Niksar® 10 mg

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIXAR® 10 MG (NIXAR® 10 MG)

Composition:

Active substance: bilastine;

One orodispersible tablet contains 10 mg of bilastine;

Excipients: mannitol, sodium croscarmellose, sodium stearyl fumarate, sucralose (E 955), red grape flavor (main components: gum arabic, ethyl butyrate, triacetin, methyl anthranilate, ethanol, D-limonene, linalool).

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties: white, slightly biconvex, round tablets, 8 mm in diameter.

Pharmacotherapeutic group.

Antihistamines for systemic use. Other antihistamines for systemic use. ATC code R06AX29.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Bilastine is a non-sedating, long-acting antihistamine 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 such as wheal and erythema for up to 24 hours.

Clinical efficacy. The efficacy of bilastine has been studied in adults and adolescents. According to guidelines, the proven efficacy in adults and adolescents may be considered acceptable for children, given that the systemic exposure to 10 mg of bilastine in children aged 6 to 11 years with body weight ≥ 20 kg corresponds to that in adults receiving 20 mg of 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 clinical studies conducted in 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 ocular redness. Symptoms were effectively controlled by bilastine over 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 effects on the cardiovascular system 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-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 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 and did not impair the ability to drive in a standard driving test.

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

Clinical safety. In a 12-week controlled clinical study 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; 249 children 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 resulted in a slight reduction in somnolence and sedative effect as assessed by the pediatric sleep quality questionnaire, with no statistically significant difference between treatment groups. In children aged 2 to 11 years, no significant difference in QTc was observed after administration of 10 mg bilastine daily compared to placebo. A specific quality-of-life questionnaire for children with allergic rhinoconjunctivitis or chronic urticaria demonstrated overall improvement at 12 weeks, with no statistically significant difference between the bilastine and placebo groups. A total of 509 children participated in the study, including 479 participants with allergic rhinoconjunctivitis and 30 with diagnosed chronic urticaria. 260 children received bilastine, of whom 252 (96.9%) were treated for allergic rhinoconjunctivitis and 8 (3.1%) for chronic urticaria. Similarly, 249 children received placebo: 227 (91.2%) 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 participants under 2 years of age (see section "Posology and method of 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 dosing. 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": "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, 84–90% of bilastine is 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. In a mass balance study conducted in healthy adult volunteers, after a single 20 mg dose of 14C-bilastine, almost 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 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. The effects of bilastine in renal impairment were studied in adults.

In a study involving patients with renal impairment, the mean AUC0-∞ (SD) increased from 737.4 (± 260.8) ng•h/mL in individuals 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 mean elimination half-life (SD) of bilastine was 9.3 hours (± 2.8) in individuals with normal renal function, 15.1 hours (± 7.7) in patients with mild impairment, 10.5 hours (± 2.3) in patients with moderate impairment, and 18.4 hours (± 11.4) in patients with severe impairment. Bilastine was almost undetectable in urine 48–72 hours after administration in all patients. These pharmacokinetic changes are not expected to have a clinically significant impact on the safety of bilastine, as plasma levels of bilastine 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. Results from a study in patients with renal impairment indicate that bilastine is primarily eliminated via the kidneys, with only a minor fraction likely excreted in bile. 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 one 10 mg orodispersible tablet of bilastine once daily. Pharmacokinetic analysis of plasma bilastine concentrations showed that after administration of the recommended 10 mg once-daily dose for pediatric patients, 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 mainly 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 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.

Preclinical safety data.

Preclinical data obtained from standard studies of pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential of bilastine revealed no special hazard for humans.

In reproductive toxicity studies, effects of bilastine on the fetus (pre- and post-implantation fetal loss in rats and incomplete ossification of skull bones, sternebrae, and limbs in rabbits) were observed only at doses toxic to the mother. At doses without marked adverse effects (NOAEL), systemic exposure was significantly higher (> 30-fold) than systemic exposure in humans after administration of the recommended therapeutic dose.

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

In a fertility study in rats, oral administration of bilastine up to 1000 mg/kg/day showed no effect on male or female reproductive organs. Mating, fertility, and pregnancy indices were unchanged.

According to data from a distribution study in rats using whole-body autoradiography, bilastine does not accumulate in the CNS.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria. The medicinal product Nixar® 10 mg is indicated in 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 interactions.

Interaction studies have been conducted only in adults.

Interaction with food. Food significantly reduces the oral bioavailability of bilastine, particularly when administered as 20 mg tablets – by 30%, and as 10 mg orodispersible tablets – by 20%.

Interaction with grapefruit juice. When bilastine 20 mg and grapefruit juice are taken 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, such as ritonavir or rifampicin, may also reduce bilastine plasma concentrations.

Interaction with ketoconazole or erythromycin. When 20 mg bilastine once daily and 400 mg ketoconazole once daily or 500 mg erythromycin three times daily are taken concomitantly, the AUC of bilastine increases twofold and Cmax increases 2–3 times. These changes can be explained by interaction at the level of transporter proteins responsible for drug efflux from intestinal cells, since bilastine is a substrate for 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, such as cyclosporine, may also increase bilastine plasma concentrations.

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

Interaction with alcohol. After concomitant administration of alcohol and 20 mg bilastine once daily, psychomotor functions were similar to those observed after administration of alcohol and placebo.

Interaction with lorazepam. When 20 mg bilastine once daily was administered concomitantly with 3 mg lorazepam 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 orodispersible tablets 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, interaction data obtained in adults should currently be considered when prescribing bilastine to pediatric patients. There are no clinical data available to conclude whether interaction-related changes in AUC or Cmax affect the safety profile of bilastine in children.

Special precautions for use

Pediatric population. Since 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, 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, such as ketoconazole, erythromycin, cyclosporine, ritonavir, or diltiazem, may lead to increased plasma levels of bilastine and, consequently, to an increased risk of adverse reactions. Therefore, concomitant use of bilastine and P-glycoprotein inhibitors should be avoided in patients with moderate or severe renal impairment.

This medicinal product contains 0.0015 mg of alcohol (ethanol) in each orodispersible tablet, i.e. 1 mg / 100 g (0.001% w/w). The amount in one orodispersible tablet weighing 150 mg is equivalent to 0.00004 ml of beer or 0.00002 ml of wine. This negligible amount of ethanol in the medicinal product has no noticeable effects.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e. it is practically 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 revealed any direct or indirect harmful effects on reproductive performance, parturition, or postnatal development (see section "Preclinical safety data"). For safety reasons, it is advisable to avoid taking Nixar® 10 mg during pregnancy.

Breastfeeding. Studies on the excretion of bilastine into human breast milk have not been conducted. Available pharmacokinetic data have shown that bilastine passes into milk in animals (see section "Preclinical safety data"). A decision on continuing breastfeeding or discontinuing/withholding Nixar® 10 mg therapy 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 lacking or limited. Animal studies in rats did not reveal any negative effect on fertility (see section "Preclinical safety data").

Ability to influence reaction speed when driving or operating machinery.

A study conducted in adults to assess the effect of bilastine on the ability to drive demonstrated that treatment with bilastine at a dose of 20 mg did not impair driving ability. 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.

Method of Administration and Dosage.

Method of Administration.

Oral administration.

The orodispersible tablet should be placed in the oral cavity, where it rapidly disperses in saliva, making it easy to swallow.

Alternatively, the orodispersible tablet may be dispersed in water prior to administration. Grapefruit juice or any other fruit juices should not be used for dispersion (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Dosage.

Pediatric Population.

• Children aged 6 to 11 years with body weight of at least 20 kg.

10 mg of bilastine (1 orodispersible tablet) once daily for relief of symptoms of allergic rhinoconjunctivitis (seasonal allergic rhinitis and perennial allergic rhinitis) and urticaria.

The orodispersible tablet should be administered 1 hour before or 2 hours after food or fruit juice intake (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

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

Current data are described in the sections "Special Warnings and Precautions for Use," "Undesirable Effects," "Pharmacodynamics," and "Pharmacokinetics," but dosage recommendations cannot be provided. Therefore, bilastine should not be used in this age group.

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

Treatment Duration.

In allergic rhinoconjunctivitis, treatment should be limited to the allergen exposure period. In seasonal allergic rhinitis, treatment may be discontinued after symptoms resolve and resumed upon their recurrence. In perennial allergic rhinitis, continuous treatment may be offered during allergen exposure periods. In urticaria, the treatment course depends on the type, duration, and course 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 dosage 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. There is no clinical experience with bilastine use in patients with hepatic impairment, either in adults or 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 systemic exposure to a dangerous level in adult patients. Therefore, dosage adjustment is not required in adult patients with hepatic impairment (see section "Pharmacokinetics").

Children.

Since 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, bilastine should not be prescribed to these age groups.

Overdose.

Data on overdose in children are lacking.

Information regarding acute bilastine overdose was obtained from clinical trials conducted during development involving adults and from post-marketing surveillance. In clinical studies, after administration of doses exceeding the therapeutic dose by 10–11 times (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 commonly reported adverse reactions included dizziness, headache, and nausea. No reports of serious adverse reactions or significant QTc interval prolongation were observed. Information collected during post-marketing surveillance is consistent with data obtained during clinical trials.

In a thorough QT/QTc cross-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.

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

There is no specific antidote 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 confirmed the results of clinical trials.

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

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

Table of adverse reactions in pediatric patients. The table below lists adverse reactions that were likely related to bilastine and occurred in more than 0.1% of children (2–11 years of age) who received 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); 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.

#260 children received the drug during safety clinical trials, 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 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.

Overall safety profile in adult and adolescent patients. In clinical trials involving adult and adolescent patients suffering from allergic rhinoconjunctivitis or chronic idiopathic urticaria, the incidence of adverse reactions during treatment with bilastine at a dose of 20 mg was comparable to that in patients receiving 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 at a dose of 20 mg. In these studies, 1362 patients received placebo. The most commonly reported adverse reactions in patients treated with bilastine 20 mg for allergic rhinoconjunctivitis or chronic idiopathic urticaria were headache, somnolence, dizziness, and fatigue. These adverse reactions occurred at frequencies comparable to those 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 occurred in more than 0.1% of patients who received bilastine 20 mg during clinical development (N = 1697).

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); not known (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.

Frequency unknown (cannot be estimated from available data). During the post-marketing period, increased heart rate, tachycardia, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnea, rash, localized/local 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 both in patients treated with bilastine 20 mg and in patients receiving 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 collected during post-marketing surveillance confirmed the safety profile observed during clinical development.

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

Shelf life.

5 years.

Storage conditions.

No special storage conditions required.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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.