AERINAZE 2.5mg / 120mg modified release tablets medication leaflet

Aerinaze 2.5 mg/120 mg modified-release tablets

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

For the full list of excipients, see section 6.1.

Modified-release tablet.

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

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

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 thesymptoms have disappeared. It is advisable to limit treatment to about 10 days, as during chronicadministration the activity of pseudoephedrine sulphate may diminish. After improvement of thecongestive condition of the mucosae of the upper airway, treatment may be maintained withdesloratadine alone, if necessary.

Patients of 60 years or older are more likely to experience adverse reactions to sympathomimeticmedicinal products, such as pseudoephedrine sulphate. The safety and efficacy of Aerinaze have notbeen established in this population, and there are insufficient data to give adequate doserecommendations. Therefore Aerinaze should be used with caution in patients above 60 years of age.

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

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.

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.

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

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

Aerinaze is also contraindicated in patients with:

* narrow-angle glaucoma,

* urinary retention,

* cardiovascular diseases such as ischaemic heart disease and tachyarrhythmia,

* severe hypertension or uncontrolled hypertension,

* hyperthyroidism,

* a history of haemorrhagic stroke or with risk factors which could increase the risk ofhaemorrhagic stroke. This is due to the alpha-mimetic activity of pseudoephedrine sulphate incombination with other vasoconstrictors such as bromocripitine, pergolide, lisuride, cabergoline,ergotamine, dihydroergotamine or any other decongestant medicinal product used as a nasaldecongestant, either by oral route or by nasal route (phenylpropanolamine, phenylephrine,ephedrine, oxymetazoline, naphazoline…),

* severe acute or chronic kidney disease/renal failure.

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 asheadache 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, orpositive 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 obstructionof the vesical cervix.

Central nervous system effects

Caution should also be exercised in patients being treated with other sympathomimetics (seesection 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 withergot alkaloid vasoconstrictors (see section 4.5).

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstrictionsyndrome (RCVS)

Cases of PRES and RCVS have been reported with the use of pseudoephedrine containing products(see section 4.8). The risk is increased in patients with severe or uncontrolled hypertension, or withsevere acute or chronic kidney disease/renal failure (see section 4.3).

Pseudoephedrine should be discontinued and immediate medical assistance sought if the followingsymptoms occur: sudden severe headache or thunderclap headache, nausea, vomiting, confusion,seizures and/or visual disturbances. Most reported cases of PRES and RCVS resolved followingdiscontinuation and appropriate treatment.

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

Central nervous system stimulation with convulsions or cardiovascular collapse with accompanyinghypotension may be produced by sympathomimetic amines. These effects may be more likely to occurin 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 mayfollow rapid withdrawal.

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

Interference with serological testing

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

The administration of Aerinaze should be discontinued at least 48 hours before skin tests sinceantihistamines 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 withpseudoephedrine-containing products. Patients should be carefully monitored. If signs and symptomssuch as pyrexia, erythema or many small pustules are observed, administration of Aerinaze should bediscontinued and appropriate measures taken if needed.

Ischaemic optic neuropathy

Cases of ischaemic optic neuropathy have been reported with pseudoephedrine. Pseudoephedrineshould be discontinued and medical advice sought if sudden loss of vision or decreased visual acuitysuch as scotoma occurs.

Ischaemic colitis

Some cases of ischaemic colitis have been reported with pseudoephedrine. Pseudoephedrine should bediscontinued and medical advice sought if sudden abdominal pain, rectal bleeding or other symptomsof ischaemic colitis develop.

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 andpseudoephedrine sulphate.

The interaction with Aerinaze and alcohol has not been studied. However, in a clinical pharmacologytrial desloratadine taken concomitantly with alcohol did not potentiate the performance impairingeffects of alcohol. No significant differences were found in the psychomotor test results betweendesloratadine and placebo groups, whether administered alone or with alcohol. Alcohol use should beavoided during Aerinaze treatment.

Desloratadine

No clinically relevant interactions or changes in desloratadine plasma concentrations were observed inclinical 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 notinhibit 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 bloodpressure.

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

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

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 α-methyldopa, mecamylamine,reserpine, veratrum alkaloids, and guanethidine.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of thecombination of desloratadine and pseudoephedrine sulphate in pregnant women. Animal studies donot indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Asa precautionary measure, it is preferable to avoid the use of Aerinaze during pregnancy.

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

There are no data available on male and female fertility.

Aerinaze has no or negligible influence on the ability to drive and use machines. Patients should beinformed that most people do not experience drowsiness. Nevertheless, as there is individual variation inresponse to all medicinal products, it is recommended that patients are advised not to engage in activitiesrequiring mental alertness, such as driving a car or using machines, until they have established their ownresponse to the medicinal product.

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 %).

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 notknown (cannot be estimated from the available data).

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

System Organ Class Frequency Adverse reactions seen with Aerinaze

Metabolism and nutrition Common Decreased appetitedisorders

Uncommon Thirst, glycosuria, hyperglycaemia

Psychiatric disorders Common Insomnia, somnolence, sleep disorder,nervousness

Uncommon Agitation, anxiety, irritability

Nervous system disorders Common Dizziness, psychomotor hyperactivity

Uncommon Hyperkinesia, confusional state

Eye disorders Uncommon Vision blurred, dry eye

Cardiac disorders Common Tachycardia

Uncommon Palpitation, supraventricular extrasystoles

Respiratory, thoracic and Common Pharyngitismediastinal disorders

Uncommon Rhinitis, sinusitis, epistaxis, nasal discomfort,rhinorrhea, dry throat, hyposmia

Gastrointestinal disorders Common Constipation

Uncommon Dyspepsia, nausea, abdominal pain,gastroenteritis, abnormal faeces

Skin and subcutaneous Uncommon Pruritustissue disorders

Renal and urinary disorders Uncommon Dysuria, micturition disorder

General disorders and Common Headache, fatigue, dry mouthadministration siteconditions Uncommon Chills, flushing, hot flush

Investigations Uncommon Hepatic enzymes increased

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

System Organ Class Frequency Adverse reactions

Immune system disorders Very rare Hypersensitivity (such as anaphylaxis,angioedema, dyspnoea, pruritus, rash, andurticaria)

Metabolism and nutrition Not known Increased appetitedisorders

Psychiatric disorders Very rare Hallucination

Not known Abnormal behaviour, aggression, depressedmood

Nervous system disorders Very rare Convulsion

Cardiac disorders Not known QT prolongation

Gastrointestinal disorders Very rare Vomiting, diarrhoea

Hepatobiliary disorders Very rare Hepatitis

Musculoskeletal and Very rare Myalgiaconnective tissue disorders

Investigations Very rare Blood bilirubin increased

Not known Weight increased

Other adverse reactions reported for pseudoephedrine-containing products during the post-marketingperiod are listed hereunder.

System Organ Class Frequency Adverse reactions

Nervous system disorders Not known Posterior reversible encephalopathy syndrome(PRES) (see section 4.4)

Reversible cerebral vasoconstriction syndrome(RCVS) (see section 4.4)

Eye disorders Not known Ischaemic optic neuropathy

Gastrointestinal disorders Not known Ischaemic colitis

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms of overdose are mostly of a sympathomimetic nature. Symptoms may vary from CNSdepression (sedation, apnoea, diminished mental alertness, cyanosis, coma, cardiovascular collapse) to

CNS stimulation (insomnia, hallucination, tremors, convulsions) with possible fatal outcome. Othersymptoms 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 andhypertension or hypotension. CNS stimulation is particularly likely in children, as are atropine-likesymptoms (dry mouth, fixed and dilated pupils, flushing, hyperthermia, and gastrointestinalsymptoms). Some patients may present a toxic psychosis with delusions and hallucinations.

In the event of overdose, symptomatic and supportive treatment immediately should be started andmaintained it for as long as necessary. Adsorption of active substance remaining in the stomach maybe attempted by administration of active charcoal suspended in water. Gastric lavage with physiologicsaline solution may be performed, particularly in children. In adults, tap water can be used. As muchas possible of the amount administered should be removed before the next instillation. Desloratadine isnot removed by haemodialysis and it is not known if it is eliminated by peritoneal dialysis. Afteremergency 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 agentand tachycardia with a beta-blocking agent. Short acting barbiturates, diazepam or paraldehyde maybe administered to control seizures. Hyperpyrexia, especially in children, may require treatment withtepid water sponge baths or hypothermia blanket. Apnoea is treated with respiratory assistance.

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

R01BA52.

Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H1-receptorantagonist 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 inhibitingthe release of proinflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mastcells/basophils, as well as inhibition of the expression of the adhesion molecule P-selectin onendothelial cells.

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

Pseudoephedrine sulphate (d-isoephedrine sulphate) is a sympathomimetic agent with mostly α-mimetic activity in comparison with the β-activity. Pseudoephedrine sulphate provides a nasaldecongestant effect after oral administration due to its vasoconstrictive action. It has an indirectsympathomimetic effect due primarily to the release of adrenergic mediators from the post-ganglionicnerve endings.

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

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

The clinical efficacy and safety of Aerinaze tablets was evaluated in two, 2-week multicentre,randomised parallel group clinical trials involving 1,248 patients 12 to 78 years of age with seasonalallergic 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 significantlygreater than pseudoephedrine sulphate alone over the 2-week treatment period. In addition, thedecongestant efficacy of Aerinaze tablets, as measured by nasal stuffiness/congestion, wassignificantly greater than desloratadine alone over the 2-week treatment period.

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

- Desloratadine and Pseudoephedrine sulphate:

In a single dose pharmacokinetic study with Aerinaze, plasma concentration of desloratadine can bedetected 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 plasmaconcentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 1.09 ng/mland 31.6 ng*hr/ml, respectively, were observed. For pseudoephedrine sulphate, the mean Tmax occurredat 6-7 hours post dose and mean peak plasma concentrations (Cmax and AUC) of approximately263 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 is27.4 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-stateconditions were reached on day 10 for desloratadine, 3-hydroxydesloratadine and pseudoephedrinesulphate. For desloratadine, mean steady state peak plasma concentrations (Cmax and AUC (0-12 h)) ofapproximately 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 and4,658 ng*hr/ml were observed.

- Desloratadine

In a series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration ofdesloratadine. The prevalence of this poor metaboliser phenotype was greater among Black adults than

Caucasian adults (18 % vs. 2 %) however the safety profile of these subjects was not different fromthat of the general population. In a multiple-dose pharmacokinetic study conducted with the tabletformulation in healthy adult subjects, four subjects were found to be poor metabolisers ofdesloratadine. These subjects had a Cmax concentration about 3-fold higher at approximately 7 hourswith a terminal phase half-life of approximately 89 hours.

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

- Pseudoephedrine sulphate

A component interaction study demonstrated that the exposure (Cmax and AUC) of pseudoephedrinesulphate following administration of pseudoephedrine sulphate alone was bioequivalent topseudoephedrine sulphate exposure following administration of the Aerinaze tablet. Thereforeabsorption of pseudoephedrine sulphate was not affected by the Aerinaze formulation.

Pseudoephedrine sulphate is presumed to cross the placenta and the haematoencephalic barrier.

The active substance is excreted in breast milk of breast-feeding women.

Its elimination half-life in humans, at an approximate urinary pH of 6, ranges from 5 to 8 hours. Theactive substance and its metabolite are excreted in urine; 55-75 % of the administered dose is excretedunchanged. The rate of excretion is accelerated and the duration of action decreased in acidic urine(pH5). In case of alkalinisation of the urine, a partial resorption takes place.

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

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

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 individualcomponents, and observed effects were generally related to the pseudoephedrine sulphate component.

During reproductive toxicity studies, the combination of loratadine/pseudoephedrine sulphate was notteratogenic when administered orally to rats at doses up to 150 mg/kg/day and rabbits at doses up to120 mg/kg/day.

Blue, immediate-release layermaize starchmicrocrystalline celluloseedetate disodiumcitric acidstearic acidcolorant (Indigo carmine E132 Aluminium lake).

White, sustained-release layerhypromellose 2208microcrystalline cellulosepovidone K30silicon dioxidemagnesium stearate.

Not applicable.

2 years.

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

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

The blister consists of clear polychlorotrifluorethylene/polyvinyl chloride (PCTFE/PVC) film, sealedwith 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.

No special requirements for disposal.

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

N.V. Organon

Kloosterstraat 65349 AB Oss

The Netherlands

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

Date of first authorisation: 30 July 2007

Date of latest renewal: 22 May 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.