Bilastine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BILASTINE

Composition:

Active substance: bilastine;

1 tablet contains 20 mg of bilastine;

Excipients: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, oval-shaped, biconvex tablets with a score line on one side and smooth on the other.

The score line is intended solely for ease of tablet 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 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 relieving symptoms such as sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus, tearing, and eye 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 alleviating discomfort caused by urticaria. Patients also experienced improved sleep and quality of life.

In clinical studies, no clinically significant QTc interval prolongation or other cardiovascular effects were observed with bilastine, 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 did not differ statistically 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 standardized driving test.

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

In a 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 received bilastine during clinical trials (81 in double-blind studies for allergic rhinoconjunctivitis), while the remaining 116 were randomized to active comparator or placebo groups. No differences in efficacy or safety between adults and adolescents were observed.

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; 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). Adverse reactions were 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 sleepiness and sedative effect as assessed by a 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 did not result in a significant difference in QTc interval compared to placebo. A specific pediatric quality-of-life questionnaire for 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. 260 children received bilastine: 252 (96.9%) for treatment of 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.

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

Pharmacokinetics

Absorption. After oral administration, bilastine is rapidly absorbed, with maximum plasma concentration (Cmax) reached approximately 1.3 hours post-dose. No accumulation was observed. The average oral bioavailability of bilastine 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 transporters (see section "Interaction with grapefruit juice"). Bilastine does not appear to be a substrate of 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 calculated Cmax at clinical doses of bilastine. Thus, such interactions are not expected to be clinically relevant. However, these studies indicate that inhibition of transporter proteins 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.

Metabolism. 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 volunteers, after a single 20 mg dose of 14C-bilastine, nearly 95% of the administered dose was recovered in urine (28.3%) and feces (66.5%) 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 demonstrated linear pharmacokinetics with low inter-individual variability.

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

The mean elimination half-life (± SD) of bilastine was 9.3 hours (±2.8) in patients with normal renal function, 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. Bilastine was not detectable in urine in almost all patients 48–72 hours after administration. Such pharmacokinetic changes are not expected to have clinical significance or impact on the safety profile of bilastine, as plasma concentrations remain within safe limits in patients with renal impairment.

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

Elderly patients. Pharmacokinetic data in patients aged 65 years and older are limited. No statistically significant differences in pharmacokinetic parameters of bilastine were observed between patients aged ≥65 years and those aged 18–35 years.

Children. Pharmacokinetic data in adolescents (12–17 years) are not available; extrapolation of data from adults is considered acceptable for bilastine.

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 systemic exposure after administration of the recommended pediatric dose of 10 mg once daily corresponds to that observed in adults and adolescents receiving 20 mg. The mean AUC 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. 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 of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

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 reduction in bilastine bioavailability may vary depending on the juice manufacturer and fruit variety. 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 administered concomitantly, the AUC of bilastine increases twofold and Cmax increases 2–3 fold. 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 does not undergo metabolism (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 bilastine and 60 mg diltiazem are administered concomitantly, the Cmax of bilastine increases by 50%. This similar effect can be explained by interaction at the level of efflux transporter proteins responsible for drug efflux from intestinal cells; this effect is unlikely to affect the safety profile of bilastine.

Interaction with alcohol. Following concomitant administration of alcohol and bilastine 20 mg, psychomotor performance remained at the same level as that 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.

Children. 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, results obtained in adults should be taken into account when prescribing bilastine to children.

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-gp inhibitors such as ketoconazole, erythromycin, cyclosporine, ritonavir, or diltiazem may lead to increased plasma levels of bilastine, thereby increasing the risk of adverse reactions. Therefore, concomitant use of bilastine and P-gp inhibitors should be avoided in patients with moderate or severe renal impairment.

Cases of QT interval prolongation on electrocardiogram have been reported in patients taking bilastine (see sections "Adverse reactions", "Overdose", "Pharmacological properties"). It is presumed that medicinal products causing QT/QTc prolongation may increase the risk of torsade de pointes (ventricular tachycardia).

Therefore, caution should be exercised when prescribing bilastine to patients who have an increased risk of QT/QTc interval prolongation. These include patients with a history of cardiac arrhythmias; patients with hypokalemia, hypomagnesemia, or hypocalcemia; patients with known QT prolongation or significant bradycardia; and patients concurrently using other medicinal products associated with QT/QTc prolongation.

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 revealed any direct or indirect harmful effects on reproductive function, delivery, or postnatal development. As a precautionary measure, it is advisable to avoid using the drug during pregnancy.

Breastfeeding period

Studies on the passage of bilastine into human breast milk have not been conducted. Available pharmacokinetic data indicate that bilastine passes into breast milk in animals. A decision on continuing/discontinuing breastfeeding or on continuing/interrupting therapy with the drug should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment for the mother.

Reproductive function

Clinical data are limited or unavailable. Animal studies in rats did not reveal any negative effect on reproductive function.

Ability to influence the capacity to drive and use machines.

Studies on the effect of bilastine on the ability to drive vehicles demonstrated that treatment with bilastine at a dose of 20 mg did not affect driving ability in adults. However, since individual response to the medicinal product may vary, patients should be advised to refrain from driving vehicles 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 food or fruit juice intake (see section "Interaction with other medicinal products and other forms of interaction").

Duration of treatment: For allergic rhinoconjunctivitis, the drug should be taken only during periods of allergen exposure. In seasonal allergic rhinitis, treatment may be discontinued after symptom relief and resumed if symptoms reappear. For perennial allergic rhinitis, continuous administration may be used throughout the period of allergen exposure.

For urticaria, the duration of treatment depends on the nature, duration of symptoms, and their dynamics.

Special patient groups

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

Renal impairment: Studies conducted in adult patients at special risk (patients with renal impairment) have shown that dose adjustment of bilastine in adults is not necessary (see section "Pharmacokinetics").

Hepatic impairment: Clinical experience with bilastine in patients with hepatic impairment is lacking. However, since bilastine is not subject to metabolism and is primarily excreted by the kidneys, 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 patients with hepatic impairment (see section "Pharmacokinetics").

Children

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

Bilastine orodispersible tablets 10 mg or bilastine oral solution 2.5 mg/mL may be administered to this patient group.

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

Current available data are described in the sections "Pharmacodynamics", "Pharmacokinetics", "Special precautions for use", and "Undesirable effects", 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 sufficient amount of water. The daily dose should be taken as a single dose.

Children

Bilastine medicinal product is indicated for use in children aged 12 years and older.

Overdose

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

In a thorough cross-study QT/QTc evaluation involving 30 healthy adult volunteers, a critical assessment of the effect of multiple doses of bilastine (100 mg daily for 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 known specific antidote for bilastine.

Adverse reactions.

Overall safety profile in adults and adolescents

During clinical trials in adult and adolescent patients with allergic rhinoconjunctivitis or chronic idiopathic urticaria, adverse reactions with bilastine 20 mg occurred at approximately the same frequency as with placebo (12.7% and 12.8%, respectively). 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 treated with 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.

The table below lists adverse reactions that were likely related to bilastine and reported in more than 0.1% of patients who received bilastine 20 mg during clinical development (n = 1697).

The frequency of adverse reactions was 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 (frequency cannot be estimated from the available data).

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

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

During the post-marketing period, adverse reactions with unknown frequency have been observed: palpitations, tachycardia, hypersensitivity reactions (anaphylaxis, angioneurotic edema, dyspnea, rash, localized/local swelling and erythema), as well as vomiting.

Description of individual adverse reactions observed in adults and adolescents. Somnolence, headache, dizziness, and fatigue were observed both in patients treated with bilastine at a dose of 20 mg and in those who received placebo. The incidence of these reactions was 3.06% vs. 2.86% for somnolence; 4.01% and 3.38% for headache; 0.83% and 0.59% for dizziness; 0.83% and 1.32% for fatigue, respectively.

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

General 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. The 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%).

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

The table below lists adverse reactions that were probably related to bilastine and occurred in more than 0.1% of children (2–11 years) treated with 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 with unknown frequency, were not included 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 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 following drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature of 25°C, in a place inaccessible to children.

Packaging.

10 tablets per blister; 1 blister per cardboard box.

Supply classification.

Over-the-counter (without prescription).

Manufacturer.

Vivimed Labs Ltd.

Manufacturer's address and location of its business operations.

D-125 and 128, Phase-III, IDA, Jeedimetla, Medchal-Malkajgiri District – 500055, Telangana State, India.