Denovals

Denovals is indicated in adults and adolescents aged 12 years and older for the relief of symptoms associated with:

- allergic rhinitis

- urticaria

Denovals is indicated in adults, adolescents and children over the age of 1 year for the relief of symptoms associated with:

- allergic rhinitis

- urticaria.

Posology

Adults and adolescents (12 years of age and over)

The recommended dose of Denovals is one tablet once a day.

Intermittent allergic rhinitis (presence of symptoms for less than 4 days per week or for less than 4 weeks) should be managed in accordance with the evaluation of patient's disease history and the treatment could be discontinued after symptoms are resolved and reinitiated upon their reappearance.

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

Paediatric population

There is limited clinical trial efficacy experience with the use of desloratadine in adolescents 12 through 17 years of age.

The safety and efficacy of Denovals 5 mg film-coated tablets in children below the age of 12 years have not been established. No data are available.

Method of administration

Oral use.

The dose can be taken with or without food.

Posology

Adults and adolescents 12 years of age and over.

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

Paediatric Population

The prescriber should be aware that most cases of rhinitis below 2 years of age are of infectious origin and there are no data supporting the treatment of infectious rhinitis with Denovals oral solution.

Children 1 through 5 years of age: 2.5 ml (1.25 mg) Denovals oral solution once a day.

Children 6 through 11 years of age: 5 ml (2.5 mg) Denovals oral solution once a day.

The safety and efficacy of Denovals 0.5mg/ml oral solution in children below the age of 1 year have not been established. No data are available.

There is limited clinical trial efficacy experience with the use of Denovals in children 1 through 11 years of age and adolescents 12 through 17 years of age.

Intermittent allergic rhinitis (presence of symptoms for less than 4 days per week or for less than 4 weeks) should be managed in accordance with the evaluation of patient's disease history and the treatment could be discontinued after symptoms are resolved and reinitiated upon their reappearance.

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

Method of Administration

Oral use.

The dose can be taken with or without food.

In the case of severe renal insufficiency, Denovals should be used with caution.

Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children, being more susceptible to develop new seizures under desloratadine treatment. Healthcare providers may consider discontinuing desloratadine in patients who experience a seizure while on treatment.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Paediatric population

In children below 2 years of age, the diagnosis of allergic rhinitis is particularly difficult to distinguish from other forms of rhinitis. The absence of upper respiratory tract infection or structural abnormalities, as well as patient history, physical examinations, and appropriate laboratory and skin tests should be considered.

Approximately 6 % of adults and children 2- to 11-year old are phenotypic poor metabolisers of Denovals and exhibit a higher exposure. The safety of Denovals in children 2- to 11-years of age who are poor metabolisers is the same as in children who are normal metabolisers. The effects of Denovals in poor metabolisers < 2 years of age have not been studied.

In the case of severe renal insufficiency, Denovals oral solution should be used with caution.

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Denovals has no or negligible influence on the ability to drive and use machines based on clinical trials. Patients should be informed that most people do not experience drowsiness. Nevertheless, as there is individual variation in response to all medicinal products, it is recommended that patients are advised not to engage in activities requiring mental alertness, such as driving a car or using machines, until they have established their own response to the medicinal product.

Denovals oral solution has no or negligible influence on the ability to drive and use machines based on clinical trials. Patients should be informed that most people do not experience drowsiness. Nevertheless, as there is individual variation in response to all medicinal products, it is recommended that patients are advised not to engage in activities requiring mental alertness, such as driving a car or using machines, until they have established their own response to the medicinal product.

Summary of the safety profile

In clinical trials in a range of indications including allergic rhinitis and chronic idiopathic urticaria, at the recommended dose of 5 mg daily, undesirable effects with Denovals were reported in 3 % of patients in excess of those treated with placebo. The most frequent of adverse reactions reported in excess of placebo were fatigue (1.2 %), dry mouth (0.8 %) and headache (0.6 %).

Paediatric population

In a clinical trial with 578 adolescent patients, 12 through 17 years of age, the most common adverse event was headache; this occurred in 5.9 % of patients treated with desloratadine and 6.9 % of patients receiving placebo.

Tabulated list of adverse reactions

The frequency of the clinical trial adverse reactions reported in excess of placebo and other undesirable effects reported during the post-marketing period 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).

Paediatric population

Other undesirable effects reported during the post-marketing period in paediatric patients with an unknown frequency included QT prolongation, arrhythmia, bradycardia, abnormal behaviour, and aggression.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Summary of the safety profile

Paediatric population

In clinical trials in a paediatric population, the Denovals syrup formulation was administered to a total of 246 children aged 6 months through 11 years. The overall incidence of adverse events in children 2 through 11 years of age was similar for the Denovals and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse events reported in excess of placebo were diarrhoea (3.7 %), fever (2.3 %) and insomnia (2.3 %). In an additional study, no adverse events were seen in subjects between 6 and 11 years of age following a single 2.5 mg dose of Denovals oral solution.

In a clinical trial with 578 adolescent patients, 12 through 17 years of age, the most common adverse event was headache, this occurred in 5.9% of patients treated with Denovals and 6.9% of patients receiving placebo.

Adults and adolescents

At the recommended dose, in clinical trials involving adults and adolescents in a range of indications including allergic rhinitis and chronic idiopathic urticaria, undesirable effects with Denovals were reported in 3 % of patients in excess of those treated with placebo. The most frequent of adverse events reported in excess of placebo were fatigue (1.2 %), dry mouth (0.8 %) and headache (0.6 %).

Tabulated list of adverse reactions

The frequency of the clinical trial adverse reactions reported in excess of placebo and other undesirable effects reported during the post-marketing period 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).

Paediatric population

Other undesirable effects reported during the post-marketing period in paediatric patients with an unknown frequency included QT prolongation, arrhythmia and bradycardia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard

The adverse event profile associated with overdosage, as seen during post-marketing use, is similar to that seen with therapeutic doses, but the magnitude of the effects can be higher.

Treatment

In the event of overdose, consider standard measures to remove unabsorbed active substance. Symptomatic and supportive treatment is recommended.

Desloratadine is not eliminated by haemodialysis; it is not known if it is eliminated by peritoneal dialysis.

Symptoms

Based on a multiple dose clinical trial, in which up to 45 mg of desloratadine was administered (nine times the clinical dose), no clinically relevant effects were observed.

Paediatric population

The adverse event profile associated with overdosage, as seen during post-marketing use, is similar to that seen with therapeutic doses, but the magnitude of the effects can be higher.

The adverse event profile associated with overdosage, as seen during post-marketing use, is similar to that seen with therapeutic doses, but the magnitude of the effects can be higher.

Treatment

In the event of overdose, consider standard measures to remove unabsorbed active substance. Symptomatic and supportive treatment is recommended.

Denovals is not eliminated by haemodialysis; it is not known if it is eliminated by peritoneal dialysis.

Symptoms

Based on a multiple dose clinical trial in adults and adolescents, in which up to 45 mg of Denovals was administered (nine times the clinical dose), no clinically relevant effects were observed.

Paediatric population

The adverse event profile associated with overdosage, as seen during post-marketing use, is similar to that seen with therapeutic doses, but the magnitude of the effects can be higher.

Pharmacotherapeutic group: antihistamines - H₁ antagonist, ATC code: R06A X27

Mechanism of action

Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H₁-receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H₁-receptors because the substance is excluded from entry to the central nervous system.

Desloratadine has demonstrated antiallergic properties from in vitro studies. These include inhibiting the release of proinflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mast cells/basophils, 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

In a multiple dose clinical trial, in which up to 20 mg of desloratadine was administered daily for 14 days, no statistically or clinically relevant cardiovascular effect was observed. In a clinical pharmacology trial, in which desloratadine was administered at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of QTc interval was seen.

No clinically relevant changes in desloratadine plasma concentrations were observed in multiple-dose ketoconazole and erythromycin interaction trials.

Desloratadine does not readily penetrate the central nervous system. In controlled clinical trials, at the recommended dose of 5 mg daily, there was no excess incidence of somnolence as compared to placebo. Denovals given at a single daily dose of 7.5 mg did not affect psychomotor performance in clinical trials. In a single dose study performed in adults, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

In clinical pharmacology trials, co-administration with alcohol did not increase the alcohol-induced impairment in performance or increase in sleepiness. No significant differences were found in the psychomotor test results between desloratadine and placebo groups, whether administered alone or with alcohol.

In patients with allergic rhinitis, Denovals was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Denovals effectively controlled symptoms for 24 hours.

Paediatric population

The efficacy of Denovals tablets has not been clearly demonstrated in trials with adolescent patients 12 through 17 years of age.

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

Denovals was effective in alleviating the burden of seasonal allergic rhinitis as shown by the total score of the rhino-conjunctivitis quality of life questionnaire. The greatest amelioration was seen in the domains of practical problems and daily activities limited by symptoms.

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, desloratadine 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 two placebo-controlled six week trials in patients with chronic idiopathic urticaria, Denovals was effective in relieving pruritus and decreasing the size and number of hives by the end of the first dosing interval. In each trial, the effects were sustained over the 24 hour dosing interval. As with other antihistamine trials in chronic idiopathic urticaria, the minority of patients who were identified as non-responsive to antihistamines was excluded. An improvement in pruritus of more than 50 % was observed in 55 % of patients treated with desloratadine compared with 19 % of patients treated with placebo. Treatment with Denovals also significantly reduced interference with sleep and daytime function, as measured by a four-point scale used to assess these variables.

Pharmacotherapeutic group: antihistamines - H₁ antagonist

ATC code: R06A X27

Mechanism of action

Denovals is a non-sedating, long-acting histamine antagonist with selective peripheral H₁-receptor antagonist activity. After oral administration, Denovals selectively blocks peripheral histamine H₁-receptors because the substance is excluded from entry to the central nervous system.

Denovals has demonstrated antiallergic properties from in vitro studies. These include inhibiting the release of proinflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mast cells/basophils, 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

Paediatric population

Efficacy of Denovals oral solution has not been investigated in separate paediatric trials. However, the safety of Denovals syrup, which contains the same concentration of Denovals as Denovals oral solution, was demonstrated in three paediatric trials. Children, 1-11 years of age, who were candidates for antihistamine therapy received a daily Denovals dose of 1.25 mg (1 through 5 years of age) or 2.5 mg (6 through 11 years of age). Treatment was well tolerated as documented by clinical laboratory tests, vital signs, and ECG interval data, including QTc. When given at the recommended doses, the plasma concentrations of Denovals were comparable in the paediatric and adult populations. Thus, since the course of allergic rhinitis/chronic idiopathic urticaria and the profile of Denovals are similar in adults and paediatric patients, Denovals efficacy data in adults can be extrapolated to the paediatric population. Efficacy of Denovals syrup has not been investigated in paediatric trials in children less than 12 years of age.

Adults and adolescents

In a multiple dose clinical trial, in adults and adolescents, in which up to 20 mg of Denovals was administered daily for 14 days, no statistically or clinically relevant cardiovascular effect was observed. In a clinical pharmacology trial, in adults and adolescents, in which Denovals was administered to adults at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of QTc interval was seen.

Denovals does not readily penetrate the central nervous system. In controlled clinical trials, at the recommended dose of 5 mg daily for adults and adolescents, there was no excess incidence of somnolence as compared to placebo. Denovals tablets given at a single daily dose of 7.5 mg to adults and adolescents did not affect psychomotor performance in clinical trials. In a single dose study performed in adults, Denovals 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

In clinical pharmacology trials in adults, co-administration with alcohol did not increase the alcohol-induced impairment in performance or increase in sleepiness. No significant differences were found in the psychomotor test results between Denovals and placebo groups, whether administered alone or with alcohol.

No clinically relevant changes in Denovals plasma concentrations were observed in multiple-dose ketoconazole and erythromycin interaction trials.

In adult and adolescent patients with allergic rhinitis, Denovals tablets were effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Denovals effectively controlled symptoms for 24 hours. The efficacy of Denovals tablets has not been clearly demonstrated in trials with adolescent patients 12 through 17 years of age.

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

Denovals tablets were effective in alleviating the burden of seasonal allergic rhinitis as shown by the total score of the rhino-conjunctivitis quality of life questionnaire. The greatest amelioration was seen in the domains of practical problems and daily activities limited by symptoms.

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, Denovals 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 two placebo-controlled six week trials in patients with chronic idiopathic urticaria, Denovals was effective in relieving pruritus and decreasing the size and number of hives by the end of the first dosing interval. In each trial, the effects were sustained over the 24 hour dosing interval. As with other antihistamine trials in chronic idiopathic urticaria, the minority of patients who were identified as non-responsive to antihistamines was excluded. An improvement in pruritus of more than 50 % was observed in 55 % of patients treated with Denovals compared with 19 % of patients treated with placebo. Treatment with Denovals also significantly reduced interference with sleep and daytime function, as measured by a four-point scale used to assess these variables.

Absorption

Desloratadine plasma concentrations can be detected within 30 minutes of administration. Desloratadine is well absorbed with maximum concentration achieved after approximately 3 hours; the terminal phase half-life is approximately 27 hours. The degree of accumulation of desloratadine was consistent with its half-life (approximately 27 hours) and a once daily dosing frequency. The bioavailability of desloratadine was dose proportional over the range of 5 mg to 20 mg.

In a pharmacokinetic trial in which patient demographics were comparable to those of the general seasonal allergic rhinitis population, 4 % of the subjects achieved a higher concentration of desloratadine. This percentage may vary according to ethnic background. Maximum desloratadine concentration was about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89 hours. The safety profile of these subjects was not different from that of the general population.

Distribution

Desloratadine is moderately bound (83 % - 87 %) to plasma proteins. There is no evidence of clinically relevant medicine accumulation following once daily dosing of desloratadine (5 mg to 20 mg) for 14 days.

Biotransformation

The enzyme responsible for the metabolism of desloratadine has not been identified yet, and therefore, some interactions with other medicinal products cannot be fully excluded. Desloratadine does not inhibit CYP3A4 in vivo, and in vitro studies have shown that the medicinal product does not inhibit CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein.

Elimination

In a single dose trial using a 7.5 mg dose of desloratadine, there was no effect of food (high-fat, high caloric breakfast) on the disposition of desloratadine. In another study, grapefruit juice had no effect on the disposition of desloratadine.

Renally impaired patients

The pharmacokinetics of desloratadine in patients with chronic renal insufficiency (CRI) was compared with that of healthy subjects in one single-dose study and one multiple dose study. In the single-dose study, the exposure to desloratadine was approximately 2 and 2.5-fold greater in subjects with mild to moderate and severe CRI, respectively, than in healthy subjects. In the multiple-dose study, steady state was reached after Day 11, and compared to healthy subjects the exposure to desloratadine was ~1.5-fold greater in subjects with mild to moderate CRI and ~2.5-fold greater in subjects with severe CRI. In both studies, changes in exposure (AUC and C_max) of desloratadine and 3-hydroxydesloratadine were not clinically relevant.

Absorption

Denovals plasma concentrations can be detected within 30 minutes of Denovals administration in adults and adolescents. Denovals is well absorbed with maximum concentration achieved after approximately 3 hours; the terminal phase half-life is approximately 27 hours. The degree of accumulation of Denovals was consistent with its half-life (approximately 27 hours) and a once daily dosing frequency. The bioavailability of Denovals was dose proportional over the range of 5 mg to 20 mg.

In a series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of Denovals. The prevalence of this poor metaboliser phenotype was comparable for adult (6 %) and paediatric subjects 2- to 11-year old (6 %), and greater among Blacks (18 % adult, 16 % paediatric) than Caucasians (2 % adult, 3 % paediatric) in both populations.

In a multiple-dose pharmacokinetic study conducted with the tablet formulation in healthy adult subjects, four subjects were found to be poor metabolisers of Denovals. These subjects had a C_max concentration about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89 hours.

Similar pharmacokinetic parameters were observed in a multiple-dose pharmacokinetic study conducted with the syrup formulation in paediatric poor metaboliser subjects 2- to 11-year old diagnosed with allergic rhinitis. The exposure (AUC) to Denovals was about 6-fold higher and the Cmax was about 3 to 4 fold higher at 3-6 hours with a terminal half-life of approximately 120 hours. Exposure was the same in adult and paediatric poor metabolisers when treated with age-appropriate doses. The overall safety profile of these subjects was not different from that of the general population. The effects of Denovals in poor metabolizers < 2 years of age have not been studied.

In separate single dose studies, at the recommended doses, paediatric patients had comparable AUC and C_max values of Denovals to those in adults who received a 5 mg dose of Denovals syrup.

Distribution

Denovals is moderately bound (83 % - 87 %) to plasma proteins. There is no evidence of clinically relevant active substance accumulation following once daily adult and adolescent dosing of Denovals (5 mg to 20 mg) for 14 days.

In a single dose, crossover study of Denovals, the tablet and the syrup formulations were found to be bioequivalent. As Denovals oral solution contains the same concentration of Denovals, no bioequivalence study was required and it is expected to be equivalent to the syrup and tablet.

Biotransformation

The enzyme responsible for the metabolism of Denovals has not been identified yet, and therefore, some interactions with other medicinal products cannot be fully excluded. Denovals does not inhibit CYP3A4 in vivo, and in vitro studies have shown that the medicinal product does not inhibit CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein.

Elimination

In a single dose trial using a 7.5 mg dose of Denovals, there was no effect of food (high-fat, high caloric breakfast) on the disposition of Denovals. In another study, grapefruit juice had no effect on the disposition of Denovals.

Renally impaired patients

The pharmacokinetics of Denovals in patients with chronic renal insufficiency (CRI) was compared with that of healthy subjects in one-single-dose study and one multiple dose study. In the single-dose study, the exposure to Denovals was approximately 2 and 2.5-fold greater in subjects with mild to moderate and severe CRI, respectively, than in healthy subjects. In the multiple-dose study, steady state was reached after Day 11, and compared to healthy subjects the exposure to Denovals was ~1.5-fold greater in subjects with mild to moderate CRI and ~2.5-fold greater in subjects with severe CRI. In both studies, changes in exposure (AUC and C_max) of Denovals and 3-hydroxyDenovals were not clinically relevant.

Not applicable.

Not applicable

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.