Ostiban

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OSTIBAN

Composition:

Active ingredient: ebastine;

One film-coated tablet contains: ebastine 10 mg or 20 mg;

Excipients: stearyl macrogolglycerides, microcrystalline cellulose, sodium glycolate corn starch, magnesium stearate;
Coating: Opadry White (06F28753): hypromellose, polyethylene glycol, titanium dioxide (E 171), purified water.

Pharmaceutical form.
Film-coated tablets.

Main physico-chemical properties:
White film-coated tablets.

Pharmacotherapeutic group.
Antihistamines for systemic use. Ebastine.

ATC code R06AX22.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Ebastine causes 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 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 H1-histamine receptor antagonist, with no negative impact on the CNS and no anticholinergic effects.

Pharmacodynamic Effects

Studies conducted on histamine-induced wheals 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 metabolite, carebastine.

Following repeated administration, peripheral receptor blockade is maintained at a constant level without tachyphylaxis. These results suggest that ebastine at a dose of at least 10 mg produces rapid, potent, and prolonged blockade of peripheral H1-histamine 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, where the incidence of sedation was similar with both placebo and ebastine.

Clinical studies have been conducted on the effects of ebastine on cardiac function. A detailed analysis at doses up to 100 mg per day (ten times the recommended daily dose) showed no significant effects on cardiac function.

Pharmacokinetics

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

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

After a single oral dose of 20 mg, maximum plasma levels of the metabolite are reached within 1–3 hours, with a mean value of 2.8 ng/mL, while plasma levels of the carebastine metabolite reach a mean value of 157 ng/mL.

No saturation phenomena in absorption, distribution, or elimination have been observed. Kinetic linearity has been confirmed with respect to the area under the concentration-time curve (AUC) for ebastine doses ranging from 10 to 40 mg, and the time to reach maximum concentration (Tmax) is independent of the administered dose.

In vitro studies using human liver microsomes show that ebastine is metabolized to carebastine via the CYP3A4 enzyme. Concomitant administration of ebastine with ketoconazole or erythromycin (both CYP3A4 inhibitors) in healthy volunteers resulted in a significant increase in plasma concentrations of ebastine and carebastine, particularly with ketoconazole (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Protein binding of ebastine and carebastine to plasma proteins exceeds 97%.

No statistically significant differences in pharmacokinetic profiles have been observed between elderly patients and younger individuals.

Plasma concentrations of ebastine and carebastine obtained on the first and fifth days of treatment in patients with mild, moderate, or severe renal impairment (daily doses of 20 mg), as well as those with mild, moderate (both groups receiving 20 mg/day), or severe hepatic impairment (dose of 10 mg/day), were similar to those observed in healthy volunteers, indicating that the pharmacokinetic profile of ebastine and its metabolite is 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 toxicology.

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 leads to QT interval prolongation on ECG. In both cases, pharmacokinetic and pharmacodynamic interactions are observed, resulting in increased plasma levels of ebastine and, to a lesser extent, carebastine, without clinically significant pharmacodynamic consequences. QTc prolongation is approximately 10 ms greater than that observed with ketoconazole or erythromycin alone. Particular caution should be exercised when co-administering the drug 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 of ebastine with theophylline, warfarin, cimetidine, diazepam, or alcohol have been reported.

Plasma levels and AUC of the main metabolite of ebastine increase 1.5 to 2 times when ebastine is taken with food. This increase does not alter the Tmax. Administration of ebastine with food does not affect its clinical effect.

The drug may influence the results of skin allergy tests; therefore, it is recommended to discontinue the drug 5–7 days prior to testing.

The drug may potentiate the effects 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 interactions").

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

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

Use during pregnancy or breastfeeding

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

Breastfeeding period
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. As a precautionary measure, ebastine use should be avoided during breastfeeding.

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

Ability to influence reaction speed when driving or operating machinery

Detailed studies on the effect of ebastine on human psychomotor function have confirmed the absence of any negative effect of Ostiban. At recommended therapeutic doses, ebastine does not impair reaction speed during driving or operating machinery.

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

Administration and Dosage.

Tablets for oral administration. The medicinal product Ostiban can be taken regardless of food intake, with 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 cases of pronounced symptoms – 20 mg (1 tablet of 20 mg) once daily.

Ostiban tablets must not be administered to patients with impaired swallowing function.

Elderly patients:
no dose adjustment is required.

Patients with renal impairment:
no dose adjustment is required.

Patients with hepatic impairment:
those with mild or moderate impairment do not require dose adjustment. In patients with severe hepatic impairment, the maximum recommended dose should not exceed 10 mg daily, as there is no safety data available for higher doses in such patients.

Duration of treatment may be extended until symptoms disappear or as individually determined by the physician.

Children.

Ostiban, 10 mg or 20 mg film-coated tablets, must not be administered to children under 12 years of age (see section "Administration and Dosage").

Overdose.

In 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 reactions.

In a pooled analysis of placebo-controlled clinical studies involving 5708 patients who received ebastine, the most commonly reported adverse reactions were headache, dry mouth, and somnolence.

Adverse reactions reported in clinical studies conducted in children (number = 460) have the same characteristics as those in adults.

Adverse reactions are classified by frequency of occurrence into the following categories: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000).

System organ class	Adverse reactions
	Very common	Common	Rare
Immune system disorders			Hypersensitivity reactions (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 suspected adverse reactions

Information about adverse reactions collected after drug registration plays an important role. It enables 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 in place.

Shelf life.
4 years. Do not use after the expiry date stated on the packaging.

Storage conditions.
No special storage conditions required. Keep out of reach and sight of children.

Packaging.
Tablets, film-coated, 10 mg or 20 mg; 10 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.
Over-the-counter (without prescription).

Manufacturer.

Generis Farmaceutica, S.A. / Generis Farmaceutica, S.A.

Manufacturer's address
and address of its place of business.

Rua Joao de Deus, n. 19, Venda Nova, 2700-487 Amadora, Portugal /
Rua Joao de Deus, n. 19, Venda Nova, 2700-487 Amadora, Portugal.

Marketing Authorization Holder.

LLC "VORWARTS PHARMA".

Address of the Marketing Authorization Holder.

4 Prytsaka Omelyana Street, Kyiv, 03142, Ukraine.