Bilastine-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BILASTINE-TEVA (Bilastine-Teva)

Composition:

Active substance: bilastine;

1 tablet contains 20 mg of bilastine;

Excipients: mannitol (E 421), microcrystalline cellulose, sodium starch glycolate (type A), magnesium aluminometasilicate, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex, smooth tablets of white to almost white color, approximately 7 mm in diameter.

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 for up to 24 hours the development of skin reactions such as wheals and erythema induced by histamine.

Clinical efficacy. In clinical studies involving adults and adolescents with allergic rhinoconjunctivitis (seasonal and perennial), administration of 20 mg of bilastine once daily for 14–28 days was effective in alleviating symptoms such as sneezing, nasal discharge, 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, treatment with 20 mg of bilastine once daily for 28 days was effective in reducing the intensity of itching, as well as the number and size of wheals, and in relieving discomfort associated with urticaria. Patients showed improvement in 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 involving 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 that with placebo. Bilastine at doses up to 40 mg daily had no effect on psychomotor performance in clinical studies and did not impair the ability to drive in a standard driving test.

In elderly patients (≥65 years of age) participating in Phase II and III studies, efficacy and safety of the drug did not differ from those in younger patients. In a post-marketing study involving 146 elderly patients, no differences in safety profile were observed compared to other adult participants.

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

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" regarding use in children).

Pharmacokinetics.

Absorption. After oral administration, bilastine is rapidly absorbed, with peak plasma concentration reached in approximately 1.3 hours. 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 interactions": "Interaction with ketoconazole or erythromycin" and "Interaction with 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, which greatly exceeds the calculated maximum plasma concentration (Cmax) following clinical use of bilastine. Thus, such interactions are not expected to be clinically relevant. However, results from similar studies suggest that inhibition of transporter proteins 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.

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

Elimination. In a mass balance study conducted in healthy adult volunteers, after a single 20 mg dose of 14C-bilastine, nearly 95% of the administered dose was recovered in urine (28.3%) and feces (66.5%) as unchanged bilastine, indicating minimal metabolism of bilastine 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-subject variability.

Renal impairment. In a study involving patients with renal impairment, mean AUC0–∞ (standard deviation [SD]) increased from 737.4 (±260.8) ng·h/mL in subjects with normal renal function (GFR >80 mL/min/1.73 m²) to 967.4 (±140.2) ng·h/mL in patients with mild impairment (GFR 50–80 mL/min/1.73 m²), 1384.2 (±263.23) ng·h/mL in patients with moderate impairment (GFR 30–<50 mL/min/1.73 m²), and 1708.5 (±699.0) ng·h/mL in patients with severe impairment (GFR <30 mL/min/1.73 m²). Mean elimination half-life (SD) of bilastine was 9.3 hours (±2.8) in subjects 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. In all patients, bilastine was almost undetectable in urine 48–72 hours after administration. These pharmacokinetic changes are not expected to have clinically significant effects 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 minimal biliary excretion expected. Changes in liver function are not expected to have clinically significant effects 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 of age do not differ significantly from those in patients aged 18–35 years.

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

Preclinical safety data

In standard preclinical studies of pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential, bilastine did not reveal any 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 maternally toxic doses. At doses without marked 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 rats after a single oral dose (20 mg/kg). The concentration of bilastine in milk was approximately half of that in maternal plasma. The relevance of these findings to humans is unknown.

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

According to distribution studies in rats using quantitative whole-body autoradiography, bilastine does not accumulate in the CNS.

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.

Interaction with food. Food significantly reduces the oral bioavailability of bilastine, particularly when administered in 20 mg tablets, reducing bilastine bioavailability by 30%.

Interaction with grapefruit juice. When bilastine 20 mg was administered concomitantly with grapefruit juice, bilastine bioavailability decreased 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 was administered concomitantly with 400 mg ketoconazole once daily or 500 mg erythromycin three times daily, the AUC of bilastine increased twofold and Cmax increased 2- to 3-fold.

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-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 was administered concomitantly with 60 mg diltiazem once daily, the Cmax of bilastine increased 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. Following 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.

Paediatric population. Interaction studies with other medicinal products have been conducted only in adults. Since there is no clinical experience regarding bilastine interactions with other medicinal products, food, or fruit juices in children, when prescribing bilastine to children, the results of interaction studies obtained in adults should currently be considered. There are no clinical data available to determine whether interaction-related changes in AUC or Cmax affect the safety profile of bilastine in children.

Special precautions for use

Cases of QT interval prolongation on the electrocardiogram (ECG) have been reported in patients treated with bilastine (see sections "Adverse reactions", "Overdose"). Medicinal products that induce QT/QTc interval prolongation may increase the risk of developing torsade de pointes.

Therefore, caution should be exercised when prescribing bilastine to patients at increased risk of QT/QTc interval prolongation. This includes patients with a history of cardiac arrhythmias; patients with hypokalaemia, hypomagnesaemia, or hypocalcaemia; patients with known QT interval prolongation or significant bradycardia; and patients who are concurrently receiving other medicinal products associated with QT/QTc interval prolongation.

Paediatric 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 administered to these age groups (see section "Posology and method of administration").

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, increase the risk of adverse reactions. Therefore, concomitant administration of bilastine and P-glycoprotein inhibitors should be avoided in patients with moderate or severe renal impairment.

This medicinal product contains less than 1 mmol of sodium (23 mg) 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 shown direct or indirect harmful effects on reproductive performance, labour, or postnatal development (see section "Preclinical safety data"). For safety reasons, it is advisable to avoid taking bilastine-teva 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 (see section "Preclinical safety data"). A decision on continuing/discontinuing breastfeeding or continuing/withholding bilastine-teva 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 limited or unavailable. Studies in rats did not show any negative effect on fertility (see section "Preclinical safety data").

Ability to affect 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 determine their individual response 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 (see section "Interaction with other medicinal products and other forms of interaction").

Special patient groups

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

Patients with renal impairment: The safety and efficacy of bilastine in children with renal impairment have not been established. Studies conducted in adult patients at special risk (patients with renal impairment) have shown that dose adjustment in adults is not necessary (see section "Pharmacokinetics").

Patients with 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. However, since bilastine is not metabolized and is excreted unchanged in urine and feces, hepatic impairment is not expected to increase 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: The efficacy and safety of bilastine in children under 2 years of age have not been established; clinical experience in children aged 2 to 5 years is limited; therefore, bilastine should not be prescribed to these age groups. Children aged 6 to 11 years should be treated with bilastine in other pharmaceutical forms (oral solution or 10 mg orally disintegrating tablets). Bilastine-Teva 20 mg tablets may be used in children aged 12 years and older.

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 progression of symptoms.

Administration method

For oral use.

Tablets should be taken with water.

Children: Bilastine-Teva is indicated for use in children aged 12 years and older.

Overdose

Data on overdose in children are lacking.

Information on acute bilastine overdose has been obtained from clinical trials conducted during drug development in adults and from post-marketing surveillance. In clinical studies, after administration of bilastine at doses 10–11 times higher than the therapeutic dose (220 mg as a single dose or 200 mg daily for 7 days) to 26 healthy adult volunteers, the incidence of adverse reactions was twice as high compared to placebo. The most frequently reported adverse reactions were dizziness, headache, and nausea. There were no reports of serious adverse reactions or significant QTc interval prolongation. Data from post-marketing surveillance are consistent with findings 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 × 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 clinical studies in adult and adolescent patients with allergic rhinoconjunctivitis or chronic idiopathic urticaria, the incidence of adverse reactions during treatment with bilastine 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 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 similar to that observed in patients receiving placebo.

List of adverse reactions

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

The 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); frequency 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.

* Prolongation of the QT interval on ECG has also been reported in the post-marketing period.

In the post-marketing period, palpitations, tachycardia, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnea, rash, localized/local swelling, erythema), and vomiting have been observed – frequency unknown.

Description of selected adverse reactions. Somnolence, headache, dizziness, and fatigue were observed both in patients treated with bilastine 20 mg and in those who received placebo. The frequency of somnolence was 3.06% vs. 2.86%; headache was 4.01% vs. 3.38%; dizziness was 0.83% vs. 0.59%; fatigue was 0.83% vs. 1.32%.

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

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

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer. Saneca Pharmaceuticals AT.

Manufacturer's address and location of its operations. Nitrianska 100, Glogovec, 920 27, Slovak Republic.