Rupafin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RUPAFIN (RUPAFIN)

Composition:

Active substance: rupatadine fumarate;

1 ml of solution contains rupatadine fumarate 1.28 mg, equivalent to 1 mg of rupatadine;

Excipients: propylene glycol, anhydrous citric acid, anhydrous disodium phosphate, sodium saccharin, sucrose, methylparahydroxybenzoate (E 218), quinoline yellow (E 104), banana flavoring, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear yellow solution with banana odor and taste.

Pharmacotherapeutic group. Drugs acting on the respiratory system. Other antihistamines for systemic use. Rupatadine. ATC code R06AX28.

Pharmacological Properties

Pharmacodynamics.

Rupatadine belongs to second-generation antihistamines 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 has yet to be confirmed.

Oral solution rupatadine demonstrated a similar pharmacokinetic profile in children aged 6–11 years and in older patients (>12 years): a pharmacodynamic effect (edema suppression, antihistaminic effect) was observed after 4 weeks of treatment. A randomized, double-blind, placebo-controlled confirmatory study in children aged 6 to 11 years with persistent allergic rhinitis showed that rupatadine oral solution provided greater improvement in nasal symptoms (rhinorrhea, nasal, throat, and/or ear pruritus) compared to placebo after 4 and 6 weeks of treatment. Furthermore, a significant improvement in quality of life was observed throughout the study compared to placebo.

Chronic spontaneous urticaria has been studied as a clinical model to evaluate the efficacy of anti-H1 compounds in all forms of urticaria, as the underlying pathophysiology is similar regardless of etiology, and patients with chronic conditions are generally easier to recruit into clinical trials. Urticaria is a mast cell-mediated disease, and histamine and other mediators (TNF and cytokines) are the primary mediators of all urticarial lesions. Since rupatadine is capable of blocking the release of histamine and other inflammatory mediators, it is expected to be effective in alleviating symptoms of other types of urticaria beyond chronic spontaneous urticaria, as recommended in clinical guidelines.

The efficacy of rupatadine oral solution in children aged 2–11 years with chronic spontaneous urticaria was demonstrated in a multicenter, randomized, active- and placebo-controlled trial. A total of 206 children were enrolled in the study, including 113 children aged 2–5 years and 93 children aged 6–11 years. Children received rupatadine (n = 66), placebo (n = 69), or desloratadine (n = 71). The dose of rupatadine was 2.5 mg for children with body weight ≤25 kg and 5 mg for children with body weight >25 kg. The dose of desloratadine was 1.25 mg for children with body weight ≤25 kg and 2.5 mg for children with body weight >25 kg. Statistically significant improvement compared to placebo was demonstrated in the mean change in weekly urticaria activity score (UAS7; includes wheals and pruritus)—the primary endpoint assessed at 6 weeks of treatment (rupatadine -11.77 vs. placebo -5.55; p < 0.001). The mean percentage reduction in weekly wheal frequency at the study endpoint compared to baseline was 56.7% with rupatadine, 49.4% with desloratadine, and 22.7% with placebo. The mean percentage reduction in pruritus episodes at the study endpoint compared to baseline was 56.8% with rupatadine, 46.7% with desloratadine, and 33.4% with placebo. Both active treatments (rupatadine and desloratadine) achieved statistically significant greater improvements than placebo in reducing wheal and pruritus episodes, while no statistically significant differences were observed between the two active treatments. The proportion of patients achieving more than 50% reduction in weekly urticaria activity score (UAS7; wheals and pruritus) was 61% in the rupatadine group compared to 36% in the placebo group and 54% in the desloratadine group.

During clinical trials, administration of rupatadine at doses ranging from 2 mg to 100 mg in volunteers (n = 393) and patients (n = 2650) with allergic rhinitis and chronic idiopathic urticaria did not reveal any significant effect of the drug on electrocardiographic parameters.

The European Medicines Agency has waived the obligation to submit results of rupatadine oral solution studies in all pediatric subpopulations for allergic rhinitis and chronic urticaria (see section "Indications").

Pharmacokinetics.

Pediatric population

In children aged 2–5 and 6–11 years, rupatadine was rapidly absorbed, with mean Cmax values of 1.9 and 2.5 ng/mL, respectively, after repeated oral administration. Regarding exposure, the mean total area under the curve (AUC) was 10.4 ng·h/mL in children aged 2–5 years and 10.7 ng·h/mL in children aged 6–11 years. All these values are similar to those obtained in adults and children aged 12 years and older.

The mean elimination half-life of rupatadine was 15.9 hours in children aged 2–5 years and 12.3 hours in children aged 6–11 years, which is longer than that observed in adults and children aged 12 years and older when rupatadine tablets are administered.

Effect of food intake

No food interaction studies were conducted with rupatadine oral solution. Food effects were studied in adults and children aged 12 years and older receiving 10 mg rupatadine tablets. Food intake increased systemic exposure (AUC) of rupatadine by approximately 23%. Food had no effect on maximum plasma concentration (Cmax). These differences are not 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 detected only in negligible amounts in urine and feces, indicating that rupatadine is almost completely metabolized. The active metabolite desloratadine and other hydroxylated derivatives accounted for approximately 27% and 48%, respectively, of the total systemic exposure to the active moiety. 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 on CYP1A2, CYP2B6, CYP2C8, CYP2C19, UGT1A1, and UGT2B7 is unlikely. Rupatadine is not expected to inhibit the following transporters in systemic circulation: OATP1B1, OATP1B3, and BCRP (breast cancer resistance protein)—hepatic and intestinal. In addition, moderate inhibition of intestinal P-gp (P-glycoprotein) has been observed.

Based on in vitro CYP induction studies, the risk of in vivo induction of CYP1A2, CYP2B6, and CYP3A4 in the liver by rupatadine is considered unlikely. In vivo data indicate that rupatadine acts as a weak inhibitor of CYP3A4.

Preclinical safety data

Preclinical study data do not indicate a specific risk to humans based on standard repeated-dose pharmacotoxicology, genotoxicity, and carcinogenicity studies.

Doses of rupatadine 100 times higher than the recommended clinical dose (10 mg) did not affect QTc and QRS intervals or cause arrhythmia symptoms in various animal species, such as rats, guinea pigs, and dogs. Rupatadine and its main metabolite, 3-hydroxydesloratadine, detected in humans, did not affect the action potential in Purkinje fibers in dogs at concentrations at least 2000 times higher than the maximum plasma concentration in humans receiving 10 mg. In a study assessing the effect of rupatadine on the cloned gene of the specific cardiac potassium channel, it inhibited this channel at a concentration 1685 times higher than the maximum plasma concentration achieved with 10 mg. Desloratadine, the metabolite with the highest activity, showed no effect at a concentration of 10 µmol/L. Tissue distribution studies in rats using radiolabeled rupatadine showed no accumulation in cardiac tissues.

A significant reduction in fertility in both male and female rats was observed at a dose of 120 mg/kg/day, where the maximum concentration was 268 times higher than the Cmax in humans at the therapeutic dose (10 mg/day). Toxic effects on the fetus (developmental delay, incomplete ossification, minor skeletal variations) were reported in rats at maternally toxic doses (25 and 120 mg/kg/day). In rabbits, developmental toxicity was observed at doses up to 100 mg/kg. The no-observed-adverse-effect level (NOAEL) was 5 mg/kg/day in rats and 100 mg/kg/day in rabbits, corresponding to Cmax values 45 and 116 times higher, respectively, than those achieved with the therapeutic dose in humans (10 mg/day).

Clinical characteristics.

Indications.

For symptomatic treatment:

• allergic rhinitis (including persistent allergic rhinitis) in children aged 2 to 11 years (see section "Pharmacological properties");
• urticaria in children aged 2 to 11 years (see section "Pharmacological properties").

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies with Rupafin oral solution involving children have not been conducted.

Interaction studies of rupatadine in the 10 mg tablet formulation were performed only in adults and children aged 12 years and older.

Effect of other medicinal products on rupatadine

Concomitant use with strong CYP3A4 inhibitors (such as itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, nefazodone) should be avoided, and caution is advised when using moderate CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem).

Concomitant administration of rupatadine 20 mg with ketoconazole or erythromycin increases systemic exposure to rupatadine by 10-fold and 2–3-fold, respectively. These changes were not associated with effects on the QT interval or an increase in adverse reactions compared to those observed with individual administration of the drugs.

Interaction with grapefruit

Concomitant intake of grapefruit juice increased systemic exposure to rupatadine in the 10 mg tablet formulation by 3.5-fold. This occurs because grapefruit contains one or more compounds that inhibit CYP3A4 and may increase plasma concentrations of drugs metabolized by CYP3A4, such as rupatadine. In addition, grapefruit is thought to affect drug transporters in the gastrointestinal tract, particularly P-glycoprotein. Grapefruit juice should not be taken concurrently with rupatadine.

Effect of rupatadine on other medicinal products

Caution should be exercised when administering rupatadine concomitantly with other drugs having a narrow therapeutic index, as data on the effect of rupatadine on other medicinal products are limited.

Interaction with alcohol

Rupatadine 10 mg administered after alcohol intake had a minor effect on the results of certain psychomotor tests – these were not significantly different from those obtained after alcohol alone. The 20 mg dose enhanced impairments caused by alcohol intake.

Interaction with CNS depressants

As with other antihistamines, interaction with CNS depressants cannot be excluded.

Interaction with statins

In clinical studies of rupatadine, asymptomatic increases in creatine phosphokinase were rarely reported. The risk of interaction with statins, some of which are also metabolized by cytochrome P450 isoenzyme CYP3A4, is unknown. For these reasons, rupatadine should be used with caution when administered concomitantly with statins.

Interaction with midazolam

After administration of 10 mg rupatadine in combination with 7.5 mg midazolam, a slight increase in exposure (Cmax and AUC) of midazolam was observed. Therefore, rupatadine acts as a weak inhibitor of CYP3A4.

Special precautions for use

The safety of Rupafin oral solution in children under 2 years of age has not been established.

Concomitant use of rupatadine with strong CYP3A4 inhibitors should be avoided, and co-administration with moderate CYP3A4 inhibitors should be done with caution (see section "Interaction with other medicinal products and other forms of interactions").

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

It is not recommended to take rupatadine with grapefruit juice (see section "Interaction with other medicinal products and other forms of interactions").

Cardiac safety of rupatadine in the 10 mg tablet formulation was evaluated in a thorough QT/QTc study in adults. Rupatadine at doses 10 times higher than the therapeutic dose did not affect the ECG and therefore does not demonstrate a negative effect on the heart.

However, rupatadine should be used with caution in patients with known QT interval prolongation, in patients with uncorrected hypokalemia, and in patients with current proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia.

Elevations in blood creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase levels, as well as abnormal liver function test results, are rare adverse reactions reported during treatment with the 10 mg tablet formulation of rupatadine in adults.

This medicinal product contains sucrose and therefore may be harmful to teeth. Patients with rare hereditary problems of fructose intolerance, glucose/galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

This medicinal product contains methyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).

This medicinal product contains 200 mg of propylene glycol per 1 ml. It may cause symptoms similar to those produced by alcohol consumption.

Concomitant administration with any substrate for alcohol dehydrogenase, such as ethanol, may cause undesirable effects in children under 5 years of age.

Although propylene glycol has not been shown to cause reproductive toxicity or adverse developmental effects in animals or humans, it may cross the placental barrier and has been detected in breast milk. Therefore, the use of propylene glycol in pregnant women or breastfeeding women should be considered on a case-by-case basis.

Patients with renal or hepatic impairment require medical monitoring, as various adverse events related to propylene glycol have been reported, such as renal dysfunction (acute tubular necrosis), acute renal failure, and hepatic dysfunction.

This medicinal product contains less than 1 mmol of sodium (23 mg) per 1 ml, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of rupatadine in pregnant women are limited. Animal studies do not indicate a direct or indirect harmful effect on the embryo/fetus or peri- and postnatal development (see section "Pharmacological properties"). As a precautionary measure, rupatadine should be avoided during pregnancy.

Breastfeeding

Rupatadine is excreted in animal milk. It is unknown whether rupatadine passes from a breastfeeding woman into human milk. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from rupatadine therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Clinical data on the effect on fertility are lacking. Animal studies indicate a significant reduction in fertility at concentrations higher than the maximum therapeutic concentrations in humans (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery

The effect of rupatadine at a dose of 10 mg on the ability to drive or operate machinery is negligible. However, caution should be exercised when driving or operating machinery until the individual's response to rupatadine is known.

Method of Administration and Dosage

Children aged 2 to 11 years

Dosage for children with body weight ≥25 kg: 5 mL (5 mg of rupatadine) of oral solution once daily, with or without food.

Dosage for children with body weight from 10 kg to 25 kg: 2.5 mL (2.5 mg of rupatadine) of oral solution once daily, with or without food.

Children under 2 years of age

The use of this medicinal product is not recommended in children under 2 years of age due to lack of data on safety and efficacy in this patient population (see section "Special Warnings and Precautions for Use").

Adults and children aged 12 years and older

For adults and children aged 12 years and older, rupatadine tablets 10 mg are more appropriate.

Patients with renal or hepatic impairment

Since there is no clinical experience with rupatadine in patients with renal or hepatic impairment, the use of rupatadine in such patients is currently not recommended.

The duration of treatment should be determined by the physician.

Method of Administration

For oral administration.

Instructions for use:

• To open the bottle, press down on the cap and turn it counterclockwise.
• Take the syringe, insert it into the perforated stopper, and invert the bottle.
• Draw up the prescribed dose into the syringe.
• Administer the medication directly into the oral cavity from the dosing syringe.
• Wash the syringe after use.

Children.

This medicinal product is not recommended for use in children under 2 years of age due to insufficient data on safety and efficacy.

Overdose.

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

Adverse Reactions

In clinical studies of oral rupatadine solution, 626 children aged 2 to 11 years participated. Of these, 147 patients received rupatadine at a dose of 2.5 mg, 159 patients received rupatadine at a dose of 5 mg, 249 patients received placebo, and 71 patients received desloratadine.

The frequency of adverse reactions is categorized as follows:

• Common (from ≥ 1/100 to < 1/10)
• Uncommon (from ≥ 1/1,000 to < 1/100)

Adverse reactions reported in patients who received oral rupatadine solution during clinical studies:

Reporting of suspected adverse reactions

Reporting of adverse reactions after authorization of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 30 months.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

120 ml in a bottle.

One 125 ml bottle with perforated stopper and tamper-evident cap, together with a 5 ml syringe, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Italfarmaco, S.A.

Manufacturer's address and site of operations.

Calle De San Rafael, 3, Alcobendas Industrial Estate, Alcobendas, 28108, Spain.