Bilastine-Teva tablets 20 mg blister No. 10

Instructions for use Bilastine-Teva tablets 20 mg blister No. 10

Composition

active ingredient: bilastine;

1 tablet contains bilastine 20 mg;

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

Dosage form

Pills.

Main physicochemical properties: round biconvex smooth tablets from white to almost white in color, with a diameter of about 7 mm.

Pharmacotherapeutic group

Antihistamines for systemic use. Other antihistamines for systemic use. Bilastine. ATX code R06A X29.

Pharmacological properties

Pharmacodynamics.

Mechanism of action: Bilastine is a long-acting, non-sedating histamine antagonist, a highly selective blocker of peripheral H1 receptors that does not bind to muscarinic receptors.

After a single application, bilastine inhibits the development of skin reactions with blisters and redness caused by histamine for 24 hours.

Clinical efficacy: In clinical studies conducted in adults and adolescents with allergic rhinoconjunctivitis (seasonal and perennial), bilastine 20 mg once daily for 14-28 days was effective in relieving symptoms such as sneezing, nasal discharge, nasal itching, nasal congestion, itchy eyes, tearing and redness. Symptoms were effectively controlled by bilastine for 24 hours.

In two clinical studies in patients with chronic idiopathic urticaria, bilastine 20 mg once daily for 28 days was effective in reducing the intensity of itching and the number and size of wheals, as well as the discomfort caused by urticaria. Patients also experienced improvements in sleep and quality of life.

In clinical studies of bilastine, no clinically significant prolongation of the QTc interval or any other cardiovascular effects were observed, even when administered at a dose of 200 mg per day (10 times the clinical dose) for 7 days in 9 subjects or when co-administered with P-glycoprotein (P-gp) inhibitors such as ketoconazole (24 subjects) and erythromycin (24 subjects). In addition, a thorough QT study was conducted in 30 volunteers.

In controlled clinical trials, when using bilastine at the recommended dose of 20 mg once daily, the safety profile of bilastine and placebo regarding the central nervous system (CNS) was similar, and the incidence of drowsiness with bilastine was not statistically different from that with placebo. Bilastine at doses up to 40 mg per day did not affect psychomotor performance in clinical trials and did not affect the ability to drive in a standard driving test.

In elderly patients (≥65 years) who participated in phase II and III studies, the efficacy and safety of the drug did not differ from those in younger patients. In a post-marketing study conducted in 146 elderly patients, no differences in the 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 individuals received bilastine in clinical trials (81 in double-blind studies of allergic rhinoconjunctivitis), the remaining 116 participants were randomized to active comparator or placebo. No differences in efficacy and safety were observed between adults and adolescents.

The European Medicines Agency has waived the obligation to submit the results of studies with bilastine in all subsets of the paediatric population below 2 years of age (see section 4.2 for information on paediatric use).

Pharmacokinetics.

Absorption: After oral administration, bilastine is rapidly absorbed, with peak plasma concentrations occurring approximately 1.3 hours after oral administration. No accumulation was observed. The mean 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 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"). Bilastine does not appear to be a substrate of the BCRP transporter or the renal transporters OST2, OAT1 and OAT3. In vitro data do not suggest that bilastine inhibits the activity of transport proteins such as P-gp, MRP2, BCRP, BSEP, OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2 and NTCP in the systemic circulation, as its ability to inhibit P-gp, OATP2B1 and OCT1 is negligible and is characterized by an IC50 ≥ 300 μM, which significantly exceeds the estimated maximum plasma concentration (Cmax) in the case of clinical use of bilastine. Therefore, such interactions are unlikely to be of clinical significance. However, the results of similar studies indicate that inhibition of transport proteins located in the intestinal mucosa (e.g. P-gp) by bilastine cannot be excluded.

Biotransformation: In in vitro studies, bilastine did not show 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 administration of 20 mg 14C-bilastine, almost 95% of the administered dose was recovered in urine (28.3%) and feces (66.5%) as unchanged bilastine, suggesting that bilastine is only slightly metabolized in humans. The mean elimination half-life in healthy volunteers is 14.5 hours.

Linearity: In the dose range studied (5 to 220 mg), bilastine exhibits linear pharmacokinetics with low intersubject variability.

Renal impairment: In a study in patients with renal impairment, the 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 30-2) and 1708.5 (±699.0) ng×h/mL in patients with severe impairment (GFR 2). In subjects with normal renal function, the mean half-life (T1/2) of bilastine was 9.3 h (±2.8), in subjects with mild renal impairment it was 15.1 h (±7.7), in subjects with moderate renal impairment it was 10.5 h (±2.3), and in subjects with severe renal impairment it was 18.4 h (±11.4). In all subjects, bilastine was almost undetectable in the urine 48-72 h after administration. These changes in pharmacokinetics are not expected to have a clinically significant impact on the safety of bilastine, as plasma bilastine levels in subjects with renal impairment remain within safe limits.

Hepatic impairment. Pharmacokinetic data in patients with hepatic impairment are not available. Bilastine is not metabolised in humans. A study in patients with renal impairment showed that bilastine is mainly excreted by the kidneys; it is likely to be excreted only to a minor extent in the bile. Changes in hepatic function have no clinically significant effect on the pharmacokinetics of bilastine.

Elderly patients. Data on the pharmacokinetics of the drug in patients over 65 years of age are limited. The pharmacokinetic parameters of bilastine in patients over 65 years of age and in patients 18-35 years of age are not statistically significantly different.

Children: 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

Bilastine revealed no special hazard for humans based on conventional non-clinical studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In reproductive toxicity studies, effects of bilastine on the fetus (pre- and post-implantation fetal death in rats and incomplete ossification of the skull, sternum and limbs in rabbits) were observed only at doses toxic to the mother. At the no-observed-adverse-effect level (NOAEL), systemic exposure was significantly (>30-fold) higher than the systemic exposure in humans at 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 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 did not show any effects on female or male reproductive organs. Mating, fertility and pregnancy indices were not altered.

According to a distribution study in rats, in which drug concentrations were determined by autoradiography, bilastine does not accumulate in the CNS.

Indication

For the symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria.

Contraindication

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other types of interactions

Interaction studies have been conducted only in adults.

Food Interaction: Food significantly reduces the oral bioavailability of bilastine, in particular when taken in the form of 20 mg tablets, the bioavailability of bilastine is reduced by 30%.

Interaction with grapefruit juice. When bilastine 20 mg was co-administered with grapefruit juice, the bioavailability of bilastine was reduced by 30%. A similar effect may also be observed with other fruit juices. The extent of the reduction in bioavailability may vary depending on the manufacturer of the juice and the fruit. The mechanism of this interaction is inhibition of the transporter protein OATP1A2, for which bilastine is a substrate (see section 5.2). Medicinal products that are substrates or inhibitors of OATP1A2, such as ritonavir or rifampicin, may also reduce the plasma concentration of bilastine.

Such changes can be explained by interactions at the level of transport proteins responsible for the excretion of drugs from intestinal cells, since bilastine is a substrate for P-gp and is not metabolized (see section "Pharmacokinetics"). The safety profile of bilastine, on the one hand, and ketoconazole or erythromycin, on the other, is probably not affected by these changes. Other drugs that are substrates or inhibitors of P-gp, such as cyclosporine, may also increase the plasma concentration of bilastine.

Interaction with diltiazem. When 20 mg bilastine once daily was co-administered with 60 mg diltiazem once daily, bilastine Cmax increased by 50%. This effect may be explained by an interaction at the level of transport proteins responsible for drug efflux from intestinal cells (see section 5.2), but is unlikely to affect the safety profile of bilastine.

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

Interaction with lorazepam. When 20 mg bilastine was administered once daily with 3 mg lorazepam once daily for 8 days, no increase in the CNS depressant effect of lorazepam was observed.

Children. Drug interaction studies have only been performed in adults. Since there is no clinical experience of interactions of bilastine with other drugs, food or fruit juices in children, the results of interaction studies in adults should be taken into account when prescribing bilastine to children. There are no clinical data on the basis of which it would be possible to conclude whether changes in AUC or Cmax due to interactions affect the safety profile of bilastine in children.

Application features

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 4.2).

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 therefore 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 medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Pregnancy: There are no or limited amount of data from the use of bilastine in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive function, parturition or postnatal development (see section 5.3). As a safety concern, it is preferable to avoid the use of Bilastine during pregnancy.

Breastfeeding. Studies on the excretion of bilastine in human milk have not been conducted. Available pharmacokinetic data have shown that bilastine is excreted in human milk in animals (see section 5.3). A decision on whether to continue/discontinue breast-feeding or to discontinue/abstain from Bilastine therapy should be made taking into account the benefit of breast-feeding for the child and the benefit of bilastine therapy for the mother.

Fertility: Limited or no clinical data are available. A study in rats did not reveal any adverse effects on fertility (see section 5.3).

Ability to influence reaction speed when driving vehicles or other mechanisms

A study conducted in adults to assess the effects of bilastine on driving ability demonstrated that treatment with bilastine 20 mg did not affect driving ability. However, as individual response to the drug may vary, patients should be advised to refrain from driving or operating machinery until their own response to bilastine is known.

Method of administration and doses

Dosage

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

The tablet should be taken 1 hour before or 2 hours after food or fruit juice (see section “Interaction with other medicinal products and other types of interactions”).

Special patient groups

Elderly patients: No dose adjustment is required (see sections 5.2 and 5.3).

Patients with hepatic impairment. The safety and efficacy of bilastine in children with hepatic impairment have not been established. There is no clinical experience with the drug in patients with hepatic impairment. However, since bilastine is not metabolized and is excreted unchanged in the urine and feces, hepatic impairment is not expected to increase its systemic exposure to a hazardous level in adult patients. Therefore, no dose adjustment is required in adult patients with hepatic impairment (see section 5.2).

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, so bilastine should not be prescribed to these age groups. Children aged 6 to 11 years should be given bilastine in other dosage forms (in the form of an oral solution or 10 mg orodispersible tablets). Bilastine-Teva, 20 mg tablets, can be used in children aged 12 years and older.

Duration of treatment. In allergic rhinoconjunctivitis, treatment should be limited to the period of exposure to allergens. In seasonal allergic rhinitis, treatment can be stopped after symptoms disappear and resumed when they reappear. In perennial allergic rhinitis, patients can be offered continuous treatment during periods of allergen exposure. In urticaria, the course of treatment depends on the type, duration and dynamics of complaints.

Method of application

For oral use.

The tablets should be taken with water.

Children. Bilastine-Teva should be used in children over 12 years of age.

Overdose

There are no data on overdose in children.

Information on acute overdose of bilastine was obtained during clinical trials conducted during the development with the participation of adults and post-marketing surveillance. In clinical trials, after administration of bilastine to 26 healthy adult volunteers at doses exceeding the therapeutic dose by 10-11 times (220 mg as a single dose or 200 mg per day for 7 days), the incidence of adverse reactions was twice as high as with placebo. The most frequently reported adverse reactions were dizziness, headache and nausea. There were no reports of serious adverse reactions and no significant prolongation of the QTc interval. The information collected during post-marketing surveillance is consistent with the data obtained during clinical trials.

In a thorough crossover study of QT/QTc intervals in 30 healthy adult volunteers, a critical assessment of the effects of multiple doses of bilastine (100 mg × 4 days) on ventricular repolarization revealed no significant prolongation of the QTc interval.

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

The specific antidote to bilastine is unknown.

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 frequently reported adverse reactions in patients receiving bilastine 20 mg for the indication allergic rhinoconjunctivitis or chronic idiopathic urticaria were headache, somnolence, dizziness and fatigue. These adverse reactions occurred at a frequency comparable to that seen in patients receiving placebo.

List of adverse reactions

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

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 -

Reactions that occur rarely and very rarely, as well as those whose frequency is unknown, have not been included in the table.

In the post-marketing period, palpitations, tachycardia, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, rash, localised/localised oedema, erythema) and vomiting have been observed - frequency unknown.

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

Information 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. Information collected in this group (adolescents) during post-marketing surveillance confirmed the results of clinical trials.

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

Expiration date

2.5 years.

Storage conditions

The medicine does not require any special storage conditions. Keep out of the reach of children.

Packaging

10 tablets in a blister; 1 or 3 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Saneka Pharmaceuticals JSC.

Location of the manufacturer and address of its place of business

Nitra 100, Hlohovec, 920 27, Slovak Republic.