Aerinaze - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Aerinaze 2.5 mg/120 mg modified-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg desloratadine and 120 mg pseudoephedrine sulphate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Modified-release tablet.

Blue and white bilayer oval tablet with “D12” branded to blue layer.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Aerinaze is indicated in adults and adolescents 12 years and older for the symptomatic treatment of seasonal allergic rhinitis when accompanied by nasal congestion.

4.2 Posology and method of administration

Posology

The recommended dose of Aerinaze is one tablet twice a day.

The recommended dosage and the duration of treatment should not be exceeded.

The duration of treatment should be kept as short as possible and should not be continued after the symptoms have disappeared. It is advisable to limit treatment to about 10 days, as during chronic administration the activity of pseudoephedrine sulphate may diminish. After improvement of the congestive condition of the mucosae of the upper airway, treatment may be maintained with desloratadine alone, if necessary.

Elderly patients

Patients of 60 years or older are more likely to experience adverse reactions to sympathomimetic medicinal products, such as pseudoephedrine sulphate. The safety and efficacy of Aerinaze have not been established in this population, and there are insufficient data to give adequate dose recommendations. Therefore Aerinaze should be used with caution in patients above 60 years of age.

Patients with renal or hepatic impairment

The safety and efficacy of Aerinaze have not been established in patients with impaired renal or hepatic function, and there are insufficient data to give adequate dose recommendations. Aerinaze is not recommended for use in patients with impaired renal or hepatic function.

Paediatric population

The safety and efficacy of Aerinaze in children below the age of 12 years have not been established. No data are available. Aerinaze is not recommended for use in children below the age of 12 years.

Method of administration

Oral use.

The tablet may be taken with a full glass of water but must be swallowed entirely (without crushing, breaking or chewing it). The tablet may be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, or to adrenergic medicinal products or to loratadine.

As Aerinaze contains pseudoephedrine sulphate, it is also contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitor therapy or during the 2 weeks following the stopping of such treatment.

Aerinaze is also contraindicated in patients with:

• • narrow-angle glaucoma,
• • urinary retention,
• • cardiovascular diseases such as ischaemic heart disease, tachyarrhythmia and severe hypertension,
• • hyperthyroidism,
• • a history of haemorrhagic stroke or with risk factors which could increase the risk of haemorrhagic stroke. This is due to the alpha-mimetic activity of pseudoephedrine sulphate in combination with other vasoconstrictors such as bromocripitine, pergolide, lisuride, cabergoline, ergotamine, dihydroergotamine or any other decongestant medicinal product used as a nasal decongestant, either by oral route or by nasal route (phenylpropano­lamine, phenylephrine, ephedrine, oxymetazoline, naphazoline..).

4.4 Special warnings and precautions for use

Cardiovascular and general effects

Patients should be informed that the treatment should be discontinued in case of hypertension, tachycardia, palpitations or cardiac arrhythmias, nausea or any other neurological sign (such as headache or increased headache).

Caution should be exercised in the following patient groups:

• • Patients with cardiac arrhythmias
• • Patients with hypertension
• • Patients with a history of myocardial infarction, diabetes mellitus, bladder neck obstruction, or positive anamnesis of bronchospasm
• • Patients receiving digitalis (see section 4.5)

Gastrointestinal and genitourinary effects

Use with caution in patients with stenosing peptic ulcer, pyloroduodenal obstruction, and obstruction of the vesical cervix.

Central nervous system effects

Caution should also be exercised in patients being treated with other sympathomimetics (see section 4.5). These include:

• • decongestants
• • anorexogenics or amphetamine-type psychostimulants
• • antihypertensive medicinal products
• • tricyclic antidepressants and other antihistamines.

Caution should be exercised in patients suffering from migraine who are currently being treated with ergot alkaloid vasoconstrictors (see section 4.5).

Convulsions

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.

Central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension may be produced by sympathomimetic amines. These effects may be more likely to occur in adolescents from 12 years old, elderly patients, or in cases of overdose (see section 4.9).

Risks of abuse

Pseudoephedrine sulphate carries the risk of abuse. Increased doses may ultimately produce toxicity. Continuous use can lead to tolerance resulting in an increased risk of overdosing. Depression may follow rapid withdrawal.

Other

Perioperative acute hypertension can occur if volatile halogenated anaesthetics are used during treatment with indirect sympathomimetic agents. Therefore, if surgery is scheduled, it is preferable to discontinue treatment 24 hours before anaesthesia.

Interference with serological testing

Athletes should be informed that treatment with pseudoephedrine sulphate could lead to positive doping tests.

The administration of Aerinaze should be discontinued at least 48 hours before skin tests since antihistamines maybe prevent or reduce otherwise positive reaction to dermal reactivity index.

Severe skin reactions

Severe skin reactions such as acute generalised exanthematous pustulosis (AGEP) may occur with pseudoephedrine-containing products. Patients should be carefully monitored. If signs and symptoms such as pyrexia, erythema or many small pustules are observed, administration of Aerinaze should be discontinued and appropriate measures taken if needed.

4.5 Interaction with other medicinal products and other forms of interaction

Aerinaze

The following combinations are not recommended:

• • digitalis (see section 4.4)
• • bromocriptine
• • cabergoline
• • lisuride, pergolide: risk of vasoconstriction and increase in blood pressure.

No interaction studies have been performed with the combination of desloratadine and pseudoephedrine sulphate.

The interaction with Aerinaze and alcohol has not been studied. However, in a clinical pharmacology trial desloratadine taken concomitantly with alcohol did not potentiate the performance impairing effects of alcohol. No significant differences were found in the psychomotor test results between desloratadine and placebo groups, whether administered alone or with alcohol. Alcohol use should be avoided during Aerinaze treatment.

Desloratadine

No clinically relevant interactions or changes in desloratadine plasma concentrations were observed in clinical trials with desloratadine in which erythromycin or ketoconazole were co-administered.

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.

Pseudoephedrine sulphate

Antacids increase the rate of pseudoephedrine sulphate absorption, kaolin decreases it.

Sympathomimetics

Reversible and irreversible MAO inhibitor(s) may cause: risk of vasoconstriction and increased blood pressure.

Concurrent administration with other sympathomimetics (decongestants, anorexogenics or amphetamine-type psychostimulants, antihypertensive medicinal products, tricyclic antidepressants and other antihistamines) may result in critical hypertension reactions (see section 4.4).

Dihydroergotamine, ergotamine, methylergometrine: risk of vasoconstriction and increase in blood pressure.

Other vasoconstrictors used as nasal decongestant, by oral or nasal route (phenylpropano­lamine, phenylephrine, ephedrine, oxymetazoline, naphazoline…): risk of vasoconstriction.

Sympathomimetic medicines reduce the antihypertensive effect of a-methyldopa, mecamylamine, reserpine, veratrum alkaloids, and guanethidine.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of the combination of desloratadine and pseudoephedrine sulphate in pregnant women. 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 Aerinaze during pregnancy.

Breast-feeding

Desloratadine and pseudoephedrine sulphate have been identified in breastfed newborns/infants of treated women. There is insufficient information on the effects of desloratadine and pseudoephedrine sulphate in newborns/infants. Decreased milk production in nursing mothers has been reported with pseudoephedrine sulphate. Aerinaze should not be used during breast-feeding.

Fertility

There are no data available on male and female fertility.

4.7 Effects on ability to drive and use machines

Aerinaze has no or negligible influence on the ability to drive and use machines. 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.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials involving 414 adults the most frequent of adverse reactions reported were insomnia (8.9 %), dry mouth (7.2 %) and headache (3.1 %).

Tabulated list of adverse reactions

Adverse reactions considered by investigators to be causally related to Aerinaze are listed below by System Organ Class. 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Other adverse reactions reported for desloratadine during the post-marketing period are listed hereunder.

Cases of severe skin reactions such as acute generalised exanthematous pustulosis (AGEP) have been reported with pseudoephedrine-containing products.

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

4.9 Overdose

Symptoms

Symptoms of overdose are mostly of a sympathomimetic nature. Symptoms may vary from CNS depression (sedation, apnoea, diminished mental alertness, cyanosis, coma, cardiovascular collapse) to CNS stimulation (insomnia, hallucination, tremors, convulsions) with possible fatal outcome. Other symptoms may include: headache, anxiety, micturition difficulty, muscle weakness and tenseness, euphoria, excitement, respiratory failure, cardiac arrhythmias, tachycardia, palpitations, thirst, perspiration, nausea, vomiting, precordial pain, dizziness, tinnitus, ataxia, blurred vision and hypertension or hypotension. CNS stimulation is particularly likely in children, as are atropine-like symptoms (dry mouth, fixed and dilated pupils, flushing, hyperthermia, and gastrointestinal symptoms). Some patients may present a toxic psychosis with delusions and hallucinations.

Management

In the event of overdose, symptomatic and supportive treatment immediately should be started and maintained it for as long as necessary. Adsorption of active substance remaining in the stomach may be attempted by administration of active charcoal suspended in water. Gastric lavage with physiologic saline solution may be performed, particularly in children. In adults, tap water can be used. As much as possible of the amount administered should be removed before the next instillation. Desloratadine is not removed by haemodialysis and it is not known if it is eliminated by peritoneal dialysis. After emergency treatment, medical monitoring of the patient should be continued.

Treatment of the pseudoephedrine sulphate overdose is symptomatic and supportive. Stimulants (analeptics) must not be used. Hypertension can be controlled with an adrenoceptor-blocking agent and tachycardia with a beta-blocking agent. Short acting barbiturates, diazepam or paraldehyde may be administered to control seizures. Hyperpyrexia, especially in children, may require treatment with tepid water sponge baths or hypothermia blanket. Apnoea is treated with respiratory assistance.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nasal preparations, nasal decongestants for systemic use, ATC code: R01BA52.

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.

Desloratadine does not readily penetrate the central nervous system. 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 controlled clinical trials, at the recommended dose of 5 mg daily, there was no excess incidence of somnolence as compared to placebo. Desloratadine given at a single daily dose of 7.5 mg did not affect psychomotor performance in clinical trials.

Pseudoephedrine sulphate (d-isoephedrine sulphate) is a sympathomimetic agent with mostly a-mimetic activity in comparison with the p—activity. Pseudoephedrine sulphate provides a nasal decongestant effect after oral administration due to its vasoconstrictive action. It has an indirect sympathomimetic effect due primarily to the release of adrenergic mediators from the post-ganglionic nerve endings.

Oral administration of pseudoephedrine sulphate at the recommended dose can cause other sympathomimetic effects, such as increased blood pressure, tachycardia or manifestations of central nervous system excitation.

Pharmacodynamic effects

The pharmacodynamic effects of Aerinaze tablets are directly related to that of its components.

Clinical efficacy and safety

The clinical efficacy and safety of Aerinaze tablets was evaluated in two, 2-week multicentre, randomized parallel group clinical trials involving 1,248 patients 12 to 78 years of age with seasonal allergic rhinitis, 414 of whom received Aerinaze tablets. In both trials, the antihistaminic efficacy of Aerinaze tablets as measured by total symptom score, excluding nasal congestion, was significantly greater than pseudoephedrine sulphate alone over the 2-week treatment period. In addition, the decongestant efficacy of Aerinaze tablets, as measured by nasal stuffiness/con­gestion, was significantly greater than desloratadine alone over the 2-week treatment period.

There were no significant differences in the efficacy of Aerinaze tablets across subgroups of patients defined by gender, age, or race.

5.2 Pharmacokinetic properties

• - Desloratadine and Pseudoephedrine sulphate:

Absorption

In a single dose pharmacokinetic study with Aerinaze, plasma concentration of desloratadine can be detected within 30 minutes of administration. The mean time to maximum plasma concentrations (Tmax) for desloratadine occurred at approximately 4–5 hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 1.09 ng/ml and 31.6 ng^hr/ml, respectively, were observed. For pseudoephedrine sulphate, the mean Tmax occurred at 6–7 hours post dose and mean peak plasma concentrations (Cmax and AUC) of approximately 263 ng/ml and 4,588 ng^hr/ml, respectively, were observed. Food had no effect on the bioavailability (Cmax and AUC) of desloratadine or pseudoephedrine sulphate. The half-life for desloratadine is 27.4 hours. The apparent half-life of pseudoephedrine sulphate is 7.9 hours.

Following oral administration of Aerinaze for 14 days in normal healthy volunteers, steady-state conditions were reached on day 10 for desloratadine, 3-hydroxydeslora­tadine and pseudoephedrine sulphate. For desloratadine, mean steady state peak plasma concentrations (Cmax and AUC (0–12 h)) of approximately 1.7 ng/ml and 16 ng^hr/ml were observed, respectively. For pseudoephedrine sulphate, mean steady state peak plasma concentrations (Cmax and AUC (0–12 h)) of 459 ng/ml and 4,658 ng^hr/ml were observed.

• - Desloratadine

Absorption

In a series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of desloratadine. The prevalence of this poor metabolizer phenotype was greater among Black adults than Caucasian adults (18 % vs. 2 %) however the safety profile of these subjects was not different from that of the general population. 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.

Distribution

Desloratadine is moderately bound (83 % – 87 %) to plasma proteins.

• - Pseudoephedrine sulphate

5.3 Preclinical safety data

No pre-clinical studies have been performed with Aerinaze. However, non-clinical data with desloratadine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

The lack of carcinogenic potential was demonstrated in studies conducted with desloratadine and loratadine.

The combination of loratadine/pse­udoephedrine sulphate used in acute and multiple-dose studies, exhibited a low order of toxicity. The combination was not more toxic than their individual components, and observed effects were generally related to the pseudoephedrine sulphate component.

During reproductive toxicity studies, the combination of loratadine/pse­udoephedrine sulphate was not teratogenic when administered orally to rats at doses up to 150 mg/kg/day and rabbits at doses up to 120 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Blue, immediate-release layer

maize starch

microcrystalline cellulose

edetate disodium

citric acid

stearic acid

colorant (Indigo carmine E132 Aluminium lake).

White, sustained-release layer

hypromellose 2208

microcrystalline cellulose

povidone K30 silicon dioxide magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C. Keep the blisters in the outer carton in order to protect from light.

6.5 Nature and contents of container

Aerinaze is supplied in blisters comprised of laminate blister film and foil lidding.

The blister consists of clear polychlorotri­fluorethylene/po­lyvinyl chloride (PCTFE/PVC) film, sealed with a vinyl heat seal coated aluminium foil. Pack sizes of 2, 4, 7, 10, 14 and 20 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

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

7. MARKETING AUTHORISATION HOLDER

N.V. Organon

Kloosterstraat 6

5349 AB Oss

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/399/001

EU/1/07/399/002

EU/1/07/399/003

EU/1/07/399/004

EU/1/07/399/005

EU/1/07/399/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 July 2007

Date of latest renewal: 30 July 2012