RELONCHEM HAYFEVER AND ALLERGY 10 MG TABLETS PL 20395/0088

UKPAR

TABLE OF CONTENTS

Lay Summary Page 2

Scientific discussion Page 3

Steps taken for assessment Page 11

Steps taken after authorisation – summary Page 12

Summary of Product Characteristics Page 13

Patient Information Leaflet Page 17

Labelling Page 19

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RELONCHEM HAYFEVER AND ALLERGY 10 MG TABLETS PL 20395/0088

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency granted Relonchem Limited, a Marketing Authorisation for the medicinal product RelonChem Hayfever and Allergy 10 mg Tablets (PL 20395/0088) on 3 April 2012. The product is a general sales list (GSL) medicine and is available to the general public without prescription.

RelonChem Hayfever and Allergy 10 mg Tablets contains the active ingredient, loratadine and belongs to a group of medicines called antihistamines. These medicines act to relieve the symptoms of allergies. It can be used to relieve the symptoms of sneezing, runny and itchy nose and eye irritation and other allergies such as pet and dust allergies.

It can also be used to treat raised symptoms of urticaria which is often known as hives and nettle rash.

No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking RelonChem Hayfever and Allergy 10 mg Tablets (PL 20395/0088) outweigh the risks; hence a Marketing Authorisation has been granted.

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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction Page 4

Pharmaceutical assessment Page 5

Non-Clinical assessment Page 8

Clinical assessment Page 9

Overall conclusions and risk benefit assessment Page 10

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 3 - INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted Relonchem Limited, a Marketing Authorisation for the medicinal product, RelonChem Hayfever and Allergy 10 mg Tablets (PL 20395/0088), on 3 April 2012. The product is a general sales list (GSL) medicine and is available to the general public without prescription.

This is a simple, abridged, ‘informed consent’ application submitted according to Article 10c of EC Directive 2001/83 (as amended), cross-referencing the Marketing Authorisation for Loratidine 10 mg Tablets (PL 17743/0006) authorised to Medis-Danmark A/S authorised on 22 August 2002; the licence subsequently underwent a Change of Ownership on 27 March 2009 and is currently authorised to Relonchem Limited. The reference product has been authorised in the EEA for over 10 years.

No new data were submitted nor was it necessary for this simple application as the data are identical to that of the previously granted cross-reference product. As the cross-reference product was granted prior to the introduction of current legislation, no Public Assessment Report (PAR) has been generated for it.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 4 - PHARMACEUTICAL ASSESSMENT

LICENCE NO: PL 20395/0088 PROPRIETARY NAME: RelonChem Hayfever and Allergy 10 mg Tablets ACTIVE: Loratadine COMPANY NAME: Relonchem Limited E.C. ARTICLE: Article 10c of Directive 2001/83/EC LEGAL STATUS: GSL

1. INTRODUCTION This is a simple, informed consent application for RelonChem Hayfever and Allergy 10 mg Tablets under Article 10c of Directive 2001/83/EC. The proposed Marketing Authorisation Holder is Relonchem Limited, 27 Old Gloucester Street, London, WC1 3XX, UK.

The application cross-refers to Loratadine 10 mg Tablets (PL 17734/0006) authorised to Medis- Danmark A/S since 22 August 2002. The licence subsequently underwent a Change of Ownership on 27 March 2009 and is licenced to Relonchem Limited (PL 20395/0072). The current application is considered valid.

2. MARKETING AUTHORISATION APPLICATION FORM 2.1 Name The proposed name of the product is RelonChem Hayfeverr and Allergy 10 mg Tablets. The product has been named in line with current requirements.

2.2 Strength, pharmaceutical form, route of administration, container and pack sizes Each tablet contains 10 mg loratadine.The medicinal product is licensed for marketed in blister strips composed of aluminium and polyvinylchloride (PVC) which are packed with the Patient Information Leaflet (PIL) into cardboard outer cartons, in pack sizes of 7, 10 and 14 tablets. The container closures system and pack sizes are identical to those for the reference product.

The approved shelf-life (3 years) is satisfactory. There are no special storage conditions for this product which is identical to the details registered for the cross-reference product.

2.3 Legal status This product is a general sales list (GSL) medicine.

2.4 Marketing authorisation holder/Contact Persons/Company The proposed Marketing Authorisation Holder is Relonchem Limited, 27 Old Gloucester Street, London, WC1 3XX, UK.

The Quality Person (QP) responsible for pharmacovigilance is stated and their curriculum vita has been included.

2.5 Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference product and evidence of GMP compliance has been provided.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 5 - 2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the cross-reference product.

2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the cross-reference product and the maximum batch size is stated.

2.8 Finished product/shelf-life specification The proposed finished product specification is in-line with the details registered for the cross- reference products.

2.9 Drug substance specification The proposed drug substance specification is consistent with the details registered for the cross- reference products.

2.10 TSE Compliance With the exception of lactose monohydrate, no materials of animal or human origin are included in the product. This is consistent with the cross-reference product.

A declaration has been provided that lactose used in lactose monohydrate is sourced from healthy animals under the same conditions as that for human consumption. No other material used in the manufacturing of this medicinal product is derived from animal or human origin or sourced from genticially modified organisms. This is consistent with the cross-reference product.

3. EXPERT REPORT A satisfactory quality overall summary has been prepared by an appropriately qualified expert. The CV of the expert was provided.

4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product name. The licenced product is a white, round, flat tablet with a scoreline and is identical to that of the cross-reference product.

5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The approved SmPC is consistent with the details registered for the cross-reference product.

6. PATIENT INFORMATION LEAFLET (PIL)/CARTON PIL The PIL is satisfactory and in line with the approved SmPC and has been prepared in the user- tested format.

The applicant has submitted results of PIL user testing. The results indicate that the PIL is well- structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that is contains.

Labelling Mock-up of the labelling has been provided and are satisfactory. The approved artwork is comparable to the artwork registered for the cross-reference product and complies with statutory requirements.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 6 - 7. CONCLUSIONS The data submitted with is application is acceptable. A Marketing Authorisation was, therefore, granted.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 7 - NON-CLINICAL ASSESSMENT

This is a simple, abridged, ‘informed consent’ application made under Article 10c of EC Directive 2001/83 (as amended). This application is identical to the reference product, Loratidine 10 mg Tablets (PL 20395/0072) authorised to Relonchem Ltd on 27 March 2009 in the UK, therefore, no new non-clinical data has been supplied with this application and none are required. A non-clinical overview report has been written by a suitably qualified person and is satisfactory. The CV of the non-clinical expert has been supplied.

The marketing authorisation holder has provided adequate justification for not submitting an Environment Risk Assessment (ERA). As this application is identical to already authorised reference products, it is not expected that the environmental exposure to loratidine will increase following the marketing approval of the proposed product.

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CLINICAL ASSESSMENT

This is a simple, abridged, ‘informed consent’ application made under Article 10c of EC Directive 2001/83 (as amended), cross-referring to Loratidine 10 mg Tablets (PL 20395/0072) authorised by Relonchem Ltd since 27 March 2009 in the UK.

No new clinical data has been supplied with this application and none are required. A clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the clinical expert has been supplied.

The marketing authorisation holder (MAH) has provided adequate justification for not submitting a Risk Management Plan (RMP). As this application is identical to already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, a risk minimisation system is not considered necessary. The reference products have been in use for many years and the safety profile of the active is well-established.

The MAH has provided a suitable pharmacovigilance system that fulfils the requirements and provides adequate evidence that the MAH has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 9 - OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY The data for this application is consistent with those previously assessed for the cross-reference product and as such has been judged to be satisfactory.

NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type.

EFFICACY This application is considered identical to the previously granted licence for Loratidine 10 mg Tablets (PL 20395/0072) initially authorised to Medis-Danmark A/S on 22 August 2002, the licence subsequently underwent a Change of Ownership and is currently authorised to Relonchem Limited on 27 March 2009. The current application is considered valid.

No new or unexpected safety concerns arise from this application.

PRODUCT LITERATURE The approved SmPC, PIL and labelling are satisfactory, and consistent with those for the cross- reference product.

The applicant has submitted results of PIL user testing. The results indicate that the PIL is well- structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that is contains.

Mock-ups of the labeling have been provided and are satisfactory. The labeling artwork complies with statutory requirements.

RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The applicant’s product is identical to the cross-reference product. The benefit; risk ratio is, therefore, considered to be positive.

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STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 8 July 2011.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 12 July 2011.

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 17 October 2011 and 13 March 2012.

4 The applicant responded to the MHRA’s requests, providing further information on 14 February 2012 and 14 March 2012.

5 The application was determined on 3 April 2012.

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STEPS TAKEN AFTER ASSESSMENT

Date Application Scope Outcome submitted type

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SUMMARY OF PRODUCT CHARACTERISTICS The UK Summary of Product Characteristics (SmPC) for Relonchem Hayfever and Allergy 10 mg Tablets (PL 20395/0088) is as follows:

1 NAME OF THE MEDICINAL PRODUCT RelonChem Hayfever and Allergy 10mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 10mg loratadine. For excipients see 6.1.

3 PHARMACEUTICAL FORM Tablet. Appearance: white, round, flat tablets with a scoreline

4 CLINICAL PARTICULARS 4.1 Therapeutic indications Relonchem Hayfever and Allergy 10mg tablets are indicated for the symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria.

4.2 Posology and method of administration Adults, including the elderly, and children 12 years of age and over: One 10 mg tablet once daily Children 2 to 12 years of age with: Body weight more than 30 kg: 10 mg once daily (one tablet) Body weight 30 kg or less: 5 ml (5 mg) of the syrup once daily. The 10 mg strength tablet is not appropriate in children with a body weight less than 30 kg. Efficacy and safety of Loratadine 10 mg Tablets in children under 2 years of age has not been established in this age group. Patient with severe liver impairment should be administered a lower intial dose because they may have reduced clearance of loratadine. An initial dose of 10 mg every other day is recommended for adults and children weighing more than 30 kg, and for children weighing 30 kg or less, 5 ml (5 mg) every other day is recommended. No dosage adjustments are required in the elderly or in patients with renal insufficiency

4.3 Contraindications Relonchem Hayfever and Allergy 10mg tablets are contraindicated in patients who are hypersensitive to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use Relonchem Hayfever and Allergy 10mg tablets should be administered with caution in patients with severe liver impairment (see 4.2)

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

The administration of Relonchem Hayfever and Allergy 10mg tablets should be discontinued at least 48 hours before skin tests since antihistamines may prevent or reduce otherwise positive reactions to dermal reactivity index.

4.5 Interaction with other medicinal products and other forms of interaction When administered concomitantly with alcohol, Relonchem Hayfever and Allergy 10mg tablet has no potentiating effects as measured by psychomotor performance studies.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 13 - Due to the wide therapeutic index of loratadine no clinically relevant interactions are expected and none were observed in the conducted clinical trials (see 5.2).

Loratadine is metabolised by hepatic CYP3A4 and CYP2D6 isoenzymes. 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).

4.6 Fertility, pregnancy and lactation Loratadine was not teratogenic in animal studies. The safe use of loratadine during pregnancy has not been established. The use of Relonchem Hayfever and Allergy 10mg tablets during pregnancy is therefore not recommended.

Loratadine is excreted in breast milk, therefore the use of loratadine is not recommended in breast-feeding women.

4.7 Effects on ability to drive and use machines In clinical trials that assessed driving ability, no impairment occurred in patients receiving loratadine. However, patients should be informed that very rarely some people rarely experience drowsiness, which may affect their ability to drive or use machines.

4.8 Undesirable effects In clinical trials in a paediatric population, children aged 2 through 12 years, common adverse reactions reported in excess of placebo were headache (2.7%), nervousness (2.3%), and fatigue (1%).

In clinical trials involving adults and adolescents in a range of indications including AR and CIU, at the recommended dose of 10 mg daily, adverse reactions with loratadine were reported in 2% of patients in excess of those treated with placebo. The most frequent adverse reactions reported in excess of placebo were somnolence (1.2%), headache (0.6%), increased appetite (0.5%) and insomnia (0.1%). Other adverse reactions reported very rarely during post marketing period are listed in the following table.

Immune disorders Anaphylaxis

Nervous System disorders Dizziness

Cardiac disorders Tachycardia, palpitation

Gastrointestinal disorders Nausea, dry mouth, gastritis

Hepato-bilary disorders Abnormal hepatic function

Skin and subcutaneous Rash, alopecia tissue disorders General disorders and Fatigue administration site Conditions

4.9 Overdose Overdosage with loratadine increased the occurrence of anticholinergic symptoms. Somnolence, tachycardia and headache have been reported with overdoses.

In the event of overdose, general symptomatic and supportive measures are to be instituted and maintained for as long as necessary. Administration of activated charcoal as a slurry with water may be attempted. Gastric lavage may be considered. Loratadine is not removed by haemodialysis and it is not known if loratadine is removed by peritoneal dialysis. Medical monitoring of the patient is to be continued after emergency treatment.

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5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R 06 AX 13 Loratadine the active ingredient in Relonchem Hayfever and Allergy 10mg tablets is a tricyclic antihistamine with selective, peripheral H1-receptors activity.

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 of electrocardiograms.

Loratadine has no significant H2-receptor activity. It does not inhibit noradrenaline uptake and has practically no influence on cardiovascular function or on intrinsic cardiac pacemaker activity.

5.2 Pharmacokinetic properties After oral administration, loratadine is rapidly and well and undergoes an extensive first pass metabolism, mainly by CYP 3A4 and CYP 2D6. The major metabolite – desloratadine (DL) – is pharmacologically active and responsible for a large part of clinical effect. Loratadine and DL achieve maximum plasma concentrations (Tmax) between 1 – 1.5 hours and 1.5 – 3.7 hours after administration, respectively.

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 electrocardiography).

Loratadine is highly bound (97% to 99%) and its active metabolite moderately bound (73% to 76%) to plasma proteins.

In healthy subjects, plasma distribution half-lives for loratadine and its active metabolite are approximately 1 and 2 hours, respectively. The mean elimination half-lives in healthy adult subjects were 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the major active metabolite.

Approximately 40% of the dose is excreted in the urine and 42% in the faeces over a 10-day period (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 bioavailability parameters of loratadine and of the active metabolite are dose proportional. The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy adult volunteers and healthy geriatric volunteers.

Concomitant ingestion of food can delay slightly the absorption of loratadine but without influencing the clinical effect.

In patients with chronic renal impairment, both the AUC and the peak plasma levels (Cmax) increased for loratadine and its metabolite as compared with the AUCs and Cmax of patients with normal renal function. The mean elimination half-lives of loratadine and its metabolite were not significantly different from that observed in normal subjects. Haemodialysis does not have an effect on the pharmacokinetic profile of loratadine or its active metabolite in subjects with chronic renal impairment.

In patients with chronic alcoholic liver disease, the AUC and 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.

Loratadine and its active metabolite are excreted in the breast milk of lactating women.

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 15 - 5.3 Preclinical safety data Preclinical data reveal no special hazard based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In reproductive toxicity studies, 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.

No evidence of mucous membrane irritation was observed after daily administration of up to 12 tablets (120 mg) of oral lyophilisates into the hamster cheek pouch for five days.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Microcrystalline cellulose Maize starch Magnesium stearate

6.2 Incompatibilities Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage None

6.5 Nature and contents of container Packages with 7, 10, 14 tablets in blister packs (PVC/aluminium)

6.6 Special precautions for disposal No special instructions

7 MARKETING AUTHORISATION HOLDER Relonchem Limited 27 Old Gloucester Street London WC1 3XX United Kingdom

8 MARKETING AUTHORISATION NUMBER(S) PL 20395/0088

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 03/04/2012

10 DATE OF REVISION OF THE TEXT 03/04/2012

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LABELLING

Blister:

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 19 - Please note that no carton mock ups were provided for the 10 tablet pack. In accordance with medicines legislation, the 10 tablet pack shall not be marketed in the UK until approval of the label mock-ups has been obtained.

Cartons:

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 20 -

MHRA-UKPAR – RelonChem Hayfever and Allergy 10 mg Tablet PL 20395/0088 - 21 - Cartons with Braille:

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