharmacokinetics"). Plasma concentrations of bilastine may also be reduced by medicinal products that are substrates or inhibitors of OATP1A2, such as ritonavir or rifampicin.

Interaction with ketoconazole or erythromycin. When bilastine 20 mg once daily was administered concomitantly with ketoconazole 400 mg once daily or erythromycin 500 mg three times daily, the AUC of bilastine increased by 2-fold and Cmax by 2–3-fold. These effects can be explained by interactions at the level of transporter proteins responsible for drug efflux from intestinal cells, since bilastine is a substrate of P-gp and is not metabolized (see section "Pharmacokinetics"). These effects are unlikely to influence the safety profile of bilastine on one hand, and ketoconazole or erythromycin on the other. Plasma concentrations of bilastine may also be increased by other medicinal products that are substrates or inhibitors of P-gp, such as cyclosporine.

Interaction with diltiazem. When bilastine 20 mg once daily was administered concomitantly with diltiazem 60 mg once daily, the Cmax of bilastine increased 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 influence the safety profile of bilastine.

Interaction with alcohol. Following concomitant administration of alcohol and bilastine 20 mg once daily, psychomotor functions remained at the same level as observed 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.

Pediatric population. Interaction studies of bilastine in the form of oral solution have not been conducted in children. Since there is no clinical experience regarding interactions of bilastine with other medicinal products, food, or fruit juices in children, the results of interaction studies obtained in adults should be taken into account when prescribing bilastine to pediatric patients. There are no clinical data available to conclude whether interaction-related changes in AUC or Cmax of bilastine affect its safety profile in children.

Special precautions for use.

Pediatric population. The efficacy and safety of bilastine for the treatment of children under 2 years of age have not been established, and there is only limited clinical experience in children aged 2 to 5 years. Therefore, bilastine should not be used for the treatment of patients in these age groups.

In patients with moderate or severe renal impairment, concomitant use of bilastine with P-gp inhibitors (ketoconazole, erythromycin, cyclosporine, ritonavir, diltiazem) may lead to increased plasma concentrations of bilastine and, consequently, to an increased risk of adverse reactions. For this reason, bilastine should not be co-administered with P-gp inhibitors in patients with moderate or severe renal impairment.

Niksar® contains methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed-type reactions).

This medicinal product contains up to 0.44 mg of alcohol (ethanol) per dose (4 ml), i.e. 11 mg/100 ml (0.011% mass/vol), equivalent to 0.02 ml of beer or 0.005 ml of wine. This small amount of ethanol is unlikely to have any noticeable effects.

This medicinal product contains less than 1 mmol of sodium (23 mg) per 4 ml, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of bilastine during pregnancy are limited or completely lacking.

Animal studies have not shown any direct or indirect harmful effects of the drug on reproductive function, labor, or postnatal development (see section "Preclinical safety data"). As a precautionary measure, use of Niksar® during pregnancy should be avoided.

Breastfeeding. Studies on whether bilastine passes into human breast milk have not been conducted. Available pharmacokinetic data indicate that bilastine is excreted into milk in animals (see section "Preclinical safety data"). The decision on continuing/discontinuing breastfeeding and on withholding/continuing treatment with Niksar® should be made by weighing the benefits of breastfeeding for the child against the benefits of bilastine therapy for the mother.

Fertility. Clinical data are lacking or limited. Animal studies in rats showed no negative effects on fertility (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery.

According to studies on the effect of bilastine on driving ability, administration of bilastine at a dose of 20 mg does not impair the ability to drive a vehicle. However, since individual response to the medicinal product may vary, patients should be advised to refrain from driving or operating machinery until their individual response to bilastine has been established.

Method of Administration and Dosage.

Dosing.

Pediatric Population.

• Children aged 6 to 11 years with body weight of at least 20 kg – 10 mg of bilastine (4 ml of oral solution) once daily for relief of symptoms of allergic rhinoconjunctivitis (seasonal allergic rhinitis and perennial allergic rhinitis) and urticaria.

The oral solution 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").

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

Currently available data are described in sections "Special precautions for use", "Side effects", "Pharmacodynamics", and "Pharmacokinetics", but dosage recommendations cannot be established. Therefore, bilastine should not be used in patients of this age group.

Adults and adolescents (aged 12 years and older) may take bilastine 20 mg tablets.

Treatment Duration.

For patients with allergic rhinoconjunctivitis, the drug should be administered only during periods of allergen exposure. For patients with seasonal allergic rhinitis, treatment may be discontinued after symptoms subside and resumed upon their recurrence. For patients with perennial allergic rhinitis, the drug may be administered continuously throughout the period of allergen exposure. In patients with urticaria, treatment duration depends on the nature, duration, and dynamics of symptoms.

Special Patient Groups.

Renal Impairment. The safety and efficacy of bilastine in children with renal impairment have not been established. Studies conducted in high-risk adult groups (patients with renal impairment) have shown that dose adjustment of bilastine in adults is not necessary (see section "Pharmacokinetics").

Hepatic Impairment. The safety and efficacy of bilastine in children with hepatic impairment have not been established. Clinical experience with the use of the drug in patients with hepatic impairment is lacking for both adults and pediatric patients.

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 its systemic effects to a dangerous level in adult patients. Therefore, dose adjustment is not required in adult patients with hepatic impairment (see section "Pharmacokinetics").

Method of Administration.

For oral use.

The bottle of oral solution is equipped with a child-resistant cap that opens as follows: press down on the plastic cap while simultaneously turning it counterclockwise.

The oral solution packaging includes a dosing cup with markings corresponding to 4 ml (10 mg bilastine per dose).

Children.

The safety and efficacy 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.

Overdose.

Data on overdose in children are lacking.

Information regarding acute overdose of bilastine comes only from clinical trials conducted during drug development and from post-marketing surveillance. In clinical trials, when bilastine was administered at doses 10–11 times higher than the therapeutic dose (220 mg as a single dose, or 200 mg/day for 7 days), adverse reactions occurred twice as frequently in 26 healthy adult volunteers compared to placebo. The most commonly reported adverse reactions included dizziness, headache, and nausea. No serious adverse reactions or significant prolongation of the QTc interval were observed. Information collected during post-marketing surveillance is consistent with data obtained from clinical trials.

In a crossover study measuring QT/QTc intervals, the effect of multiple doses of bilastine (100 mg/day for 4 days) on ventricular repolarization was evaluated in 30 healthy adult volunteers. No statistically significant QTc interval prolongation was observed.

In case of overdose, symptomatic and supportive therapy is recommended.

There is no specific antidote known for bilastine.

Adverse reactions.

Overall safety profile in pediatric patients. During clinical development, the frequency, type, and severity of adverse reactions in adolescents (aged 12 to 17 years) were similar to those in adults. Information collected in this group (adolescents) during post-marketing surveillance has confirmed the results of clinical trials.

The percentage of children (aged 2 to 11 years) who experienced adverse reactions (ARs) after taking bilastine 10 mg for the treatment of allergic rhinoconjunctivitis or chronic idiopathic urticaria during a 12-week controlled clinical study was comparable to the percentage in the placebo group (68.5% vs. 67.5%).

The most commonly reported adverse reactions in 291 children (aged 2 to 11 years) who received bilastine 10 mg (in the form of orally disintegrating tablets) during clinical trials (#260 children received the drug in safety clinical studies, 31 children received the drug in pharmacokinetic studies) were headache, allergic conjunctivitis, rhinitis, and abdominal pain. These same adverse reactions were observed at a comparable frequency in 249 patients who received placebo.

Table with data on adverse reactions in pediatric patients. Below are the adverse reactions whose association with bilastine is considered established or at least possible, and which were observed during the clinical development program in more than 0.1% of children (2–11 years) treated with bilastine.

Adverse reactions are categorized by frequency as follows:

Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1000 to < 1/100)
Not known (available data do not allow estimation)

Adverse reactions occurring rarely and very rarely, as well as those with unknown frequency, are not listed in the table.

#260 children received the drug during clinical safety studies, and 31 children received the drug during pharmacokinetic studies.

Description of individual adverse reactions in the pediatric population. Headache, abdominal pain, allergic conjunctivitis, and rhinitis were observed in children receiving bilastine 10 mg or placebo. The following frequency rates were reported: headache – 2.1% and 1.2%; abdominal pain – 1.0% and 1.2%; allergic conjunctivitis – 1.4% and 2.0%; and rhinitis – 1.0% and 1.2%.

Overall safety profile in adult and adolescent patients. In clinical studies involving adult and adolescent patients suffering from allergic rhinoconjunctivitis or chronic idiopathic urticaria, the incidence of adverse reactions with bilastine 20 mg was comparable to that observed with placebo (12.7% vs. 12.8%).

Phase II and III clinical trials conducted during clinical development included 2525 adult and adolescent patients receiving various doses of bilastine; 1697 of them received bilastine 20 mg. In these studies, 1362 received placebo. When bilastine was used for symptomatic treatment of allergic rhinoconjunctivitis and chronic idiopathic urticaria at a dose of 20 mg, the most commonly reported adverse reactions were headache, somnolence, dizziness, and fatigue. These adverse events occurred at approximately the same frequency in patients receiving placebo.

Table of adverse reactions in adult and adolescent patients. The following adverse reactions, considered to be related to bilastine or at least possibly related, and observed in more than 0.1% of patients (N = 1697) receiving bilastine 20 mg in the clinical development program, are listed below.

Adverse reactions are categorized by frequency 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).

Adverse reactions occurring rarely and very rarely, as well as those with unknown frequency, are not listed in the table.

Frequency unknown (cannot be estimated based on available data). In the post-marketing period, increased heart rate, tachycardia, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnea, rash, localized/swelling and erythema) and vomiting have been observed.

Description of individual adverse reactions in adult and adolescent patients. Somnolence, headache, dizziness, and fatigue were observed in patients receiving bilastine 20 mg or placebo. The respective 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.

Information obtained during post-marketing surveillance confirmed the safety profile established during clinical development.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years. The shelf life after first opening of the bottle is 6 months.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Packaging.

120 ml in a bottle; 1 bottle with a measuring cup in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and location of operations.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg SA.

Address of the Marketing Authorization Holder.

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