desloratadine: prescribing information – dosing, contraindications, interactions, side effects

Aerius is indicated in adults and adolescents aged 12 years and older for the relief of symptoms associated with:
- allergic rhinitis (see section 5.1)
- urticaria (see section 5.1)

Aerius is indicated in adults, adolescents and children over the age of 1 year for the relief of symptoms associated with:
- allergic rhinitis (see section 5.1)
- urticaria (see section 5.1)

Posology

Adults and adolescents (12 years of age and over)
The recommended dose of Aerius 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 (see sections 4.8 and 5.1).

The safety and efficacy of Aerius 5 mg film-coated tablets in children below the age of 12 years have not been established.

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 Aerius is 10 ml (5 mg) 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 (see section 4.4) and there are no data supporting the treatment of infectious rhinitis with Aerius.

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

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

The safety and efficacy of Aerius 0.5 mg/ml oral solution in children below the age of 1 year have not been established.

There is limited clinical trial efficacy experience with the use of desloratadine in children 1 through 11 years of age and adolescents 12 through 17 years of age (see sections 4.8 and 5.1).

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.

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to loratadine.

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 Aerius 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 %).

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).

System Organ Class
Frequency
Adverse reactions seen with Aerius
Metabolism and nutrition disorders
Not known
Increased appetite
Psychiatric disorders
Very rare
Not known
Hallucinations
Abnormal behaviour*, aggression*, depressed mood
Nervous system disorders
Common
Very rare
Headache
Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Eye disorders
Not known
Eye dryness
Cardiac disorders
Very rare
Not known
Tachycardia, palpitations
QT prolongation*
Gastrointestinal disorders

Common
Very rare
Dry mouth
Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders

Very rare

Not known
Elevations of liver enzymes, increased bilirubin, hepatitis
Jaundice
Skin and subcutaneous tissue disorders
Not known
Photosensitivity
Musculoskeletal and connective tissue disorders
Very rare
Myalgia
General disorders and administration site conditions

Common
Very rare

Not known
Fatigue
Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased * Undesirable effects reported during the post-marketing period also in paediatric patients.

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

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.

A retrospective observational safety study indicated an increased incidence of new-onset seizure in patients 0 to 19 years of age when receiving desloratadine compared with periods not receiving desloratadine. Among children 0-4 years old, the adjusted absolute increase was 37.5 (95 %

Confidence Interval (CI) 10.5-64.5) per 100,000 person years (PY) with a background rate of new onset seizure of 80.3 per 100,000 PY. Among patients 5-19 years of age, the adjusted absolute increase was 11.3 (95 % CI 2.3-20.2) per 100,000 PY with a background rate of 36.4 per 100,000 PY.
(See section 4.4.)

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 listed in Appendix V.

Summary of the safety profile

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 Aerius 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).

System Organ Class
Frequency
Adverse reactions seen with Aerius
Metabolism and nutrition disorders
Not known
Increased appetite
Psychiatric disorders
Very rare
Not known
Hallucinations
Abnormal behaviour*, aggression*, depressed mood
Nervous system disorders

Common
Common (children less than 2 years)
Very rare
Headache
Insomnia

Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Eye disorders
Not known
Eye dryness
Cardiac disorders
Very rare
Not known
Tachycardia, palpitations
QT prolongation*
Gastrointestinal disorders

Common
Common (children less than 2 years)
Very rare
Dry mouth
Diarrhoea

Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders

Very rare

Not known
Elevations of liver enzymes, increased bilirubin, hepatitis
Jaundice
Skin and subcutaneous tissue disorders
Not known
Photosensitivity
Musculoskeletal and connective tissue disorders
Very rare
Myalgia
General disorders and administration site conditions

Common
Common (children less than 2 years)
Very rare

Not known
Fatigue
Fever

Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased * Undesirable effects reported during the post-marketing period also in paediatric patients.

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

In clinical trials in a paediatric population, the desloratadine 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 desloratadine and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse reactions 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 desloratadine 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 desloratadine and 6.9 % of patients receiving placebo.

A retrospective observational safety study indicated an increased incidence of new-onset seizure in patients 0 to 19 years of age when receiving desloratadine compared with periods not receiving desloratadine. Among children 0-4 years old, the adjusted absolute increase was 37.5 (95 %

Confidence Interval (CI) 10.5-64.5) per 100,000 person years (PY) with a background rate of new onset seizure of 80.3 per 100,000 PY. Among patients 5-19 years of age, the adjusted absolute increase was 11.3 (95 % CI 2.3-20.2) per 100,000 PY with a background rate of 36.4 per 100,000 PY.
(See section 4.4.)

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 listed in Appendix V.

Renal function impairment
In the case of severe renal insufficiency, Aerius should be used with caution (see section 5.2).

Seizures
Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children (see section 4.8), 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.

Aerius tablet contains lactose
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Renal function impairment
In the case of severe renal insufficiency, Aerius should be used with caution (see section 5.2).

Seizures
Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children (see section 4.8), 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.

Aerius oral solution contains sorbitol (E420)
This medicinal product contains 150 mg sorbitol (E420) in each ml of oral solution.

The additive effect of concomitantly administered products containing sorbitol (E420) (or fructose) and dietary intake of sorbitol (E420) (or fructose) should be taken into account. The content of sorbitol (E420) in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Sorbitol is a source of fructose; patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Aerius oral solution contains propylene glycol (E1520)
This medicinal product contains 100.19 mg propylene glycol (E1520) in each ml of oral solution.

Aerius oral solution contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Aerius oral solution contains benzyl alcohol
This medicinal product contains 0.375 mg benzyl alcohol in each ml of oral solution.

Benzyl alcohol may cause anaphylactoid reactions.

Increased risk due to accumulation in young children. It is not recommended to be used for more than a week in young children (less than 3 years old).

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

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 desloratadine and exhibit a higher exposure (see section 5.2). The safety of desloratadine 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 desloratadine in poor metabolisers < 2 years of age have not been studied.

No clinically relevant interactions were observed in clinical trials with desloratadine tablets in which erythromycin or ketoconazole were co-administered (see section 5.1).

Paediatric population
Interaction studies have only been performed in adults.

In a clinical pharmacology trial, Aerius tablets taken concomitantly with alcohol did not potentiate the performance impairing effects of alcohol (see section 5.1). However, cases of alcohol intolerance and intoxication have been reported during post-marketing use. Therefore, caution is recommended if alcohol is taken concomitantly.

Pregnancy
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicates no malformative nor foetal/ neonatal toxicity of desloratadine. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Aerius during pregnancy.

Breast-feeding
Desloratadine has been identified in breastfed newborns/infants of treated women. The effect of desloratadine on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Aerius therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility
There are no data available on male and female fertility.

Aerius 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.

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.

5.
PHARMACOLOGICAL PROPERTIES

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 adults and adolescents, 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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06AX27

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.

Pharmacodynamic effects
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. Aerius 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, Aerius was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Aerius effectively controlled symptoms for 24 hours.

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

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06AX27

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

Paediatric population
Efficacy of Aerius oral solution has not been investigated in separate paediatric trials. However, the safety of desloratadine syrup formulation, which contains the same concentration of desloratadine as Aerius oral solution, was demonstrated in three paediatric trials. Children, 1-11 years of age, who were candidates for antihistamine therapy received a daily desloratadine 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 desloratadine (see section 5.2) were comparable in the paediatric and adult populations. Thus, since the course of allergic rhinitis/chronic idiopathic urticaria and the profile of desloratadine are similar in adults and paediatric patients, desloratadine efficacy data in adults can be extrapolated to the paediatric population.

Efficacy of Aerius 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 desloratadine 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 desloratadine 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.

Pharmacodynamic effects
Desloratadine 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. Aerius 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, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

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

Absorption
Desloratadine plasma concentrations can be detected within 30 minutes of desloratadine administration in adults and adolescents. 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 series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of desloratadine. 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 desloratadine. These subjects had a Cmax 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 desloratadine 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 desloratadine in poor metabolizers < 2 years of age have not been studied.

Azomyr is indicated in adults and adolescents aged 12 years and older for the relief of symptoms associated with:
- allergic rhinitis (see section 5.1)
- urticaria (see section 5.1)

Azomyr is indicated in adults, adolescents and children over the age of 1 year for the relief of symptoms associated with:
- allergic rhinitis (see section 5.1)
- urticaria (see section 5.1)

Posology

Adults and adolescents (12 years of age and over)
The recommended dose of Azomyr 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 (see sections 4.8 and 5.1).

The safety and efficacy of Azomyr 5 mg film-coated tablets in children below the age of 12 years have not been established.

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 Azomyr is 10 ml (5 mg) 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 (see section 4.4) and there are no data supporting the treatment of infectious rhinitis with Azomyr.

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

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

The safety and efficacy of Azomyr 0.5 mg/ml oral solution in children below the age of 1 year have not been established.

There is limited clinical trial efficacy experience with the use of desloratadine in children 1 through 11 years of age and adolescents 12 through 17 years of age (see sections 4.8 and 5.1).

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.

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to loratadine.

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 Azomyr 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 %).

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).

System Organ Class
Frequency
Adverse reactions seen with Azomyr
Metabolism and nutrition disorders
Not known
Increased appetite
Psychiatric disorders
Very rare
Not known
Hallucinations
Abnormal behaviour*, aggression*, depressed mood
Nervous system disorders
Common
Very rare
Headache
Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Eye disorders
Not known
Eye dryness
Cardiac disorders
Very rare
Not known
Tachycardia, palpitations
QT prolongation*
Gastrointestinal disorders

Common
Very rare
Dry mouth
Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders

Very rare

Not known
Elevations of liver enzymes, increased bilirubin, hepatitis
Jaundice
Skin and subcutaneous tissue disorders
Not known
Photosensitivity
Musculoskeletal and connective tissue disorders
Very rare
Myalgia
General disorders and administration site conditions

Common
Very rare

Not known
Fatigue
Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased * Undesirable effects reported during the post-marketing period also in paediatric patients.

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

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.

A retrospective observational safety study indicated an increased incidence of new-onset seizure in patients 0 to 19 years of age when receiving desloratadine compared with periods not receiving desloratadine. Among children 0-4 years old, the adjusted absolute increase was 37.5 (95 %



Confidence Interval (CI) 10.5-64.5) per 100,000 person years (PY) with a background rate of new onset seizure of 80.3 per 100,000 PY. Among patients 5-19 years of age, the adjusted absolute increase was 11.3 (95 % CI 2.3-20.2) per 100,000 PY with a background rate of 36.4 per 100,000 PY.
(See section 4.4.)

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 listed in Appendix V.

Summary of the safety profile

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 Azomyr 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).



System Organ Class
Frequency
Adverse reactions seen with Azomyr
Metabolism and nutrition disorders
Not known
Increased appetite
Psychiatric disorders
Very rare
Not known
Hallucinations
Abnormal behaviour*, aggression*, depressed mood
Nervous system disorders

Common
Common (children less than 2 years)
Very rare
Headache
Insomnia

Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Eye disorders
Not known
Eye dryness
Cardiac disorders
Very rare
Not known
Tachycardia, palpitations
QT prolongation*
Gastrointestinal disorders

Common
Common (children less than 2 years)
Very rare
Dry mouth
Diarrhoea

Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders

Very rare

Not known
Elevations of liver enzymes, increased bilirubin, hepatitis
Jaundice
Skin and subcutaneous tissue disorders
Not known
Photosensitivity
Musculoskeletal and connective tissue disorders
Very rare
Myalgia
General disorders and administration site conditions

Common
Common (children less than 2 years)
Very rare

Not known
Fatigue
Fever

Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased * Undesirable effects reported during the post-marketing period also in paediatric patients.

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

In clinical trials in a paediatric population, the desloratadine 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 desloratadine and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse reactions 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 desloratadine 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 desloratadine and 6.9 % of patients receiving placebo.

A retrospective observational safety study indicated an increased incidence of new-onset seizure in patients 0 to 19 years of age when receiving desloratadine compared with periods not receiving desloratadine. Among children 0-4 years old, the adjusted absolute increase was 37.5 (95 %



Confidence Interval (CI) 10.5-64.5) per 100,000 person years (PY) with a background rate of new onset seizure of 80.3 per 100,000 PY. Among patients 5-19 years of age, the adjusted absolute increase was 11.3 (95 % CI 2.3-20.2) per 100,000 PY with a background rate of 36.4 per 100,000 PY.
(See section 4.4.)

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 listed in Appendix V.

Renal function impairment
In the case of severe renal insufficiency, Azomyr should be used with caution (see section 5.2).

Seizures
Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children (see section 4.8), 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.

Azomyr tablet contains lactose
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Renal function impairment
In the case of severe renal insufficiency, Azomyr should be used with caution (see section 5.2).

Seizures
Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children (see section 4.8), 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.

Azomyr oral solution contains sorbitol (E420)
This medicinal product contains 150 mg sorbitol (E420) in each ml of oral solution.

The additive effect of concomitantly administered products containing sorbitol (E420) (or fructose) and dietary intake of sorbitol (E420) (or fructose) should be taken into account. The content of sorbitol (E420) in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Sorbitol is a source of fructose; patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Azomyr oral solution contains propylene glycol (E1520)
This medicinal product contains 100.19 mg propylene glycol (E1520) in each ml of oral solution.

Azomyr oral solution contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Azomyr oral solution contains benzyl alcohol
This medicinal product contains 0.375 mg benzyl alcohol in each ml of oral solution.

Benzyl alcohol may cause anaphylactoid reactions.

Increased risk due to accumulation in young children. It is not recommended to be used for more than a week in young children (less than 3 years old).

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

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 desloratadine and exhibit a higher exposure (see section 5.2). The safety of desloratadine 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 desloratadine in poor metabolisers < 2 years of age have not been studied.

No clinically relevant interactions were observed in clinical trials with desloratadine tablets in which erythromycin or ketoconazole were co-administered (see section 5.1).

Paediatric population
Interaction studies have only been performed in adults.

In a clinical pharmacology trial, Azomyr tablets taken concomitantly with alcohol did not potentiate the performance impairing effects of alcohol (see section 5.1). However, cases of alcohol intolerance and intoxication have been reported during post-marketing use. Therefore, caution is recommended if alcohol is taken concomitantly.

Pregnancy
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicates no malformative nor foetal/ neonatal toxicity of desloratadine. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Azomyr during pregnancy.

Breast-feeding
Desloratadine has been identified in breastfed newborns/infants of treated women. The effect of desloratadine on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Azomyr therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility
There are no data available on male and female fertility.

Azomyr 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.



Azomyr 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.

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.

5.
PHARMACOLOGICAL PROPERTIES

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 adults and adolescents, 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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06AX27

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.



Pharmacodynamic effects
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. Azomyr 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, Azomyr was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Azomyr effectively controlled symptoms for 24 hours.

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

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06AX27

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

Paediatric population
Efficacy of Azomyr oral solution has not been investigated in separate paediatric trials. However, the safety of desloratadine syrup formulation, which contains the same concentration of desloratadine as Azomyr oral solution, was demonstrated in three paediatric trials. Children, 1-11 years of age, who were candidates for antihistamine therapy received a daily desloratadine 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 desloratadine (see section 5.2) were comparable in the paediatric and adult populations. Thus, since the course of allergic rhinitis/chronic idiopathic urticaria and the profile of desloratadine are similar in adults and paediatric patients, desloratadine efficacy data in adults can be extrapolated to the paediatric population.

Efficacy of Azomyr 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 desloratadine 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 desloratadine 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.

Pharmacodynamic effects
Desloratadine 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. Azomyr 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, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

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

Absorption
Desloratadine plasma concentrations can be detected within 30 minutes of desloratadine administration in adults and adolescents. 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 series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of desloratadine. 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 desloratadine. These subjects had a Cmax 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 desloratadine 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 desloratadine in poor metabolizers < 2 years of age have not been studied.

Neoclarityn is indicated in adults and adolescents aged 12 years and older for the relief of symptoms associated with:
- allergic rhinitis (see section 5.1)
- urticaria (see section 5.1)

Neoclarityn is indicated in adults, adolescents and children over the age of 1 year for the relief of symptoms associated with:
- allergic rhinitis (see section 5.1)
- urticaria (see section 5.1)

Posology

Adults and adolescents (12 years of age and over)
The recommended dose of Neoclarityn 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 (see sections 4.8 and 5.1).

The safety and efficacy of Neoclarityn 5 mg film-coated tablets in children below the age of 12 years have not been established.

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 Neoclarityn is 10 ml (5 mg) 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 (see section 4.4) and there are no data supporting the treatment of infectious rhinitis with Neoclarityn.

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

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

The safety and efficacy of Neoclarityn 0.5 mg/ml oral solution in children below the age of 1 year have not been established.

There is limited clinical trial efficacy experience with the use of desloratadine in children 1 through 11 years of age and adolescents 12 through 17 years of age (see sections 4.8 and 5.1).

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.

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to loratadine.

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 Neoclarityn 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 %).

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).

System Organ Class
Frequency
Adverse reactions seen with
Neoclarityn
Metabolism and nutrition disorders
Not known
Increased appetite
Psychiatric disorders
Very rare
Not known
Hallucinations
Abnormal behaviour*, aggression*, depressed mood
Nervous system disorders
Common
Very rare
Headache
Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Eye disorders
Not known
Eye dryness
Cardiac disorders
Very rare
Not known
Tachycardia, palpitations
QT prolongation*
Gastrointestinal disorders

Common
Very rare
Dry mouth
Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders

Very rare

Not known
Elevations of liver enzymes, increased bilirubin, hepatitis
Jaundice
Skin and subcutaneous tissue disorders
Not known
Photosensitivity
Musculoskeletal and connective tissue disorders
Very rare
Myalgia
General disorders and administration site conditions

Common
Very rare

Not known
Fatigue
Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased * Undesirable effects reported during the post-marketing period also in paediatric patients.

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

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.

A retrospective observational safety study indicated an increased incidence of new-onset seizure in patients 0 to 19 years of age when receiving desloratadine compared with periods not receiving desloratadine. Among children 0-4 years old, the adjusted absolute increase was 37.5 (95 %

Confidence Interval (CI) 10.5-64.5) per 100,000 person years (PY) with a background rate of new onset seizure of 80.3 per 100,000 PY. Among patients 5-19 years of age, the adjusted absolute increase was 11.3 (95 % CI 2.3-20.2) per 100,000 PY with a background rate of 36.4 per 100,000 PY.
(See section 4.4.)

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 listed in Appendix V.

Summary of the safety profile

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 Neoclarityn 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).

System Organ Class
Frequency
Adverse reactions seen with
Neoclarityn
Metabolism and nutrition disorders
Not known
Increased appetite
Psychiatric disorders
Very rare
Not known
Hallucinations
Abnormal behaviour*, aggression*, depressed mood
Nervous system disorders

Common
Common (children less than 2 years)
Very rare
Headache
Insomnia

Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Eye disorders
Not known
Eye dryness
Cardiac disorders
Very rare
Not known
Tachycardia, palpitations
QT prolongation*
Gastrointestinal disorders

Common
Common (children less than 2 years)
Very rare
Dry mouth
Diarrhoea

Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders

Very rare

Not known
Elevations of liver enzymes, increased bilirubin, hepatitis
Jaundice
Skin and subcutaneous tissue disorders
Not known
Photosensitivity
Musculoskeletal and connective tissue disorders
Very rare
Myalgia
General disorders and administration site conditions

Common
Common (children less than 2 years)
Very rare

Not known
Fatigue
Fever

Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria) Asthenia Investigations Not known Weight increased * Undesirable effects reported during the post-marketing period also in paediatric patients.

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

In clinical trials in a paediatric population, the desloratadine 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 desloratadine and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse reactions 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 desloratadine 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 desloratadine and 6.9 % of patients receiving placebo.

A retrospective observational safety study indicated an increased incidence of new-onset seizure in patients 0 to 19 years of age when receiving desloratadine compared with periods not receiving desloratadine. Among children 0-4 years old, the adjusted absolute increase was 37.5 (95 %

Confidence Interval (CI) 10.5-64.5) per 100,000 person years (PY) with a background rate of new onset seizure of 80.3 per 100,000 PY. Among patients 5-19 years of age, the adjusted absolute increase was 11.3 (95 % CI 2.3-20.2) per 100,000 PY with a background rate of 36.4 per 100,000 PY.
(See section 4.4.)

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 listed in Appendix V.

Renal function impairment
In the case of severe renal insufficiency, Neoclarityn should be used with caution (see section 5.2).

Seizures
Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children (see section 4.8), 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.

Neoclarityn tablet contains lactose
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

Renal function impairment
In the case of severe renal insufficiency, Neoclarityn should be used with caution (see section 5.2).

Seizures
Desloratadine should be administered with caution in patients with medical or familial history of seizures, and mainly young children (see section 4.8), 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.

Neoclarityn oral solution contains sorbitol (E420)
This medicinal product contains 150 mg sorbitol (E420) in each ml of oral solution.

The additive effect of concomitantly administered products containing sorbitol (E420) (or fructose) and dietary intake of sorbitol (E420) (or fructose) should be taken into account. The content of sorbitol (E420) in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Sorbitol is a source of fructose; patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Neoclarityn oral solution contains propylene glycol (E1520)
This medicinal product contains 100.19 mg propylene glycol (E1520) in each ml of oral solution.

Neoclarityn oral solution contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Neoclarityn oral solution contains benzyl alcohol
This medicinal product contains 0.375 mg benzyl alcohol in each ml of oral solution.

Benzyl alcohol may cause anaphylactoid reactions.

Increased risk due to accumulation in young children. It is not recommended to be used for more than a week in young children (less than 3 years old).

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

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 desloratadine and exhibit a higher exposure (see section 5.2). The safety of desloratadine 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 desloratadine in poor metabolisers < 2 years of age have not been studied.

No clinically relevant interactions were observed in clinical trials with desloratadine tablets in which erythromycin or ketoconazole were co-administered (see section 5.1).

Paediatric population
Interaction studies have only been performed in adults.

In a clinical pharmacology trial, Neoclarityn tablets taken concomitantly with alcohol did not potentiate the performance impairing effects of alcohol (see section 5.1). However, cases of alcohol intolerance and intoxication have been reported during post-marketing use. Therefore, caution is recommended if alcohol is taken concomitantly.

Pregnancy
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicates no malformative nor foetal/ neonatal toxicity of desloratadine. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Neoclarityn during pregnancy.

Breast-feeding
Desloratadine has been identified in breastfed newborns/infants of treated women. The effect of desloratadine on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Neoclarityn therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility
There are no data available on male and female fertility.

Neoclarityn 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.

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.

5.
PHARMACOLOGICAL PROPERTIES

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 adults and adolescents, 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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06AX27

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.

Pharmacodynamic effects
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. Neoclarityn 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, Neoclarityn was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate.
Neoclarityn effectively controlled symptoms for 24 hours.

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

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06AX27

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

Paediatric population
Efficacy of Neoclarityn oral solution has not been investigated in separate paediatric trials. However, the safety of desloratadine syrup formulation, which contains the same concentration of desloratadine as Neoclarityn oral solution, was demonstrated in three paediatric trials. Children, 1-11 years of age, who were candidates for antihistamine therapy received a daily desloratadine 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 desloratadine (see section 5.2) were comparable in the paediatric and adult populations. Thus, since the course of allergic rhinitis/chronic idiopathic urticaria and the profile of desloratadine are similar in adults and paediatric patients, desloratadine efficacy data in adults can be extrapolated to the paediatric population.

Efficacy of Neoclarityn 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 desloratadine 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 desloratadine 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.

Pharmacodynamic effects
Desloratadine 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. Neoclarityn 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, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

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

Absorption
Desloratadine plasma concentrations can be detected within 30 minutes of desloratadine administration in adults and adolescents. 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 series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of desloratadine. 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 desloratadine. These subjects had a Cmax 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 desloratadine 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 desloratadine in poor metabolizers < 2 years of age have not been studied.