Rupafin

Tablet: Each tablet contains rupatadine (as fumarate) 10 mg.
Oral solution: Each ml of oral solution contains: 1 mg of rupatadine (as fumarate).
Excipients/Inactive Ingredients: Tablet: Lactose monohydrate 57.57 mg, pregelatinised maize starch, microcrystalline cellulose, red iron oxide (E-172), yellow iron oxide (E-172), magnesium stearate.
Oral solution: Sucrose 300 mg/ml; Methyl Parahydroxybenzoate (E218) 1.00 mg/ml.
Propylene glycol Citric acid anhydrous; Disodium phosphate anhydrous Saccharin sodium; Sucrose; Methyl parahydroxybenzoate (E218) Quinoline yellow (E104); Banana flavour (Blend of flavouring substances, flavouring preparations and natural flavouring substances, and propilenglicol); Purified water.

Pharmacotherapeutic group: Other antihistamines for systemic use. ATC code: R06A X28.
Pharmacology: Pharmacodynamics: Rupatadine is a second generation antihistamine, long-acting histamine antagonist, with selective peripheral H₁-receptor antagonist activity. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain an antihistaminic activity and may partially contribute to the overall efficacy of the drug.
In vitro studies with rupatadine at high concentration have shown an inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli as well as the release of cytokines, particularly of the TNF_α in human mast cells and monocytes. The clinical relevance of the observed experimental data remains to be confirmed.
Tablet: Clinical trials in volunteers (n=375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria did not show significant effect on the electrocardiogram when rupatadine was administered at doses ranging from 2 mg to 100 mg.
Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a causal factor in all urticarial diseases, rupatadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines.
In a placebo-controlled trials in patients with Chronic Idiopathic Urticaria, rupatadine was effective reducing the mean pruritus score from baseline over the 4 week treatment period (change vs baseline: rupatadine 57.5%, placebo 44.9%) and decreasing the mean number of wheals (54.3% vs 39.7%).
Oral solution: Rupatadine oral solution had a similar pharmacokinetic profile in children between 6-11 years to that in adults (> 12 year): a pharmacodynamic effect was also observed (suppression of the wheal area, antihistamine effect) after 4 weeks of treatment. A randomised, double blind and placebo controlled confirmatory study in children with persistent allergic rhinitis aged 6 to 11 years, showed that rupatadine oral solution had a better profile in the reduction of nasal symptoms (rhinorrea and itchy nose mouth throat and/or ears) than placebo in children with persistent allergic rhinitis after 4 and 6 weeks of treatment. Furthermore, a significant improvement in quality of life was also observed throughout the study in comparison with placebo.
Chronic spontaneous urticaria was studied as a clinical model to assess the efficacy of antiH₁ compounds for all urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and basically these chronic patients can be more easily recruited into a clinical study. Urticaria is a mast cell-driven disease and histamine and other mediators (PAF and cytokines) are the principal mediators to develop all urticarial lesions. Since rupatadine has capacity to block the release of histamine and other inflammatory mediators, it is expected to be effective treatment in providing symptomatic relief for other urticarial conditions, in addition to chronic spontaneous urticaria, as recommended in clinical guidelines.
The efficacy of rupatadine oral solution in chronic spontaneous urticaria in children aged 2-11 years has been demonstrated in a multicentre, randomized, active- and placebo-controlled study. Overall, 206 children were included. Of them, 113 were between 2-5 years and 93 of them were between 6-11 years. Children were treated with rupatadine (n=66), placebo (n=69) or desloratadine (n=71). Rupatadine dose administered was 2.5 mg in children weighting up to 25 kg and 5 mg in children weighting over 25 kg. Desloratadine dose administered was 1.25 mg in children weighting up to 25 kg and 2.5 mg in children weighting over 25 kg. A statistically significant improvement versus placebo was demonstrated in the mean change in weekly urticaria activity score (UAS7; comprising hives and pruritus), the main endpoint, evaluated after 6 weeks of treatment (rupatadine -11.77 vs. placebo -5.55; p <0.001).
The mean percent reduction in the weekly number of hives at study endpoint versus baseline was 56.7% with rupatadine, 49.4% with desloratadine and 22.7% with placebo. The mean percent reduction in pruritus at study endpoint versus 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 the reduction in hives and pruritus, while there were not statistically significant differences between the active treatments regarding these outcomes. The percentage of patient responders of more than 50% in weekly urticaria activity score (UAS7 scale; urticaria and pruritus) was observed in 61% of children treated with rupatadine compared with 36% of children treated with placebo and 54% of children treated with desloratadine.
Clinical trials in volunteers (n= 375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria did not show significant effect on the electrocardiogram when rupatadine tablets was administered at doses ranging from 2 mg to 100 mg.
The European Medicines Agency has waived the obligation to submit the results of studies with Rupafin oral solution in all subsets of the paediatric population in allergic rhinitis and chronic urticaria (see Dosage & Administration).
Pharmacokinetics: Absorption and bioavailability: Tablet: Rupatadine is rapidly absorbed after oral administration, with a t_max of approximately 0.75 hours after intake. The mean C_max was 2.6 ng/ml after a single oral dose of 10 mg and 4.6 ng/ml after a single oral dose of 20 mg. Pharmacokinetics of rupatadine was linear for a dose between 10 and 40 mg. After a dose of 10 mg once a day for 7 days, the mean C_max was 3.8 ng/ml. The plasma concentration followed a bi-exponential dropoff with a mean elimination half-life of 5.9 hours. The binding-rate of rupatadine to plasma proteins was 98.5-99%.
As rupatadine has never been administered to humans by intravenous route, no data is available on its absolute bioavailability.
Effect of the intake of food: Tablet: Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The exposure to one of its active metabolites and to the main inactive metabolite was practically the same (reduction of about 5% and 3% respectively). The time taken to reach the maximum plasma concentration (t_max) of rupatadine was delayed by 1 hour. The maximum plasma concentration (C_max) was not affected by food intake. These differences had no clinical significance.
Oral solution: No interaction food study has been performed with rupatadine oral solution. The influence of food was performed in adults and adolescents with rupatadine 10 mg tablets. Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The maximum plasma concentration (C_max) was not affected by food intake. These differences had no clinical significance.
Metabolism and elimination: Tablet: In a study of excretion in humans (40 mg of ¹⁴C-rupatadine), 34.6% of the radioactivity administered was recovered in urine and 60.9% in faeces collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by oral route. The amounts of unaltered active substance found in urine and faeces were insignificant. This means that rupatadine is almost completely metabolised. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly metabolised by the cytochrome P450 (CYP3A4).
Oral solution: In a study of excretion in adults, 34.6% of rupatadine administered was recovered in urine and 60.9% in faeces collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by oral route. The amounts of unaltered active substance found in urine and faeces were insignificant. This means that rupatadine is almost completely metabolised. Roughly, the active metabolites desloratadine and other hydroxylated derivatives accounted for 27% and 48%, respectively, of the total systemic exposure of the active substances. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly metabolised by the cytochrome P450 (CYP 3A4).
Specific patient groups: Tablet: In a study on healthy volunteers to compare the results in young adults and elderly patients, the values for AUC and C_max for rupatadine were higher in the elderly than in young adults. This is probably due to a decrease of the first-pass hepatic metabolism in the elderly. These differences were not observed in the metabolites analysed. The mean elimination half-life of rupatadine in elderly and young volunteers was 8.7 hours and 5.9 hours respectively. As these results for rupatadine and for its metabolites were not clinically significant, it was concluded that it is not necessary to make any adjustment when using a dose of 10 mg in the elderly.
Oral solution: Paediatric population: In the subgroup of children 2-5 and 6-11 years old, rupatadine was rapidly absorbedand the mean Cmax was of 1.9 and 2.5 ng/ml after repeated oral dose, respectively. In term of exposition, the mean total area under the curve (AUC) value was 10.4 ng.h/ml in children 2-5 years and 10.7 ng·h/ml in children 6-11 years. All these values are similar to those obtained in adults and adolescents.
The mean elimination half-life of rupatadine in childen 2-5 years was 15.9 h and in children 6-11 years was 12.3 h, which are longer than that reported with tablets in adults and adolescents.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
More than 100 times the clinically recommended dose (10 mg) of rupatadine did neither extend the QTc or QRS interval nor produce arrhythmia in various species of animals such as rats, guinea pigs and dogs. Rupatadine and one of its main active metabolites in humans, 3-hydroxydesloratadine, did not affect the cardiac action potential in isolated dog Purkinje fibres at concentrations at least 2000 times greater than the C_max reached after the administration of a dose of 10 mg in humans. In a study that evaluated the effect on cloned human HERG channel, rupatadine inhibited that channel at a concentration 1685 times greater than the C_max obtained after the administration of 10 mg of rupatadine. Desloratadine, the metabolite with the greatest activity, had no effect at a 10 micromolar concentration. Studies of tissue distribution in rats with radiolabelled rupatadine showed that rupatadine does not accumulate in heart tissue.
In the rat, a significant reduction of male and female fertility occurred at the high dose of 120 mg/kg/day, providing C_max 268 times those measured in humans at the therapeutic dose (10 mg/day). Foetal toxicity (growth delay, incomplete ossification, minor skeletal findings) was reported in rats at maternotoxic dose-levels only (25 and 120 mg/kg/day). In rabbits, no evidence of developmental toxicity was noted at doses up to 100 mg/kg. The developmental No Adverse Effect Levels were determined at 5 mg/kg/day in rats and 100 mg/kg/day in rabbits, yielding C_max 45 and 116 times higher, respectively, than those measured in humans at the therapeutic dose (10 mg/day).

Tablet: Symptomatic treatment of allergic rhinitis and urticaria in adults and adolescents (12 year and above).
Oral solution: Rupafin 1 mg/ml oral solution is indicated for the symptomatic treatment of: Allergic rhinitis (including persistent allergic rhinitis) in children aged 2 to 11 years (see Pharmacology: Pharmacodynamics under Actions); Urticaria in children aged 2 to 11 years (see Pharmacology: Pharmacodynamics under Actions).

Tablet: Adults and adolescents (12 year and above): The recommended dose is 10 mg (one tablet) once a day, with or without food.
Elderly: Rupatadine should be used with caution in elderly people (see Precautions).
Paediatric patients: Rupatadine 10 mg Tablets is not recommended for use in children below age 12 due to a lack of data on safety and efficacy.
Patients with renal or hepatic insufficiency: As there is no clinical experience in patients with impaired kidney or liver functions, the use of Rupatadine 10 mg Tablets is at present not recommended in these patients.
Oral solution: Children aged 2 to 11 years: Dosage in children weighing equal or more than 25 kg: 5 ml (5 mg of rupatadine) of oral solution once a day, with or without food.
Dosage in children weighing equal or more than 10kg up to less than 25kg: 2.5ml (2.5mg of rupatadine) of oral solution once a day, with or without food.
The administration of the product to children aged under 2 years is not recommended due to the lack of data in this population (see Precautions).
In adults and adolescents (over 12 years of age), the administration of rupatadine 10 mg tablets is more appropriate.
Patients with renal or hepatic insufficiency: As there is no clinical experience in patients with impaired kidney or liver functions, the use of rupatadine is at present not recommended in these patients.
Instructions of use: To open the bottle press the cap and turn it anticlockwise.
Take the syringe and put it in the perforated stopper and turn the bottle upside down.
Fill the syringe with the prescribed dose.
Administer directly from the dosing syringe.
Wash the syringe after use.

No case of overdose has been reported in adults and children. In a clinical safety study in adults rupatadine at daily dose of 100 mg during 6 days was well tolerated. The most common adverse reaction was somnolence. If accidental ingestion of very high doses occurs symptomatic treatment together with the required supportive measures should be given.

Hypersensitivity to rupatadine or to any of the excipients.

Tablet: The administration of rupatadine with grapefruit juice is not recommended (see Interactions). Cardiac safety of rupatadine was assessed in a Thorough QT/QTc study. Rupatadine up to 10 times therapeutic dose did not produce any effect on the ECG and hence raises no cardiac safety concerns. However rupatadine should be used with caution in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia, acute myocardial ischemia.
Rupatadine 10 mg Tablets should be used with caution in elderly patients (65 years and older). Although no overall differences in effectiveness or safety were observed in clinical trials, higher sensitivity of some older individuals cannot be excluded due to the low number of elderly patients enrolled (see Pharmacology: Pharmacodynamics under Actions).
Regarding use in children less than 12 years old and in patients with renal or hepatic impairment, see Dosage & Administration.
Due to the presence of lactose monohydrate in rupatadine 10 mg tablets, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Oral solution: Safety of rupatadine oral solution in children aged less than 2 years have not been established.
The combination of rupatadine with potent CYP3A4 inhibitors should be avoided and with moderate CYP3A4 inhibitors should beadministered with caution (see Interactions).
Dose adjustment of sensitive CYP3A4 substrates (e.g. simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic index (e.g. cyclosporine, tacrolimus, sirolimus, everolimus, cisapride) could be required as rupatadine may increase plasma concentrations of these drugs (see Interactions).
The administration of rupatadine with grapefruit juice is not recommended (see Interactions).
Cardiac safety of rupatadine 10 mg tablets was assessed in a Thorough QT/QTc study in adults. Rupatadine up to 10 times therapeutic dose did not produce any effect on the ECG and hence raises no cardiac safety concerns. However rupatadine should be used with caution in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia, acute myocardial ischemia.
Increases of blood creatine phosphokinase, alanine aminotransferase and aspartate aminotransferase, as well as abnormalities of liver function tests are uncommon adverse reaction reported with rupatadine 10 mg tablets in adults.
This medicinal product contains sucrose, so it may be harmful to the teeth. Patients with rare hereditary problems of fructose intolerance, glucose/galactose malabsorption or sucraseisomaltase insufficiency should not take this medicine.
This medicinal product contains methyl parahydroxybenzoate, may cause allergic reactions (possibly delayed).
Effects on the ability to drive and use machines: Rupatadine 10 mg had no influence on the ability to drive and use machines in a performed clinical trial. Nevertheless, care should be taken before driving or using machinery until the patient's individual reaction on rupatadine has been established.

Pregnancy: Data on a limited number (2) of exposed pregnancies indicate no adverse effects of rupatadine on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of rupatadine during pregnancy.
Breastfeeding: Tablet: Rupatadine is excreted in animal milk. It is unknown whether rupatadine is excreted into breastmilk. Due to the lack of human data, caution should be exercised when prescribing rupatadine to lactating women.
Oral solution: Rupatadine is excreted in animal milk. It is unknown whether rupatadine is excreted into breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from rupatadine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: There are no clinical data on fertility. Studies in animals have shown a significant reduction of fertility at exposure levels higher than those observed in humans at the maximum therapeutic dose (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Tablet: Rupatadine 10 mg has been administered to over 2025 patients in clinical studies, 120 of whom received rupatadine for at least 1 year.
The most common adverse reactions in controlled clinical studies were somnolence (9.5%), headache (6.9%) and fatigue (3.2%).
The majority of adverse reactions observed in clinical trials were mild to moderate in severity and usually did not require cessation of therapy. The frequencies are summarised according to the following scheme: (See Table 1.)

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Oral solution: Clinical trials with rupatadine oral solution in children aged 2-11 years included 626 patients. From these, 147 patients were treated with rupatadine 2.5 mg, 159 patients were treated with rupatadine 5 mg, 249 received placebo and 71 received desloratadine.
The frequencies of adverse reactions are assigned as follows: Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1000 to < 1/100).
The frequencies of adverse reactions reported in patients treated with rupatadine oral solution during clinical trials were as follows: (See Table 2.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Interaction with alcohol: After administration of alcohol, a dose of 10 mg of rupatadine produced marginal effects in some psychomotor performance tests although they were not significantly different from those induced by intake of alcohol only. A dose of 20 mg increased the impairment caused by the intake of alcohol.
Interaction with CNS depressants: As with other antihistamines, interactions with CNS depressants cannot be excluded.
Interaction with statins: Asymptomatic CPK increases have been uncommonly reported in rupatadine clinical trials. The risk of interactions with statins, some of which are also metabolised by the cytochrome P450 CYP3A4 isoenzyme, is unknown. For these reasons, rupatadine should be used with caution when it is coadministered with statins.
Tablet: Interaction with ketoconazole or erythromycin: The concomitant administration of rupatadine 20 mg and ketoconazole or erythromycin increases the systemic exposure to rupatadine 10 times and 2-3 times respectively. These modifications were not associated with an effect on the QT interval or with an increase of the adverse reactions in comparison with the drugs when administered separately. However, rupatadine should be used with caution when it is administered concomitanly with these drug substances and other inhibitors of the isozyme CYP3A4.
Interaction with grapefruit: The concomitant administration of grapefruit juice increased 3.5 times the systemic exposure of rupatadine. Grapefruit juice should not be taken simultaneously.
Oral solution: No interaction studies have been performed in children with rupatadine oral solution.
Interaction studies have only been performed in adults and adolescents (over 12 years of age) with rupatadine 10 mg tablets.
Effects of other drugs on rupatadine: Co-administration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, nefazodone) should be avoided and co-medication with moderate CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem) should be used with caution.
The concomitant administration of rupatadine 20 mg and ketoconazole or erythromycin increases the systemic exposure to rupatadine 10 times and 2-3 times respectively. These modifications were not associated with an effect on the QT interval or with an increase of the adverse reactions in comparison with the drugs when administered separately.
Interaction with grapefruit: The concomitant administration of grapefruit juice increased 3.5 times the systemic exposure of rupatadine 10 mg tablet. This occurs because grapefruit has one or more compounds that inhibit the CYP3A4 and can increase the plasmatic concentrations of drugs metabolised through this CYP3A4, like rupatadine. In addition, it has been suggested that the grapefruit can affect intestinal drug transport systems as the glicoprotein-P. Grapefruit juice should not be taken simultaneously.
Effects of rupatadine on other drugs: Caution should be taken when rupatadine is co-administered with other metabolised drugs with narrow therapeutic windows since knowledge of the effect of rupatadine on other drugs is limited.

Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product: No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Store below 30°C.
Tablet: Keep the blister in the outer carton in order to protect from light.
Shelf-Life: Tablet: 2 years.
Oral solution: 30 months.

Antihistamines & Antiallergics

R06AX28 - rupatadine ; Belongs to the class of other antihistamines for systemic use.

POM