Clarinase Repetabs is indicated for the symptomatic treatment of seasonal allergic rhinitis when accompanied by nasal congestion in adults and children 12 years of age and over.

Posology Adults and children 12 years of age and over: One Clarinase Repetabs prolonged-release tablet twice daily with a glass of water. 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 may diminish. After improvement of the congestive condition of the mucosae of the upper airway, treatment may be maintained with loratadine alone, if necessary. Paediatric population The safety and efficacy of Clarinase Repetabs in children below the age of 12 years have not been established. No data are available. Clarinase Repetabs are not recommended for use in children below the age of 12 years. Elderly patients The combination product should not be administered to patients above 60 years of age. Patients 60 years or older are more likely to experience adverse reactions to sympathomimetic medications (see section 4.4). Patients with renal or hepatic impairment The combination product should not be used in patients with impaired renal or hepatic function (see section 4.4). Method of administration Oral use. The prolonged-release tablet must be swallowed entirely (without crushing, breaking or chewing it). The prolonged-release tablet may be taken without regard to mealtime.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to adrenergic medicinal products. As Clarinase Repetabs contains pseudoephedrine, it is also contraindicated in patients who are receiving irreversible monoamine oxidase (MAO) inhibitor therapy or during the 2 weeks following the stopping of such treatment, and in patients with: - narrow-angle glaucoma, - urinary retention, - cardiovascular diseases such as ischaemic heart disease, tachyarrhythmia and severe hypertension, - hyperthyroidism, - a history of haemorhagic stroke or with risk factors which could increase the risk of haemorhagic stroke. This is due to the alpha-mimetic activity of pseudoephedrine, in combination with other vasoconstrictors such as bromocripitine, pergolide, lisuride, cabergoline, ergotamine, dihydroergotamine or any other decongestant medication used as a nasal decongestant, either by oral route or by nasal route (such as phenylpropanolamine, phenylephrine, ephedrine, oxymetazoline, naphazoline).

Do not exceed the recommended dosage and the duration of treatment (see section 4.2). Patients of 60 years or older are more likely to experience adverse reactions to sympathomimetic medications. The safety and efficacy of the combination have not been established in this population, and there are insufficient data to give adequate dose recommendations. The combination product should not be used in patients above 60 years of age. Renal or hepatic impairment: The safety and efficacy of the combination have not been established in patients with impaired renal or hepatic function, and there are insufficient data to give adequate dose recommendations. The combination product should not be used in patients with impaired renal or hepatic function. Patients should be informed that the treatment should be discontinued in case of hypertension, tachycardia, palpitations or cardiac arrhythmias, nausea or any other neurologic sign (such as headache or increased headache). 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 children, the elderly, or in cases of overdose (see section 4.9). Acute generalized exanthematous pustulosis (AGEP), a form of severe skin reaction, may occur with pseudoephedrine-containing products in isolated cases. If signs and symptoms such as fever, erythema, or small (generalized) pustules are observed, patients should discontinue to use the drug and consult their physician. Caution should be exercised in patients receiving digitalis, those with cardiac arrhythmias, hypertension, a history of myocardial infarction, diabetes mellitus, bladder neck obstruction, or positive anamnesis of bronchospasm. Use with caution in patients with stenosing peptic ulcer, pyloroduodenal obstruction and obstruction of the vesical cervix. Oral administration of pseudoephedrine at the recommended dose can cause other sympathomimetic effects, such as increased blood pressure, tachycardia or manifestations of central nervous system excitation. Concomitant administration of sympathomimetics and reversible MAO inhibitors (such as linezolide [non-selective] and moclobemide [MAO-A selective] are not recommended. Caution should also be exercised in patients being treated with other sympathomimetics, including decongestants, anorexogenics or amphetamine-type psychostimulants, antihypertensive agents, tricyclic antidepressants and other antihistamines. Caution should be exercised in patients who are currently being treated with ergot alkaloid vasoconstrictors. As with other CNS stimulants, 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. 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. Athletes should be informed that treatment with pseudoephedrine could lead to positive dope-tests. This medicinal product contains lactose and sucrose; thus patients with rare hereditary problems of fructose, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase isomaltase insufficiency should not take this medicine. The administration of Clarinase Repetabs should be discontinued at least 48 hours before skin tests since antihistamines may prevent or reduce otherwise positive reactions to dermal reactivity index

When administered concomitantly with alcohol, loratadine has no potentiating effects as measured by psychomotor performance studies. CYP3A4 and CYP2D6 inhibitors have been shown to increase loratadine and desloratadine exposure. However, due to the wide therapeutic index of loratadine, no clinically relevant interactions are expected and none were observed with co-administration of erythromycin, ketoconazole and cimetidine in the conducted clinical trials (see section 5.2). Concurrent administration of monoamine oxidase inhibitors (reversible or irreversible) and sympathomimetic medicines can cause critical hypertension reactions. Sympathomimetic medicines may reduce the effect of antihypertensive medicines. The following combinations are not recommended: Bromocriptine, cabergoline, lisuride, pergolide: risk of vasoconstriction and increase in blood pressure. Dihydroergotamine, ergotamine, methylergometrine: risk of vasoconstriction and increase in blood pressure. Reversible and irreversible MAO inhibitor(s): risk of vasoconstriction and increase in blood pressure. Other vasoconstrictors used as nasal decongestant, by oral or nasal route, (such as phenylpropanolamine, phenylephrine, ephedrine, oxymetazoline, naphazoline): risk of vasoconstriction. Antacids increase the rate of pseudoephedrine sulphate absorption, kaolin decreases it. Paediatric population Interaction studies have only been performed in adults

Pregnancy Neither loratadine nor the combination of loratadine and pseudoephedrine were teratogenic in animal studies. The safe use of Clarinase Repetabs during pregnancy has not been established; however experience from a large number of exposed pregnancies in humans does not reveal any increase in the frequency of malformations as compared to the incidence in the general population. Because animal reproduction studies are not always predictive of human response, and due to the vasoconstrictive properties of pseudoephedrine, Clarinase Repetabs should not be used during pregnancy. Breast-feeding Physico-chemical data suggest excretion of loratadine and pseudoephedrine/metabolites in human milk. Decreased milk production in nursing mothers has been reported with pseudoephedrine. A risk to the newborns/infants cannot be excluded. Therefore Clarinase Repetabs should not be used during breast-feeding. Fertility There are no data available on male and female fertility.

Clarinase Repetabs has no or negligible influence on the ability to drive and use machines. In clinical trials that assessed driving ability, no impairment occurred in patients receiving loratadine. However, some people very rarely experience drowsiness, which may affect their ability to drive or use machines. It is not expected that pseudoephedrine sulphate impairs psychomotor performance.

Tabulated list of adverse reactions The following adverse reactions reported during clinical trials in excess of placebo for 5 mg/120 mg prolonged-release tablets are listed in the following table by System Organ Class. Frequencies are defined as very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000); and not known (cannot be estimated from the available data). System Organ Class Frequency Category Adverse Reactions Metabolism and nutrition disorders Common Thirst Psychiatric disorders Common Nervousness, somnolence, depression, agitation, anorexia Very Common Insomnia Nervous system disorders Uncommon Confusion, tremor, increased sweating, hot flushes, taste perversion Common Dizziness, Eye disorders Uncommon Abnormal lacrimation Ear and labyrinth disorders Uncommon Tinnitus Cardiac disorders Uncommon: Palpitation Common Tachycardia Respiratory, thoracic and mediastinal disorders Uncommon: Epistaxis Common Pharyngitis, rhinitis Gastrointestinal disorders Common Constipation, nausea, dry mouth Skin and subcutaneous tissue disorders Uncommon Pruritus Renal and urinary disorders Uncommon Micturition frequency and disorder General disorders and administration site conditions Common Headache, fatigue Other adverse reactions reported during the post-marketing period are listed in the following table. System Organ Class Frequency Category Adverse Reactions Immune system disorders Very rare Hypersensitivity reactions (such as anaphylaxis, rash, urticaria, and angioedema) Nervous system disorders Very rare Vertigo, convulsions Cardiac disorders Very rare Cardiac arrhythmias Vascular disorders Very rare Hypertension Respiratory, thoracic and mediastinal disorders Very rare Cough, bronchospasm Hepatobiliary disorders Very rare Abnormal hepatic function Skin and subcutaneous tissue disorders Very rare Alopecia Renal and urinary disorders Very rare Urinary retention Other adverse reactions that were only reported for loratadine in clinical trials and during the postmarketing period include increased appetite, rash and gastritis. From post-marketing experience, isolated cases of acute generalized exanthematous pustulosis (AGEP), a form of severe skin reaction, 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. To report any side effect(s) National Pharmacovigilance and Drug Safety Center (NPC). Fax: + 966 - 11 - 205 - 7662. Call NPC at +966 - 11 - 2038222, Ext.: 2317 - 2356 - 2353 - 2354 - 2334 - 2340. Toll - free: 8002490000. E - mail: npc.drug@sfda.gov.sa. Website: www.sfda.gov.sa/npc

Symptoms of overdose Symptoms of overdose are mostly of a sympathomimetic nature, except for slight sedation that can be caused by loratadine at doses many times higher than the recommended dose. 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 with a toxic psychosis with delusions and hallucinations. Management of overdose In the event of overdosage, start symptomatic and supportive treatment immediately and maintain 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. Perform gastric lavage with physiologic saline solution, particularly in children. In adults, tap water can be used. Remove as much as possible of the amount administered before the next instillation. Loratadine is not removed by haemodialysis and it is not known if loratadine is eliminated by peritoneal dialysis. After emergency treatment, continue to monitor the patient medically. Treatment of the pseudoephedrine overdosage is symptomatic and supportive. Stimulants (analeptics) must not be used. Hypertension can be controlled with an alpha-blocking agent and tachycardia with a beta-blocking agent. Short acting barbituates, 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

Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06A X13. Pharmacotherapeutic group: Nasal decongestants for systemic use group, ATC code: R01BA52. Mechanism of action Loratadine is a tricyclic antihistamine with selective, peripheral H1-receptor activity. Pseudoephedrine sulphate (d-isoephedrine sulphate) is a sympathomimetic agent with mostly αmimetic activity in comparison with the β-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. Pharmacodynamic effects The pharmacodynamics of Clarinase Repetabs tablets are directly related to that of its components. Loratadine has no clinically significant sedative or anticholinergic properties in the majority of the population and when used at the recommended dosage. During long-term treatment there were no clinically significant changes in vital signs, laboratory test values, physical examinations or electrocardiograms. Loratadine has no significant H2-receptor activity. It does not inhibit norepinephrine uptake and has practically no influence on cardiovascular function or on intrinsic cardiac pacemaker activity.

• Loratadine Absorption Loratadine is rapidly and well-absorbed. Concomitant ingestion of food can delay slightly the absorption of loratadine but without influencing the clinical effect. The bioavailability of loratadine and of the active metabolite are dose proportional. Increase in plasma concentrations of loratadine has been reported after concomitant use with ketoconazole, erythromycin, and cimetidine in controlled trials, but without clinically significant changes (including electrocardiographic). Distribution Loratadine is highly bound (97 % to 99 %) and its active major metabolite desloratadine (DL) moderately bound (73 % to 76 %) to plasma proteins. In healthy subjects, plasma distribution half-lives of loratadine and its active metabolite are approximately 1 and 2 hours, respectively. Biotransformation After oral administration, loratadine undergoes an extensive first pass metabolism, mainly by CYP3A4 and CYP2D6. The major metabolite-desloratadine (DL) is pharmacologically active and responsible for a large part of the clinical effect. Loratadine and DL achieve maximum plasma concentrations (Tmax) between 1– 1.5 hours and 1.5–3.7 hours after administration, respectively. Elimination Approximately 40 % of the dose is excreted in the urine and 42 % in the faeces over a 10 day period and that, mainly in the form of conjugated metabolites. Approximately 27 % of the dose is eliminated in the urine during the first 24 hours. Less than 1 % of the active substance is excreted unchanged in active form, as loratadine or DL. The mean elimination half-lives are 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the active metabolite. Renal impairment In patients with chronic renal impairment, both the area under the curve (AUC) and peak plasma levels (Cmax) increased for loratadine and its active metabolite as compared to the AUCs and peak plasma levels (Cmax) of patients with normal renal function. The mean elimination half-lives of loratadine and its active metabolite were not significantly different from those observed in normal subjects. Haemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite in subjects with chronic renal impairment. Hepatic impairment In patients with chronic alcoholic liver disease, the AUC and peak plasma levels (Cmax) of loratadine were double while the pharmacokinetic profile of the active metabolite was not significantly changed from that in patients with normal liver function. The elimination half-lives for loratadine and its metabolite were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease. Elderly The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy adult volunteers and in healthy geriatric volunteers. • Pseudoephedrine sulphate Absorption After oral administration, pseudoephedrine sulphate is rapidly and completely absorbed. Onset of action occurs within 30 minutes and a dose of 60 mg has a decongestive action lasting for 4 to 6 hours. Food may increase the amount of loratadine absorbed, but without clinically significant results. This is not observed with pseudoephedrine. Distribution Pseudoephedrine is presumed to cross the placenta and the haematoencephalic barrier. The active substance is excreted in breast milk of lactating women. Biotransformation Pseudoephedrine sulphate undergoes incomplete hepatic metabolism by N-demethylation to an inactive metabolite. Elimination Its elimination half-life in humans, at an approximate urinary pH of 6, ranges from 5 to 8 hours. The active substance and its metabolite are excreted in urine, 55-75 % of the administered dose is excreted unchanged. The rate of excretion is accelerated and the duration of action decreased in acidic urine (pH5). In case of alkalinization of the urine, a partial resorption takes place.

Non-clinical data for loratadine reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. Toxicity for the combination: In acute and multiple-dose studies, the combination of loratadine/pseudoephedrine sulphate 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 component. In reproductive toxicity studies of loratadine, no teratogenic effects were observed. However, prolonged parturition and reduced viability of offspring were observed in rats at plasma levels (AUC) 10 times higher than those achieved with clinical doses. During reproductive toxicity studies, the combination of loratadine/pseudoephedrine was not teratogenic when administered orally to rats at doses up to 150 mg/kg/day (30 times the proposed clinical dose) and rabbits at doses up to 120 mg/kg/day (24 times the proposed clinical dose).

6.1 List of excipients Core: Lactose monohydrate Maize starch Povidone (E1201) Magnesium stearate Coating: Acacia (E414) Calcium sulphate anhydrous (E516) Calcium sulphate dihydrate (E516) Carnauba wax (E903) Microcrystalline cellulose Oleic acid Colophonium Soap powder Sucrose Talc (E553b) Titanium dioxide (E171) White beeswax (E901) Zein

Not applicable.

2 years

Do not store above 25°C. Store in the original blister packaging in order to protect from moisture. Do not freeze.

Blister strip consisting of a clear, transparent PVC-PCTFE film (PVC in contact with product) and a lidding of aluminium foil with vinyl heat seal coating. The blister strips are enclosed in cartons in pack sizes of 1, 7, 10, 14, 20, 28, 30, 50 and 100 tablets. Not all pack sizes may be marketed

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