DESLORATADINE ZENTIVA 0,5 mg/ml S buv Fl/150ml+ser

Desloratadine............................................................................................................................................... 0,5 mg

For 1 mL of oral solution.

Excipient with known effect: this medicine contains 147,15 mg/ml of sorbitol.

DESLORATADINE ZENTIVA is indicated in adults, adolescents and children over 1 year for the symptomatic treatment of:

• allergic rhinitis (see section Pharmacodynamics),

• urticaria (see section Pharmacodynamics).

Dosage

Adults and adolescents (aged 12 years and older)

The recommended dose of DESLORATADINE ZENTIVA is 10 ml (5 mg) of oral solution once a day.

Paediatric population

The prescriber should bear in mind that in children under 2 years of age, the majority of cases of rhinitis are of infectious origin (see section Warnings and precautions) and that there is no data validating the efficacy of DESLORATADINE ZENTIVA in the treatment of infectious rhinitis.

• Children aged 1 to 5 years: 2,5 ml (1,25 mg) of DESLORATADINE ZENTIVA oral solution once a day.

• Children aged 6 to 11 years: 5 ml (2,5 mg) of DESLORATADINE ZENTIVA oral solution once a day.

The safety and efficacy of DESLORATADINE ZENTIVA have not been established in children under the age of one year.

In children aged 1 to 11 years and adolescents aged 12 to 17 years, experience with the use of desloratadine in clinical efficacy studies is limited (see sections Adverse effects and Pharmacodynamics).

Treatment modalities for intermittent allergic rhinitis (presence of symptoms for less than 4 days per week or for a period of less than 4 weeks) should take into account the course of the symptoms, with treatment possibly being discontinued after symptoms disappear and restarted when they recur.

For persistent allergic rhinitis (presence of symptoms for 4 days or more per week and for more than 4 weeks), continuous treatment may be offered to patients during periods of allergen exposure.

Method of administration

Oral use.

Doses may be taken with or between meals.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition or to loratadine.

Desloratadine should be administered with caution to patients with a personal or family history of convulsions, and particularly in young children (see section Adverse effects) who are prone to the onset of first-time convulsive seizures under treatment with desloratadine. Discontinuation of desloratadine administration should be considered in the event of a convulsive seizure during treatment.

Paediatric population

In children under 2 years of age, it is difficult to differentiate allergic rhinitis from other forms of rhinitis. The diagnosis will be supported by the absence of upper respiratory infection or malformation, as well as personal history, clinical examination, and appropriate skin tests or biological examinations.

Approximately 6 % of adults and children aged 2 to 11 years are slow phenotypic metabolisers of desloratadine, which results in increased systemic exposure (see section Pharmacokinetics). The tolerability of desloratadine appears identical in children aged 2 to 11 years who are slow metabolisers and in those with normal metabolism. The effects of desloratadine in slow-metabolising children under 2 years of age have not been studied.

DESLORATADINE ZENTIVA should be used with caution in cases of severe renal impairment (see section Pharmacokinetics).

This medicine contains 147,15 mg/ml of sorbitol. Patients with hereditary fructose intolerance (HFI) must not take/receive this medicine.

In clinical studies carried out with desloratadine tablets in which patients received erythromycin or ketoconazole in combination, no clinically significant interaction was observed (see section Pharmacodynamics).

Paediatric population

Interaction studies were only carried out in adults.

In a clinical pharmacology study, no potentiation of the deleterious effects of alcohol on performance tests was demonstrated when combined with desloratadine tablets (see section Pharmacodynamics). However, cases of alcohol intolerance and intoxication have been reported since marketing. Therefore, caution is recommended in case of concomitant alcohol intake.

Pregnancy

In a large number of pregnancies (more than 1000 pregnancies), no malformative or toxic effect of desloratadine has been demonstrated for the foetus or newborn. Animal studies have not shown any direct or indirect harmful effects on reproduction (see section Preclinical safety). As a precaution, it is preferable to avoid the use of DESLORATADINE ZENTIVA during pregnancy.

Breast-feeding

Desloratadine has been identified in newborns/infants breastfed by a treated woman.

The effect of desloratadine on newborns/infants is unknown. A decision must be made either to discontinue breastfeeding or to discontinue/abstain from treatment with DESLORATADINE ZENTIVA, taking into account the benefit of breastfeeding for the child compared with the benefit of treatment for the woman.

Fertility

No data are available documenting effects on fertility in humans.

Based on the available clinical studies, DESLORATADINE ZENTIVA has negligible or even no effect on the ability to drive vehicles and use machines. Patients should be informed that although most people do not feel drowsy, there is inter-individual variability. Consequently, patients should be advised to test their response to this medicine before any activity requiring alertness, such as driving vehicles or operating machines.

Summary of the safety profile

Adults and adolescents

At the recommended dose, in clinical studies involving adults and adolescents conducted in various indications, such as allergic rhinitis and chronic idiopathic urticaria, adverse reactions with desloratadine were reported in 3 % more patients than those treated with placebo. The adverse reactions most frequently reported with an incidence higher than placebo were: asthenia (1,2 %), dry mouth (0,8 %) and headache (0,6 %).

Tabulated summary of adverse reactions

The frequency of adverse reactions reported in clinical trials with an incidence greater than placebo and other adverse reactions reported since marketing are listed in the following table. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

* Adverse reactions reported since marketing also in paediatric patients.

Paediatric population

Other adverse effects reported since marketing with an unknown frequency in the paediatric population include arrhythmia and bradycardia.

In clinical studies in paediatrics, desloratadine syrup has been administered to a total of 246 children aged 6 months to 11 years. The overall incidence of adverse reactions in children aged 2 years to 11 years was similar in the desloratadine and placebo groups. In infants and young children aged 6 to 23 months, the most frequently reported adverse reactions with an incidence higher than placebo were: diarrhoea (3,7%), fever (2,3%) and insomnia (2,3%). In another study, no adverse reactions were reported in subjects aged between 6 and 11 years after a single dose of 2,5 mg desloratadine oral solution.

In a clinical study conducted in 578 adolescent patients, aged 12 to 17 years, the most frequent adverse reaction was headache. This reaction occurred in 5,9% of patients treated with desloratadine and in 6,9% of patients receiving placebo.

A retrospective observational safety study showed an increased frequency of first-time seizures in patients aged 0 to 19 years treated with desloratadine compared with periods without desloratadine. In children aged 0 to 4 years, the absolute increase was 37,5 per 100 000 patient-years (confidence interval (CI) at 95% 10,5-64,5) for a usual rate of first-time seizures of 80,3 per 100 000 patient-years.

In patients aged 5 to 19 years, the absolute increase was 11,3 per 100 000 patient-years (CI 95% 2,3-20,2) for a usual rate of 36,4 per 100 000 patient-years (See section Warnings and precautions).

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

The adverse event profile observed since marketing during an overdose is similar to that observed at therapeutic doses, however these effects may be more significant.

Treatment

In case of overdose, elimination of the unabsorbed active substance by the usual methods should be considered.

Symptomatic treatment and appropriate therapeutic measures are recommended.

Desloratadine is not removed by haemodialysis; it is not known whether it is removed by peritoneal dialysis.

Symptoms

In a clinical study with repeated doses in adults and adolescents, no clinically significant effect was observed when desloratadine was administered at a dose of up to 45 mg (nine times the therapeutic dose).

Paediatric population

The adverse event profile observed since marketing during an overdose is similar to that observed at therapeutic doses, however these effects may be more significant.

Pharmacotherapeutic class: anti-H1 antihistamines, ATC code: R06A X27.

Mechanism of action

Desloratadine is a non-sedating, long-acting antihistamine exerting a selective antagonist effect on peripheral H1 receptors. After oral administration, desloratadine selectively blocks peripheral H1 histamine receptors because it does not diffuse into the central nervous system.

The antiallergic properties of desloratadine have been demonstrated from studies in vitro. Inhibition of the release of pro-inflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 by human mast cells/basophils was demonstrated, as well as inhibition of the expression of the adhesion molecule P-selectin on endothelial cells. The clinical relevance of these observations remains to be confirmed.

Clinical efficacy and safety data

Paediatric population

The efficacy of DESLORATADINE ZENTIVA 0,5 mg/ml, oral solution has not been evaluated in specific paediatric studies.

However, the safety of desloratadine syrup, which contains the same concentration of desloratadine as DESLORATADINE ZENTIVA 0,5 mg/ml, oral solution, has been demonstrated in three paediatric studies. Children aged 1 - 11 years requiring antihistamine treatment received a daily dose of desloratadine of 1,25 mg (1 to 5 years) or 2,5 mg (6 to 11 years). The treatment was well tolerated as shown by laboratory analyses, assessment of clinical signs and ECG data, including the QT interval. When desloratadine was administered at the recommended doses, plasma concentrations of desloratadine were comparable in children and adults (see section Pharmacokinetics). Thus, as the treatment of allergic rhinitis/chronic idiopathic urticaria and the profile of desloratadine are similar in adults and children, the efficacy data for desloratadine in adults can be extrapolated to the paediatric population.

The efficacy of desloratadine syrup has not been studied in pediatric studies conducted in children under 12 years of age.

Adults and adolescents

In a clinical study with repeated doses in adults and adolescents, in which up to 20 mg per day of desloratadine were administered for 14 days, no statistically or clinically significant cardiovascular effect was observed. In a clinical pharmacology study in adults and adolescents, in which desloratadine was administered to adults at a dose of 45 mg per day (9 times the therapeutic dose) for ten days, no prolongation of the QT interval was observed.

Desloratadine does not readily penetrate the central nervous system. In controlled clinical studies, at the recommended adult and adolescent dose of 5 mg per day, there was no increase in the incidence of somnolence compared with placebo. Desloratadine tablets administered once daily at a single dose of 7,5 mg in adults and adolescents did not impair psychomotor performance during clinical studies. In a single-dose study conducted in adults, desloratadine 5 mg did not alter standard measures of performance during flight, including exacerbation of subjective sleepiness or aircraft piloting activities.

During clinical pharmacology trials in adults, concomitant administration with alcohol did not increase the somnolence or the performance impairment induced by alcohol. No significant difference was demonstrated between the groups of subjects treated with desloratadine and those receiving placebo during psychomotor tests, whether the product was administered alone or in combination with alcohol.

Repeated-dose interaction studies with ketoconazole and erythromycin did not show any clinically significant changes in plasma concentrations of desloratadine.

In adults and adolescents with allergic rhinitis, desloratadine tablets relieved symptoms such as sneezing, nasal discharge and pruritus, but also ocular pruritus, lacrimation and redness, and palatal pruritus. Desloratadine properly controlled the symptoms throughout the entire nycthemeron.

The efficacy of desloratadine tablets has not been clearly demonstrated in studies conducted in adolescent patients aged 12 to 17 years.

In addition to the established classifications of seasonal and perennial allergic rhinitis, allergic rhinitis may also be classified as intermittent allergic rhinitis and persistent allergic rhinitis according to the duration of symptoms. Intermittent allergic rhinitis is defined by the presence of symptoms for less than 4 days per week or for less than 4 weeks. Persistent allergic rhinitis is defined by the presence of symptoms for 4 days or more per week and for more than 4 weeks.

Desloratadine tablets reduced the disabling nature of seasonal allergic rhinitis, as shown by the total score of the quality-of-life questionnaire in rhinoconjunctivitis. The greatest improvement was observed in the domain of practical problems and daily activities limited by symptoms.

Chronic idiopathic urticaria has been studied as a clinical model of urticarial manifestations, since the underlying pathophysiology is similar regardless of aetiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a factor responsible for all urticarial conditions, desloratadine is expected to be effective in relieving symptoms of other urticarial manifestations, in addition to chronic idiopathic urticaria, as recommended in clinical guidelines.

In two six-week controlled trials versus placebo in patients with chronic idiopathic urticaria, desloratadine was shown to be effective in relieving pruritus and in reducing the number and size of urticarial lesions as early as the end of the first dose. In each study, the effects were maintained throughout the entire nycthemeron. As in other studies of antihistamines in chronic idiopathic urticaria, the few patients identified as non-responders to antihistamines were excluded. A reduction in pruritus of more than 50% was observed in 55% of patients treated with desloratadine versus 19% of patients treated with placebo. Treatment with desloratadine also significantly reduced interference with sleep and daily activity, parameters assessed on a four-point scale.

Absorption

In adults and adolescents, plasma desloratadine levels can be detected within 30 minutes after administration. Desloratadine is well absorbed, with a maximum concentration reached after approximately 3 hours; the terminal-phase half-life is approximately 27 hours. The accumulation factor of desloratadine corresponds to its half-life (approximately 27 hours) and its once-daily dosing schedule. The bioavailability of desloratadine is dose-dependent over a range of 5 mg to 20 mg.

In a series of pharmacokinetic and clinical trials, 6% of subjects presented higher desloratadine concentrations. The frequency of this slow-metabolizer phenotype was of the same order in adults (6%) and in children aged 2 to 11 years (6%), and it was higher in Black subjects (18% in adults, 16% in children) than in Caucasian subjects (2% in adults, 3% in children) in both populations.

In a multiple-dose pharmacokinetic study conducted with the tablet formulation in healthy adult volunteers, four subjects were identified as slow metabolizers of desloratadine. In these subjects, the maximum plasma concentration (Cmax) was approximately 3 times higher at around the 7th hour, with a terminal half-life of approximately 89 hours.

The observed pharmacokinetic parameters were similar in a repeated-dose pharmacokinetic study conducted with the syrup formulation in slow-metabolizer children aged 2 to 11 years with a diagnosis of allergic rhinitis. The area under the desloratadine concentration curve (AUC) was approximately 6 times higher and the Cmax approximately 3 to 4 times higher at the 3-6th hour, with a terminal half-life of approximately 120 hours. Exposure was identical in adult and child slow metabolizers when treated at doses appropriate for their age. The safety profile in these subjects did not differ from that of the general population. The effects of desloratadine in slow metabolizers younger than 2 years have not been studied.

In other single-dose clinical studies, at the recommended doses, children had AUC and Cmax values for desloratadine comparable to those of adults who received a dose of 5 mg of desloratadine syrup.

Distribution

Desloratadine binds moderately (83 % - 87 %) to plasma proteins. After daily administration of desloratadine as a once-daily dose (5 mg to 20 mg) for 14 days to adults and adolescents, no clinical evidence suggested accumulation of the product.

In a crossover clinical study conducted with a single dose of desloratadine, bioequivalence of the tablet and syrup formulations was demonstrated. Since the desloratadine oral solution contains the same concentration of desloratadine, no bioequivalence study is required, and the desloratadine oral solution is expected to be bioequivalent to the syrup and the tablet.

Biotransformation

The enzyme involved in the metabolism of desloratadine has not yet been identified, and therefore the risk of interactions with other medicinal products cannot be completely excluded. In vivo, desloratadine does not inhibit cytochrome P3A4. In vitro studies have shown that the active substance does not inhibit cytochrome P2D6 and that it is neither a substrate nor an inhibitor of P-glycoprotein.

Elimination

In a clinical study conducted with a single dose of 7,5 mg of desloratadine, the fate of desloratadine was not altered by food (high-calorie, high-fat breakfast).

In another study, grapefruit juice did not alter the fate of desloratadine.

Renal impairment

The pharmacokinetic parameters of desloratadine in patients with chronic renal failure (CRF) and in healthy subjects were compared in a single-dose study and in a repeated-dose study. In the single-dose study, systemic exposure to desloratadine was approximately 2 and 2,5 times higher in subjects with mild to moderate CRF and severe CRF, respectively, than in healthy subjects. In the repeated-dose study, steady state was reached after the 11th day, and exposure to desloratadine was approximately 1,5 times higher in subjects with mild to moderate CRF and approximately 2,5 times higher in subjects with severe CRF than in healthy subjects. In both studies, variations in systemic exposure (AUC and Cmax) to desloratadine and to 3-hydroxydesloratadine were not clinically significant.

Desloratadine is the main active metabolite of loratadine. Non-clinical studies conducted with desloratadine and loratadine demonstrated that there was no qualitative or quantitative difference in the toxicity profile of desloratadine and loratadine at comparable levels of desloratadine exposure.

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenesis, and reproductive and developmental function studies did not reveal any particular risk for humans. The absence of carcinogenic potential was demonstrated in studies conducted with desloratadine and loratadine.

3 years.

No special precautions for storage.

No special requirements.