MHRA PAR- Cough Nurse Night Time Syrup 1

COUGH NURSE NIGHT TIME SYRUP

(Diphenydramine hydrochloride, pholcodine)

PL 00014/0657

UK PAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment Page 10 Summary of Product Characteristics Page 11 Product Information Leaflet Page 14 Labelling Page 16

MHRA PAR- Cough Nurse Night Time Syrup 2

COUGH NURSE NIGHT TIME SYRUP

PL 00014/0657

LAY SUMMARY The MHRA granted The Boots Company PLC a Marketing Authorisation (licence) for the medicinal product Cough Nurse Night Time Syrup on 29 March 2011. This is a pharmacy only medicine (P) used for the relief of the symptoms of dry, tickly and unproductive coughs. Cough Nurse Night Time Syrup contains the active ingredients diphenhydramine hydrochloride and pholcodine. Diphenhydramine hydrochloride is an antihistamine which dries up a runny nose and aids restful sleep. Pholcodine is a cough suppressant that helps relieve dry or tickly coughs. This medicine also helps relieve a sore throat. This application is a duplicate of a previously granted application for Nirolex Night Time Cough Relief Linctus (PL 00014/0230), which was granted to the Marketing Authorisation Holder The Boots Company PLC. No new or unexpected safety concerns arose from this simple application and it was, therefore, judged that the benefits of taking Cough Nurse Night Time Syrup outweigh the risks; hence a Marketing Authorisation has been granted.

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COUGH NURSE NIGHT TIME SYRUP

PL 00014/0657

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 7

Clinical assessment (including statistical assessment)

Page 8

Overall conclusions and risk benefit assessment Page 9

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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted a Marketing Authorisation for the medicinal product Cough Nurse Night Time Syrup (PL 00014/0657) to The Boots Company PLC on 29 March 2011. This is a pharmacy only medicine (P) used for symptomatic relief of dry, ticklish and unproductive coughs. Cough Nurse Night Time Syrup contains the active ingredients diphenhydramine hydrochloride and pholcodine (ATC code R05X, other cold combination preparations). Diphenhydramine hydrochloride has antihistamine properties with a pronounced sedative action. It undergoes extensive pre-systemic metabolism which results in 50% metabolism of an oral dose. The major route of elimination is in the urine, largely as metabolites with very little unchanged drug present. Pholcodine is a cough suppressant with mild sedative but little analgesic action and is readily absorbed from the gastrointestinal tract. It can relieve local irritation of the respiratory tract for approximately four to five hours. This application was submitted as simple abridged application according to Article 10c (formerly Article 10.1(a)(i)) of Directive 2001/83/EC, cross-referring to Nirolex Night Time Cough Relief Linctus (PL 00014/0230) approved on 12 February 1981 to the Marketing Authorisation Holder The Boots Company PLC. No new data were submitted nor were they necessary for this simple application, as the data are identical to that of the previously granted cross-reference product.

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PHARMACEUTICAL ASSESSMENT LICENCE NO: PL 00014/0657 PROPRIETARY NAME: Cough Nurse Night Time Syrup COMPANY NAME: The Boots Company PLC E.C. ARTICLE: Article 10(c) of Directive 2001/83/EC LEGAL STATUS: P 1 INTRODUCTION This is a simple, informed consent application for Cough Nurse Night Time Syrup submitted under Article 10(c) of Directive 2001/83/EC. The application cross-refers to Nirolex Night Time Cough Relief Linctus (PL 00014/0230), approved on 12 February 1981 to The Boots Company PLC The current application is considered valid. 2 MARKETING AUTHORISATION APPLICATION (MAA) 2.1 Name(s) The proposed name of the product is Cough Nurse Night Time Syrup. The product has been named in line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes The product contains 12.5mg/5ml diphenhydramine hydrochloride and 3.75mg/5ml pholcodine. It is to be stored in the following presentations:

1. 50ml, 100ml, 125ml, 150ml, 200ml or 250ml glass bottles either with a child resistant polypropylene cap without a liner or a roll on pilfer proof cap with a Triseal (LDPE/EPE/LDPE) liner.

2. 50ml, 100ml, 125ml, 150ml, 200ml or 250ml amber glass bottles either with a child

resistant polypropylene cap without a liner or a roll on pilfer proof cap with a Triseal (LDPE/EPE/LDPE) liner.

3. 50ml. 100ml, 125ml, 150ml, 200ml or 250ml amber PET bottle fitted with a child

resistant polypropylene cap and an expanded polyethylene liner. The proposed shelf life is 3 years. The storage conditions are ’Do not store above 25°C.’ The proposed shelf-life and storage conditions are consistent with the details registered for the cross-referenced product. 2.3 Legal status On approval, the product will be available as a pharmacy only medicine (P). 2.4 Marketing Authorisation Holder/Contact Persons/Company The proposed Marketing Authorisation Holder is The Boots Company PLC, 1 Thane Road West, Nottingham, NG2 3AA 2.5 Manufacturers The proposed manufacturing site is consistent with that registered for the reference product and evidence of compliance with current Good Manufacturing Practice has been provided.

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2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the reference product. 2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the reference product and the maximum batch size is stated. 2.8 Finished product/shelf-life specification The proposed finished product specifications are in line with the details registered for the reference product. 2.9 Drug substance specification The proposed drug substance specifications are consistent with the details registered for the cross-reference product. 2.10 TSE Compliance No materials of human or animal origin have been used in the manufacture of this product. This is consistent with the reference product. 2.11 Bioequivalence No bioequivalence data are required to support this informed consent application, as the proposed product is manufactured to the same formula utilising the same process as the reference product Nirolex Night Time Cough Relief Linctus (PL 00014/0230) 3 EXPERT REPORT The applicant has included detailed pharmaceutical expert report, written by an appropriately qualified person. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product name. The appearance of the product is identical to that of the reference product. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The proposed SmPC is consistent with the details registered for the reference product. 6. PATIENT INFORMATION LEAFLET (PIL)/LABELLING PIL The patient information leaflet has been prepared in line with the details registered for the reference products. Container The proposed artwork complies with the relevant statutory requirements. In line with current legislation, the applicant has also included the name of the product in Braille on the outer packaging and has included sufficient space for a standard UK pharmacy dispensing label. 7. CONCLUSIONS The data submitted with this application is acceptable. The grant of a Marketing Authorisation is recommended.

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PRECLINICAL ASSESSMENT

As the application is identical to the reference product, Nirolex Night Time Cough Relief Linctus (PL 00014/0230), no new preclinical data have been supplied with this application and none are required. A preclinical expert report has been written by a suitably qualified person and is satisfactory.

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CLINICAL ASSESSMENT

As the application is identical to the reference product, Nirolex Night Time Cough Relief Linctus (PL 00014/0230), no new clinical data have been supplied with this application and none are required. A clinical expert report has been written by a suitably qualified person and is satisfactory.

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OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

QUALITY The data for this application is consistent with those previously assessed for the reference product and as such have been judged to be satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY The application is identical to the previously granted application for Nirolex Night Time Cough Relief Linctus (PL 00014/0230), granted to The Boots Company PLC on 12 February 1981. SAFETY No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory and consistent with those of the reference product. Colour mock-ups of the labelling have been provided and are satisfactory. The approved labelling artwork complies with statutory requirements. The name of the product in Braille appears on the outer packaging. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The applicant’s product is identical to the reference product. Extensive clinical experience with diphenhydramine hydrochloride and pholcodine is considered to have demonstrated the therapeutic values of the compounds. The benefit/risk is therefore considered to be positive.

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COUGH NURSE NIGHT TIME SYRUP

PL 00014/0657

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation Application on6 January

2005

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 01 December 2006

3 Following assessment of the application the MHRA requested further information on 15 May 2009.

4 The applicant responded to the MHRA’s request, providing further information on 26 August 2009

5 The application was determined on 29 March 2011

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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Cough Nurse Night Time Syrup

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Active ingredient

Diphenhydramine hydrochloride Pholcodine

12.5mg/5ml 3.75mg/5ml

For excipients, see 6.1.

3 PHARMACEUTICAL FORM Oral Syrup. A clear, bright yellow-green syrup.

4 CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS

For the symptomatic relief of dry, ticklish and unproductive coughs.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION Adults and Children over 12 years: 20ml (4 teaspoonfuls) at bedtime. Children under 12 years: Not recommended. Elderly: There is no need for dosage reduction. For oral administration.

4.3 CONTRAINDICATIONS

Hypersensitivity to any of the ingredients, liver disease, ventilatory failure and porphyria.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE Children under 12 years should not be given this medicine. Cough suppressants may cause sputum retention and this may be harmful in patients with chronic bronchitis and bronchiecstasis. This medicine should be used with care in conditions such as closed angle glaucoma, urinary retention, prostatic hypertrophy or pyloroduodenal obstruction. Caution should also be observed in patients with epilepsy and severe cardiovascular disorders. As pholcodine is a sedative, caution is needed in those patients who have airway disease e.g. asthma, chronic obstructive pulmonary disease (COPD) and ventilatory insufficiency, as respiratory depression may occur. Caution is also needed in patients with kidney disease or a history of drug abuse. Warning: May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink. Do not exceed the stated dose. If symptoms persist for longer than 5 days talk to your doctor. Keep all medicines out of the sight and reach of children.

Information related specifically to the excipients in this formulation (See section 6.1)

Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase–isomaltase insufficiency should not take this medicine. Each 20ml dose contains 9g sucrose.

Ethanol. Each 20ml dose contains 0.8g alcohol (ethanol), equivalent to 20 ml beer or 8 ml wine.

Harmful for those suffering from alcoholism. To be taken into account in pregnant or breastfeeding women, children and high-risk groups such as patients with liver disease or epilepsy. Sodium. Each 20ml dose contains 41mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

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4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTION Diphenhydramine

CNS depressants: may enhance the sedative effects of CNS depressants including barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives, antipsychotics and alcohol Antimuscarinic drugs: may have an additive antimuscarinic action with other drugs, such as atropine and some antidepressants. MAOIs: Not to be used in patients taking MAOIs or within 14 days of stopping treatment as there is a risk of serotonin syndrome

Pholcodine Not to be used in patients taking MAOIs or within 14 days of stopping treatment. Interaction with neuromuscular blocking agents (anaphylaxis) has been reported. The reduction in blood pressure caused by antihypertensives may accentuate the hypotensive effects of pholcodine. Diuretics may have the same effect. Pholcodine may enhance the sedative effect of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives and tranquillisers (phenothiazines and tricyclic antidepressants).

4.6 PREGNANCY AND LACTATION

The safety of pholcodine in pregnancy has not been fully established but its use has not revealed any direct evidence of teratogenicity. However, in view of the possible association of foetal abnormalities with first trimester exposure to diphenhydramine, use of the product during pregnancy should be avoided. The safety of this product during lactation has not been established and use during this period should be avoided.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

May cause drowsiness. If affected do not drive or operate machinery.

4.8 UNDESIRABLE EFFECTS May occasionally cause nausea, vomiting, drowsiness, skin rashes and anticholinergic side effects

such as dryness of the mouth, constipation, urinary retention and blurred vision. May also cause elation or depression, irritability and nightmares. Immune system disorders: hypersensitivity reactions, anaphylaxis.

4.9 OVERDOSE Symptoms of overdosage may include nausea, vomiting, drowsiness, restlessness excitement, ataxia,

respiratory depression and occasionally convulsions and hyperpyrexia. In cases of severe overdosage, the stomach should be emptied by aspiration and lavage. The patient should be kept quiet to minimise excitation which occurs particularly in children. The specific narcotic antagonist naloxone may be used to reverse any respiratory depression. Convulsions may be controlled with intravenous diazepam. Otherwise treatment should be symptomatic and supportive.

5 PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES

Pholcodine is a cough suppressant with mild sedative but little analgesic action. Diphenhydramine has antihistamine properties with a pronounced sedative action. ATC Classification: R05X (Other cold combination preparations).

5.2 PHARMACOKINETIC PROPERTIES

Pholcodine is readily absorbed from the gastrointestinal tract. It can relieve local irritation of the respiratory tract for about 4 to 5 hours. Peak plasma levels of diphenhydramine hydrochloride occur 2 to 4 hours after administration. Diphenhydramine is about 85 - 98% bound to plasma proteins. The plasma half life ranges form 2.4 to 8 hours.

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Diphenhydramine undergoes extensive pre-systemic metabolism which results in 50% metabolism of an oral dose. The major route of elimination is in the urine, largely as metabolites with very little unchanged drug present.

5.3 PRECLINICAL SAFETY DATA

Not applicable.

6 PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS

Hyetellose (Natrosol 250 HX) Glycerol (E422) Liquid sucrose (contains invert sugar) Citric acid monohydrate Sodium citrate (E331) Sodium benzoate (E211) Quinoline yellow (E104) Blue 12401 (E131) Ethanol Grenadine flavour 514485E GIV (contains propylene glycol) Purified water

6.2 INCOMPATIBILITIES

Not applicable.

6.3 SHELF LIFE 3 years

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Do not store above 25ºC.

6.5 NATURE AND CONTENTS OF CONTAINER 1. A 50ml, 100ml, 125ml, 150ml, 200ml or 250ml glass bottle either with a child resistant polypropylene cap without a liner or a roll on pilfer proof cap with a Triseal (LDPE/EPE/LDPE) liner.

2. A 50ml, 100ml, 125ml, 150ml, 200ml, or 250ml amber glass bottle either with a child resistant polypropylene cap without a liner or a roll on pilfer proof cap with a Triseal (LDPE/EPE/LDPE) liner.

3. A 50ml, 100ml, 125ml, 150ml, 200ml or 250ml amber PET bottle fitted with a child resistant polypropylene cap and an expanded polyethylene liner.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

Not applicable.

7 MARKETING AUTHORISATION HOLDER The Boots Company PLC 1 Thane Road West Nottingham NG2 3AA

Trading as: BCM

8 MARKETING AUTHORISATION NUMBER(S)

PL 00014/0657 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 29/03/2011 10 DATE OF REVISION OF THE TEXT

29/03/2011

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LABELLING

Carton:

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Container: