Blis®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BLIS® (BLIS)

Composition:

Active substance: rupatadine fumarate;

1 tablet contains rupatadine fumarate - 12.87 mg, equivalent to rupatadine - 10.00 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; pregelatinized corn starch; magnesium stearate; iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties: light-peach-colored, round, flat tablets with the imprint "R10" on one side.

Pharmacotherapeutic group. Other antihistamines for systemic use. Rupatadine. ATC code R06AX28.

Pharmacological Properties

Pharmacodynamics.

Rupatadine belongs to the second generation of antihistamine agents and is a long-acting histamine antagonist with selective peripheral antagonistic activity at H1-receptors. Some of its metabolites (desloratadine and its hydroxylated metabolites) retain antihistaminic activity and may partially contribute to the overall efficacy of the drug.

In vitro studies of rupatadine at high concentrations have shown inhibition of mast cell degranulation induced by immunological and non-immunological stimuli, as well as reduced release of cytokines, including TNFα, from human mast cells and monocytes. The clinical significance of these observed experimental data remains to be confirmed.

Clinical studies in healthy volunteers and patients with allergic rhinitis and chronic idiopathic urticaria have not revealed any significant effect on electrocardiogram parameters following administration of rupatadine at doses ranging from 2 mg to 100 mg.

Chronic idiopathic urticaria has been studied as a clinical model of urticaria-related conditions because the underlying pathophysiology is similar regardless of etiology, and because chronic patients are easier to prospectively recruit.

Since histamine release is a causative factor in all manifestations of urticaria, rupatadine is expected to be effective in the symptomatic treatment of chronic idiopathic urticaria and other forms of urticaria.

In placebo-controlled studies in patients with chronic idiopathic urticaria, rupatadine effectively reduced the mean pruritus score from baseline over a 4-week treatment period (change from baseline: rupatadine — 57.5%, placebo — 44.9%) and decreased the mean number of wheals (54.3% vs. 39.7%).

Pharmacokinetics.

Absorption and Bioavailability

Rupatadine is rapidly absorbed after oral administration, with a tmax of approximately 0.75 hours after tablet intake. The mean Cmax was 2.6 ng/mL after a single 10 mg oral dose and 4.6 ng/mL after a single 20 mg oral dose. The pharmacokinetics of rupatadine were linear over the dose range of 10–20 mg following both single and repeated administration. After administration of a 10 mg dose once daily for 7 days, the mean Cmax was 3.8 ng/mL. Plasma concentration declined in a biexponential manner with a mean elimination half-life of 5.9 hours. The plasma protein binding of rupatadine was 98.5–99%.

As rupatadine has never been administered intravenously to humans, data on its absolute bioavailability are unavailable.

Effect of Food Intake

Food intake increases the overall systemic exposure (AUC) to rupatadine by approximately 23%. The effect on one of its active metabolites and on the main inactive metabolite was practically unchanged (decrease of approximately 5% and 3%, respectively). The time required to reach maximum plasma concentration (tmax) of rupatadine was prolonged by 1 hour. The maximum plasma concentration (Cmax) was not altered by food intake. These differences are not considered clinically significant.

Metabolism and Elimination

In a 7-day human excretion study (40 mg of 14C-rupatadine), 34.6% of the administered radioactivity was excreted in urine and 60.9% in feces. Rupatadine undergoes extensive presystemic metabolism following oral administration. The unchanged active substance was found only in negligible amounts in urine and feces. The active metabolites desloratadine and other hydroxylated derivatives accounted for approximately 27% and 48%, respectively, of the total systemic exposure to active substances. This indicates that rupatadine is almost completely metabolized. In vitro metabolism studies in human liver microsomes indicate that rupatadine is primarily metabolized by cytochrome P450 (CYP3A4).

Based on in vitro studies, the inhibitory potential of rupatadine towards CYP1A2, CYP2B6, CYP2C8, CYP2C19, UGT1A1, and UGT2B7 is unlikely. Rupatadine is not expected to inhibit systemic circulation transporters OATP1B1, OATP1B3, and BCRP (breast cancer resistance protein) in the liver and intestine. In addition, weak inhibition of intestinal P-gp (P-glycoprotein) has been observed.

In vitro induction of CYP enzymes and in vivo studies assessing the risk of induction of CYP1A2, CYP2B6, and CYP3A4 in the liver suggest that such induction by rupatadine is unlikely. According to in vivo study results, rupatadine acts as a mild inhibitor of CYP3A4.

Special Patient Populations

In a study involving healthy volunteers comparing results in young adults and elderly subjects, AUC and Cmax values of rupatadine were higher in the elderly compared to young adults. This is likely due to reduced hepatic metabolism during first-pass liver metabolism in elderly individuals. AUC and Cmax of rupatadine metabolites did not differ between young and elderly subjects. The mean elimination half-life of rupatadine was 8.7 hours in elderly subjects and 5.9 hours in young volunteers, respectively. Since differences in pharmacokinetic parameters for rupatadine and its metabolites were not clinically significant, it was concluded that dose adjustment is not required for elderly patients receiving a 10 mg dose of the drug.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinitis and urticaria in adults and adolescents (aged 12 years and older).

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults and adolescents (aged 12 years and older) who received rupatadine 10 mg tablets.

Effect of other medicinal products on rupatadine

Concomitant use with strong CYP3A4 inhibitors (including itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, nefazodone) should be avoided. Caution is required when co-administering with moderate CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem).

Concomitant administration of rupatadine at a dose of 20 mg with ketoconazole or erythromycin increases systemic exposure to rupatadine by 10-fold and 2–3-fold, respectively. These changes are not associated with alterations in QT interval or increased incidence of adverse reactions compared to administration of the respective agents alone.

Interaction with grapefruit. Concurrent intake of grapefruit juice increases overall exposure to rupatadine by 3.5-fold. Grapefruit juice should not be consumed at the same time as the medicinal product.

Effect of rupatadine on other medicinal products

Caution is advised when rupatadine is co-administered with other medicinal products that are metabolized and have a narrow therapeutic index, as data on the effect of rupatadine on other drugs are limited.

Interaction with alcohol. Following alcohol intake, a 10 mg dose of rupatadine showed a minor effect on the results of certain psychomotor performance tests, which did not significantly differ from the effect of alcohol alone. A 20 mg dose enhanced the changes induced by alcohol.

Interaction with CNS depressants. As with other antihistamines, interaction with central nervous system (CNS) depressants cannot be excluded.

Interaction with statins. Asymptomatic increases in creatine phosphokinase levels were occasionally observed during clinical studies with rupatadine. The risk of interaction with statins—some of which are also metabolized by the CYP3A4 isoenzyme of cytochrome P450—is unknown. Therefore, rupatadine should be used with caution when co-administered with statins.

Interaction with midazolam. After administration of 10 mg rupatadine in combination with 7.5 mg midazolam, a slight increase in midazolam concentrations (Cmax and AUC) was observed. Thus, rupatadine acts as a mild inhibitor of CYP3A4.

Special precautions for use

Concomitant intake of rupatadine with grapefruit juice is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Combination of rupatadine with strong CYP3A4 inhibitors should be avoided, and caution is advised when co-administering with moderate CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Dosage adjustment may be required for weak CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic index (e.g., cyclosporine, tacrolimus, sirolimus, everolimus, cisapride), since rupatadine may increase plasma concentrations of these drugs (see section "Interaction with other medicinal products and other forms of interaction").

The effect of rupatadine 10 mg tablets on cardiac function was evaluated in a "Thorough QT/QTc" study in adults, in which rupatadine at a dose 10 times higher than the therapeutic dose did not affect ECG and therefore did not raise concerns regarding cardiac safety. However, rupatadine should be used with caution in patients with QT interval prolongation, in patients with uncorrected hypokalemia, and in patients with stable proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia.

Rupatadine 10 mg tablets should be used with caution in elderly patients (aged 65 years and older). Although no overall differences in efficacy or safety were observed in clinical trials, increased sensitivity in some elderly patients cannot be ruled out due to the small number of elderly participants in the trials (see section "Pharmacological properties").

For use in children aged 12 years and older and in patients with renal or hepatic impairment, see section "Dosage and administration".

Due to the presence of lactose monohydrate, this medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of the medicinal product during pregnancy are limited. Animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonal/fetal development, course of parturition, or postnatal development. As a precautionary measure, it is recommended to avoid using the drug during pregnancy.

Breastfeeding

Rupatadine is excreted in animal milk. It is unknown whether rupatadine passes into human breast milk. The benefit of breastfeeding for the child and the benefit of using the drug for the woman should be considered when deciding whether to discontinue breastfeeding or to stop/abstain from using the drug.

Fertility

There are no clinical data on fertility. Animal studies have shown a significant reduction in fertility at exposure levels higher than those observed in humans at the maximum therapeutic dose.

Ability to influence reaction speed when driving or operating machinery

Rupatadine 10 mg had no effect on the ability to drive vehicles or operate machinery. However, caution should be exercised, and individual response to rupatadine should be assessed before driving or operating machinery.

Dosage and Administration.

Adults and children aged 12 years and older

The recommended dose is 10 mg (1 tablet) once daily, regardless of food intake.

Elderly patients

Rupatadine should be used with caution in elderly patients (see section "Special Warnings and Precautions for Use").

Patients with renal or hepatic impairment

Due to lack of clinical experience, the drug is not recommended for patients with impaired kidney or liver function.

Children.

This medicinal product is not recommended for children under 12 years of age. For children aged 2 to 11 years, rupatadine in oral solution form is recommended.

Overdose.

There have been no reports of rupatadine overdose. In clinical safety studies, rupatadine was well tolerated at a daily dose of 100 mg for 6 days. The most common adverse reaction was somnolence. In case of accidental ingestion of very high doses, symptomatic and supportive therapy is recommended.

Adverse reactions

The most commonly reported adverse reactions during controlled clinical studies were somnolence (9.44%), headache (6.9%), fatigue (3.1%), asthenia (1.5%), dry mouth (1.2%), and dizziness (1.03%).

Most of the adverse events observed during controlled clinical studies were mild to moderate in severity and generally did not require discontinuation of treatment. The frequency of adverse reactions is defined as follows: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000).

The adverse reactions listed below have been reported in patients during clinical studies and spontaneous reporting with the use of rupatadine.

In addition, during the post-registration study, three rare adverse reactions were reported: tachycardia, increased heart rate, and hypersensitivity reactions (including anaphylactic reactions, angioedema, and urticaria) with the use of rupatadine in 10 mg tablets.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required.

Keep out of the reach of children.

Packaging. 15 tablets per blister. 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Normon S.A. / Laboratorios Normon S.A. (manufacturing, primary packaging, secondary packaging, batch/quality control, batch release).

Manufacturer's address.

Ronda De Valdecarrizo 6, Tres Cantos, 28760, Spain / Ronda De Valdecarrizo 6, Tres Cantos, 28760, Spain.

Marketing Authorization Holder.

AT "Farmak".

Address of the Marketing Authorization Holder.

63 Kyrylivska Street, Kyiv, 04080, Ukraine.