Flustin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUSTINE

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: oval, biconvex, white tablets with a score line on one side and smooth on the other.

The score line is intended only for breaking the tablet to facilitate swallowing, and not for dividing it 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 (manifested as 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, nasal discharge, nasal itching, nasal congestion, ocular itching, 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 itching and decreasing the number and size of wheals, as well as alleviating 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 any other effect on the cardiovascular system was 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 in 30 volunteers. In controlled clinical trials, the 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 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 in younger patients.

In a post-marketing 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 with allergic rhinoconjunctivitis), while the remaining 116 participants were randomized into groups receiving 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 study results with bilastine in all pediatric subgroups under 2 years of age (see section "Dosage and Administration").

Pharmacokinetics.

Absorption. After oral administration, bilastine is rapidly absorbed, with peak plasma concentration reached approximately 1.3 hours after intake. Accumulation does not occur. 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-glycoprotein (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 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, since its inhibitory potential against P-gp, OATP2B1, and OCT1 is negligible, with IC50 values ≥ 300 µM, significantly exceeding the predicted maximum plasma concentration (Cmax) at clinical doses 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.

Metabolism. In vitro studies indicate that bilastine does not induce or inhibit the activity of CYP450 isoenzymes.

Elimination. In a mass balance study conducted in healthy volunteers, after single oral administration of 14C-bilastine at a dose of 20 mg, 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 in patients with normal renal function (GFR > 80 mL/min/1.73 m²), the mean AUC0–∞ (± SD) was 737.4 (± 260.8) ng·h/mL; in patients with mild renal impairment (GFR = 50–80 mL/min/1.73 m²), it was 967.4 (± 140.2) ng·h/mL; in moderate renal impairment (GFR = 30–<50 mL/min/1.73 m²), 1384.2 (± 263.23) ng·h/mL; and in severe renal impairment (GFR < 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 those with mild impairment, 10.5 hours (± 2.3) in moderate impairment, and 18.4 hours (± 11.4) in severe impairment. Bilastine was no longer detectable in urine in almost all patients within 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 in patients with renal impairment remain within safe ranges.

Hepatic impairment. Pharmacokinetic data in patients with hepatic impairment are lacking. 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. Therefore, changes in liver function are not expected to have a clinically significant effect on the pharmacokinetics of bilastine.

Elderly patients. Pharmacokinetic data for bilastine 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 older and those aged 18–35 years.

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

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 with food. Food reduces the oral bioavailability of bilastine by 30%.

Interaction with grapefruit juice. When bilastine 20 mg was administered concomitantly with grapefruit juice, the bioavailability of bilastine decreased by 30%. A similar effect may 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 bilastine was administered concomitantly with ketoconazole or erythromycin, the AUC of bilastine increased twofold and Cmax increased 2–3 times. 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 of bilastine and 60 mg of diltiazem were administered concomitantly, the Cmax of bilastine increased by 50%. This effect can be explained by interaction at the level of transporter proteins responsible for efflux of medicinal products from intestinal cells (see section "Pharmacokinetics"); this effect is unlikely to influence the safety profile of bilastine.

Interaction with alcohol. After concomitant administration of alcohol and bilastine 20 mg, psychomotor functions remained at the same level as after concomitant administration of alcohol and placebo.

Interaction with lorazepam. When bilastine 20 mg was administered concomitantly with lorazepam 3 mg 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. Since there is no clinical experience regarding interactions between bilastine and other medicinal products, food, or fruit juices in children, results obtained in adults should be taken into account when prescribing bilastine to children aged 12 to 17 years.

Special precautions for use.

In patients with moderate or severe renal function 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, patients with moderate or severe renal impairment should avoid concomitant use of bilastine and P-gp inhibitors.

Cases of QT interval prolongation on electrocardiogram have been reported in patients treated with bilastine (see sections "Adverse reactions", "Overdose", "Pharmacological properties"). It is presumed that medicinal products causing QT/QTc prolongation 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 marked bradycardia; and patients receiving concomitant medications associated with QT/QTc prolongation.

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. For safety reasons, it is advisable to avoid using the drug during pregnancy.

Breastfeeding.

Studies on the excretion of bilastine into human breast milk have not been conducted. Available pharmacokinetic data in animals have shown that bilastine is excreted into breast milk. The decision whether to continue/stop breastfeeding or to continue/interrupt treatment with bilastine should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility.

Clinical data are limited or lacking. Animal studies in rats did not reveal any negative effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies evaluating the effect of bilastine on the ability to drive vehicles have demonstrated that in adults, treatment with bilastine at a dose of 20 mg did not impair the ability to drive. However, patients should be informed that in individual cases the drug may cause dizziness and somnolence, and thus may affect the ability to drive vehicles or operate machinery.

Dosage and Administration.

Dosage.

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

For allergic rhinoconjunctivitis, the drug should be taken throughout the entire period of allergen exposure. In the case of seasonal allergic rhinitis, treatment may be discontinued after symptoms resolve and restarted if symptoms reappear. For perennial allergic rhinitis, the drug may be prescribed during periods of allergen exposure.

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

Special patient groups.

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

Renal impairment: Dose adjustment is not required in patients with impaired renal function (see section "Pharmacokinetics").

Hepatic impairment: Clinical experience with bilastine in patients with hepatic impairment is lacking. Since bilastine undergoes no metabolism and is primarily excreted by the kidneys, hepatic impairment is not expected to lead to an increase in systemic exposure to a dangerous level. Therefore, dose adjustment is not required in patients with impaired liver function (see section "Pharmacokinetics").

Administration method.

Tablets should be taken orally with sufficient amount of water. The daily dose should be taken as a single dose.

The tablet should be taken 1 hour before or 2 hours after a meal or fruit juice (see section "Interaction with other medicinal products and other forms of interaction").

Children: Bilastine should not be used in children aged 0 to 2 years.

The safety and efficacy of bilastine in children under 12 years of age have not been established.

Children:

The efficacy and safety of bilastine in children under 12 years of age have not been established.

Overdose.

Information regarding acute overdose with bilastine was obtained from clinical trials conducted during drug development and from post-marketing surveillance. In clinical trials, when healthy adult volunteers received bilastine 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 as with placebo. The most commonly reported adverse reactions were dizziness, headache, and nausea. No reports of serious adverse reactions or significant QTc interval prolongation were recorded. 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, careful assessment of the effect of multiple doses of bilastine (100 mg daily for 4 days) on ventricular repolarization revealed no significant QTc interval prolongation.

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

There is no known specific antidote for bilastine.

Adverse Reactions

General safety profile in adults and adolescents

During clinical trials in 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 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.

The table below lists adverse reactions considered 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 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); not known (frequency 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.

*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 (cannot be estimated from available data) have been observed, such as 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. The most frequently reported adverse reactions were two that occurred commonly (somnolence and headache) and two that occurred uncommonly (dizziness and fatigue). These reactions were observed in both patients receiving bilastine 20 mg and those receiving placebo. Their respective frequencies were 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.

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 to 17 years) were similar to those in adults. Data collected in this population (adolescents) during post-marketing surveillance were consistent with findings from clinical trials.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after a medicinal product's authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions.

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

Packaging.

10 tablets in a blister; 1 blister per cardboard box.

Prescription category.

Prescription-only medicine.

Manufacturer.

Vivimed Labs Ltd.

Manufacturer's address and location of operations.

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