Kestin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KESTIN (KE STIN E®)

Composition:

Active substance: ebastine;

1 tablet contains 10 mg or 20 mg of ebastine;

Excipients: microcrystalline cellulose; pregelatinized corn starch; lactose monohydrate; sodium croscarmellose; magnesium stearate;

Coating: hypromellose, polyethylene glycol 6000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round film-coated tablets with the embossing «E/10» (for 10 mg tablets) and «E20» (for 20 mg tablets).

Pharmacotherapeutic group. Antihistamines for systemic use. Ebastine. ATC code R06AX22.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ebastine results in rapid and prolonged inhibition of the effects of histamine and demonstrates high affinity for H1 receptors. After oral administration, neither ebastine nor its metabolites cross the blood-brain barrier. This characteristic corresponds to the low sedation profile observed in experimental studies evaluating the effects of ebastine on the central nervous system (CNS).

Data from in vitro and in vivo studies indicate that ebastine is a potent, long-acting, and highly selective antagonist of histamine H1 receptors, with no adverse effects on the CNS and no anticholinergic effects.

Pharmacodynamic effects

Studies conducted on histamine-induced papules have demonstrated a clinically and statistically significant antihistaminic effect, evident within 1 hour after administration and lasting more than 48 hours. After discontinuation of a five-day treatment course with ebastine, the antihistaminic effect persists for over 72 hours. This activity is proportional to plasma levels of the main active acid metabolite, carebastine.

Following repeated administration, peripheral receptor blockade is maintained at a steady level without tachyphylaxis. These results suggest that ebastine at a dose of at least 10 mg produces rapid, intense, and prolonged blockade of peripheral histamine H1 receptors when administered once daily.

Administration of 20 mg of ebastine once daily demonstrates higher activity compared to other antihistamines over a 24-hour period.

Sedation has been evaluated using electroencephalographic tests, cognitive function assessments, visual-motor coordination tests, and subjective evaluations. At the recommended dose, no significant increase in sedation was observed. These findings are consistent with results from double-blind clinical trials: the incidence of sedation is similar with both placebo and ebastine.

Clinical studies have been conducted on the effects of ebastine on cardiac function. In detailed analyses at doses up to 100 mg per day (ten times the recommended daily dose), no significant effects on cardiac function were observed.

Pharmacokinetics

After oral administration, ebastine is rapidly absorbed, undergoing extensive first-pass metabolism in the liver and converting into its active metabolite, carebastine.

Following a single 10 mg oral dose, peak plasma levels of the metabolite occur within 2.6–4 hours and reach values between 80 and 100 ng/mL. The elimination half-life of the metabolite ranges from 15 to 19 hours, with approximately 66% of the drug excreted in urine, primarily as conjugated metabolites. After repeated administration of 10 mg once daily, steady-state plasma concentrations are achieved within 3–5 days, with peak levels ranging from 130 to 160 ng/mL.

After a single 20 mg oral dose, peak plasma levels of the metabolite occur within 1–3 hours, reaching an average value of 2.8 ng/mL, while plasma levels of the carebastine metabolite reach an average of 157 ng/mL.

No saturation phenomena were observed in absorption, distribution, or elimination. Linearity in pharmacokinetics has been confirmed by area under the concentration-time curve (AUC) values following doses of 10 to 40 mg of ebastine, and the time to peak concentration (t_max) is independent of the administered dose.

In vitro studies using human liver microsomes show that ebastine is metabolized to carebastine by the CYP3A4 enzyme. Concomitant administration of ebastine with ketoconazole or erythromycin (both CYP3A4 inhibitors) to healthy volunteers resulted in significant increases in plasma concentrations of both ebastine and carebastine, particularly with ketoconazole (see section "Interaction with other medicinal products and other forms of interaction").

Plasma protein binding of ebastine and carebastine exceeds 97%.

No statistically significant differences in pharmacokinetic profiles were observed between elderly and younger patients.

Plasma concentrations of ebastine and carebastine measured on day 1 and day 5 of treatment in patients with mild, moderate, or severe renal impairment (daily dose 20 mg), as well as in patients with mild, moderate (both groups receiving 20 mg/day), or severe hepatic impairment (dose 10 mg/day), were similar to those observed in healthy volunteers. This indicates that the pharmacokinetic profiles of ebastine and its metabolite are not significantly altered in patients with varying degrees of renal or hepatic impairment.

Preclinical safety data

Preclinical data revealed no significant toxic effects based on standard assessments of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

Clinical characteristics.

Indications.

Symptomatic treatment of:

• allergic rhinitis (seasonal and perennial), associated or not associated with allergic conjunctivitis;

• chronic idiopathic urticaria and allergic dermatitis.

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Concomitant use of ebastine with ketoconazole or erythromycin results in QT interval prolongation on ECG. In both cases, pharmacokinetic and pharmacodynamic interactions are observed, leading to increased plasma levels of ebastine and, to a lesser extent, carebastine, without clinically significant pharmacodynamic consequences. QTc prolongation is approximately 10 ms higher than that observed with ketoconazole or erythromycin alone. The medicinal product should be used with particular caution when co-administered with azole antifungal agents (e.g., ketoconazole, itraconazole) and macrolides (e.g., erythromycin).

Pharmacokinetic interaction has been observed with concomitant administration of ebastine and rifampicin, which may lead to reduced plasma concentration and therapeutic effect of antihistamines.

No interactions between ebastine and theophylline, warfarin, cimetidine, diazepam, or alcohol have been observed.

When ebastine is taken with food, plasma levels and AUC (area under the concentration-time curve) of the main metabolite increase by 1.5 to 2 times. This increase does not alter Tmax (time to reach maximum concentration). Administration of ebastine with food does not affect its clinical effect.

The medicinal product may influence the results of skin allergy tests; therefore, it is recommended to discontinue the use of the product 5–7 days before testing.

The medicinal product may potentiate the effect of other antihistamines.

Special precautions for use

The drug should be used with caution in patients with prolonged QT interval, hypokalemia, and when co-administered with other medicinal products that prolong the QT interval or inhibit the CYP3A4 enzyme, such as azole antifungal agents (e.g., ketoconazole, itraconazole) and macrolides (e.g., erythromycin).

Concomitant administration of ebastine with rifampicin may result in a pharmacokinetic interaction (see section "Interaction with other medicinal products and other forms of interaction").

The drug should be used with caution in patients with severe hepatic impairment (see section "Method of administration and dosage").

Since the therapeutic effect of the drug occurs 1–3 hours after administration, Kestin should not be used in acute allergic reactions requiring emergency treatment.

Kestin, film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breast-feeding.

Pregnancy.
There are only limited data on the use of ebastine in pregnant women. Animal studies have not shown any direct or indirect toxic effects of the drug on reproductive function. Therefore, it is recommended to avoid using ebastine during pregnancy.

Breast-feeding.
The high degree of protein binding (> 97%) of ebastine and its main metabolite, carebastine, suggests that the drug is unlikely to pass into breast milk. Nevertheless, as a precautionary measure, the use of ebastine should be avoided during breast-feeding.

Fertility.
There are no data available on the effect of ebastine on human fertility.

Ability to influence reaction rate while driving or operating machinery.
Detailed studies on the effects on human psychomotor function have confirmed the absence of any negative effect of Kestin. At recommended therapeutic doses,
ebastine does not impair reaction speed while driving or operating machinery.

However, patients who are particularly sensitive to ebastine are advised to undergo additional assessment for individual reactions before driving or performing complex tasks, since the drug may cause drowsiness or dizziness (see section "Adverse reactions").

Dosage and Administration.

For oral use. The drug can be taken independently of food intake, with a sufficient amount of water.

Adults and children aged 12 years and older: the recommended dose is 10 mg (1 tablet of 10 mg) once daily; in case of pronounced symptoms – 20 mg (1 tablet of 20 mg) once daily.

Kestin tablets should not be administered to patients with impaired swallowing function.

Elderly patients
do not require dose adjustment.

Patients with renal impairment
do not require dose adjustment.

Patients with hepatic impairment
of mild or moderate degree do not require dose adjustment. In patients with severe hepatic impairment, the maximum recommended dose of 10 mg once daily should not be exceeded, as there are no safety data available for higher doses in these patients.

The duration of treatment may be extended until symptoms disappear and is determined individually by the physician.

Children.
Kestin, 10 mg or 20 mg film-coated tablets, should not be used in children under 12 years of age (see section "Dosage and Administration").

Overdose.

In clinical studies using high doses of the drug, no clinically significant signs or symptoms were observed with doses up to 100 mg once daily. There is no specific antidote. In case of overdose, gastric lavage is recommended, along with medical monitoring of vital functions (ECG) and symptomatic treatment.

Adverse Effects.

In a pooled analysis of placebo-controlled clinical trials involving 5,708 patients treated with ebastine, the most commonly reported adverse reactions were headache, dry mouth, and somnolence.

Adverse reactions reported in clinical trials conducted in children (n = 460) were of the same nature as those observed in adults.

Undesirable effects are classified by frequency of occurrence into the following categories: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000), very rare (<1/10,000).

Side effects	Very common (≥1/10)	Common (≥1/100 to < 1/10)	Rare (≥1/10,000 to < 1/1,000)
Immune system disorders			Hypersensitivity reactions (such as anaphylaxis and angioedema)
Psychiatric disorders			Nervousness, insomnia
Nervous system disorders	Headache	Somnolence	Dizziness, hypoesthesia, dysgeusia
Cardiac disorders			Palpitations, tachycardia
Gastrointestinal disorders		Dry mouth	Vomiting, abdominal pain, dyspepsia, nausea
Hepatobiliary disorders			Hepatitis, cholestasis, changes in liver function tests (increased transaminases, gamma-glutamyltransferase, alkaline phosphatase and bilirubin)
Skin and subcutaneous tissue disorders			Urticaria, rash, dermatitis
Reproductive system and breast disorders			Menstrual disorders
General disorders			Edema, asthenia

Reporting of suspected adverse reactions

Reporting of adverse reactions after registration of the medicinal product plays an important role. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions through the national reporting system.

Shelf life.
3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children!

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

Supply category.
Over-the-counter (without prescription).

Manufacturer.
Industrias Farmacéuticas Almirall S.A.

Manufacturer's address
and location of its operations.

National Highway II, km 593, Sant Andreu de la Barca, 08740 Barcelona, Spain.

Marketing Authorization Holder.
ALMIRALL, S.A.

Address of the Marketing Authorization Holder.
General Mitre, 151, 08022 Barcelona, Spain.

In case of occurrence of undesirable effects, adverse reactions or lack of therapeutic effect, please report to LLC "Alvogen Ukraine", 5I Brovarskyi Avenue, Kyiv, 02660, Ukraine; tel./fax +38 044 517-75-00; e-mail: [email protected].