public assessment report - gov.uk · pdf filethis is a summary of the public assessment report...

Public Assessment Report

UKPAR

LEMSIP MAX DAY & NIGHT COLD & FLU RELIEF CAPSULES

(paracetamol, caffeine and phenylephrine hydrochloride)

UK Licence Number: PL 00063/0143

Reckitt Benckiser Healthcare (UK) Limited.

Lemsip Max Day & Night Cold & Flu Relief Capsules PL 00063/0143

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LAY SUMMARY



This is a summary of the Public Assessment Report (PAR) for Lemsip Max Day & Night Cold & Flu Relief Capsules (PL 00063/0143). It explains how the application for Lemsip Max Day & Night Cold & Flu Relief Capsules was assessed and its authorisation recommended, as well as the conditions of use. It is not intended to provide practical advice on how to use Lemsip Max Day & Night Cold & Flu Relief Capsules. The product may be referred to as ‘Lemsip Max Cold & Flu Relief Capsules’ in this report. For practical information about using Lemsip Max Cold & Flu Relief Capsules, patients should read the package leaflet or contact their doctor or pharmacist. What are Lemsip Max Cold & Flu Relief Capsules and what are they used for? Lemsip Max Cold & Flu Relief Capsules are a medicine with ‘well-established use’. This means that the medicinal use of the active substances of Lemsip Max Cold & Flu Relief Capsules is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety. Lemsip Max Day & Night Cold & Flu Relief Capsules consist of two types of capsules: a red and yellow Day capsule for daytime use and a blue and red Night capsule for night time use. This medicine contains a combination of ingredients which are effective in relieving the symptoms associated with colds and flu, including relief of aches and pains, sore throat, headache, tiredness, drowsiness, nasal congestion and lowering of temperature. How do Lemsip Max Cold & Flu Relief Capsules work? Lemsip Max Cold & Flu Relief Capsules contain the active ingredients paracetamol, caffeine (Day capsule only) and phenylephrine hydrochloride. Paracetamol is a well-known painkiller (analgesic). It is effective against aches and pains, including headache, and can also reduce fever (antipyretic). Caffeine (a mild stimulant) helps relieve tiredness and drowsiness through the day (it is only used in the Day Capsule). Phenylephrine hydrochloride (nasal decongestant) reduces swelling in the passages of the nose, relieving nasal congestion and reducing the pressure which may cause a headache. How are Lemsip Max Cold & Flu Relief Capsules used? Lemsip Max Cold & Flu Relief Capsules are available as red and yellow capsules (to be taken during daytime) and blue and red capsules (to be taken at night time). The capsules should be taken by mouth, swallowed whole with water. It is important to drink plenty of fluids when suffering from colds and flu. Lemsip Max Cold & Flu Relief Capsules should not be chewed. The recommended dose:

Dose Daytime Night time

Adults and children over 12

Two red and yellow capsules every 4-6 hours Maximum daytime dosage: 6 capsules

Two blue and red capsules to be taken at bed time. Maximum night time dosage: 2 capsules

Do not exceed 8 capsules in total in any 24 hours.


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Lemsip Max Cold & Flu Relief Capsules should not be given to children under 12 years of age. Please read section 3 of the package leaflet (PL) for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Lemsip Max Cold & Flu Relief Capsules can be obtained without a prescription, at pharmacies, supermarkets and other retail outlets without the supervision of a pharmacist. What benefits of Lemsip Max Cold & Flu Relief Capsules have been shown in studies? As paracetamol, caffeine and phenylephrine hydrochloride are well-known substances and their use in the licensed indications is well established, the applicant presented data from the scientific literature. The literature confirmed the efficacy and safety of paracetamol, caffeine and phenylephrine hydrochloride in the licensed indications. What are the possible side effects from Lemsip Max Cold & Flu Relief Capsules? Like all medicines, Lemsip Max Cold & Flu Relief Capsules can cause side effects, although not everybody gets them. For the full list of all side effects reported with Lemsip Max Cold & Flu Relief Capsules, see section 4 of the package leaflet or the Summary of Product Characteristics available on the MHRA website. Also, for the full list of restrictions, see the package leaflet. Why are Lemsip Max Cold & Flu Relief Capsules approved? The MHRA concluded that, in accordance with EU requirements, the benefits of Lemsip Max Cold & Flu Relief Capsules outweigh the identified risks and recommended that the product be approved for use. What measures are being taken to ensure the safe and effective use of Lemsip Max Cold & Flu Relief Capsules? Safety information has been included in the Summary of Product Characteristics and the package leaflet Lemsip Max Cold & Flu Relief Capsules, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore, new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Lemsip Max Cold & Flu Relief Capsules. A Marketing Authorisation was granted in the UK on 31 July 2006. The full PAR for Lemsip Max Cold & Flu Relief Capsules follows this summary. For more information about treatment with Lemsip Max Cold & Flu Relief Capsules, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in October 2015.


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PL 00063/0143

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 5 III Non-clinical aspects Page 13 IV Clinical aspects Page 13 VI Overall conclusion, benefit/risk assessment and

recommendation Page 14

Steps Taken After Authorisation - Summary Page 16 Annex 1 Page 17


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Scientific discussion I INTRODUCTION Based on the review of the data on quality, safety and efficacy the UK granted a Marketing Authorisation for the medicinal product Lemsip Max Day & Night Cold & Flu Relief Capsules (PL 00063/0143) to Reckitt Benckiser Healthcare (UK) Limited on 31 July 2006. The product is a General Sales List (GSL) product. The product consists of a Day Capsule and a Night Capsule. The Day Capsule is indicated for the relief of symptoms associated with the common cold and influenza including relief of aches and pains, sore throat, headache, fatigue and drowsiness, nasal congestion and lowering of temperature. The Night Capsule is indicated for the relief of symptoms associated with colds and influenza including relief of aches and pains, sore throat, headache, lowering of temperature and the symptoms associated with nasal congestion to help allow sleep through relief of nasal congestion. This application was submitted as an abridged application according to Article 10a of Directive 2001/83/EC and was submitted with a complete bibliography in support of well-established use. The product contains the active ingredients: paracetamol, caffeine and phenylephrine hydrochloride. The active ingredients exert their effect by unrelated pharmacological mechanisms; paracetamol is an analgesic / antipyretic, caffeine is a mild stimulant and phenylephrine hydrochloride is a sympathomimetic which acts as a nasal decongestant. As the active ingredients are drug substances for which safety, efficacy and bioavailability from standard oral dosage forms are well established it is not considered necessary to conduct additional non-clinical or clinical studies to support this application. II QUALITY ASPECTS II.1 Introduction This is a National abridged bibliographic application (Article 10a) for a Marketing Authorisation for Lemsip Max Cold & Flu Day & Night Capsules. This Day/Night product is stated to be based on the currently marketed Lemsip Max Cold & Flu Capsules (PL 00063/0104). The formulation of the Day capsule is identical to the marketed product whilst the formulation for the Night capsule is the same except for the removal of caffeine and replacement with the same weight of maize starch. The applicant states that, as the active ingredients are drug substances for which safety, efficacy and bioavailability from standard oral dosage forms are well established it is not considered necessary to conduct additional non-clinical or clinical studies to support this application. The legal status for this application is GSL. As the name suggests, the product has been designed as a ‘maximum strength’ product, where the contents of paracetamol (500mg) and phenylephrine hydrochloride (6.1mg) in the formulation have been set so that the adult dose of two capsules will provide the maximum allowed dose of these two ingredients in products available for self-selection, that is 1000mg paracetamol and 12.2mg phenylephrine hydrochloride. The pack size will be 8 and 16 capsules. As discussed by the applicant there are several marketed products containing the same three active although the quantities of paracetamol (300mg) and phenylephrine (5mg) are lower than in the current product. A related product Lemsip Max Cold & Flu Lemon (PL 00063/0069) contains paracetamol 1000mg and phenylephrine hydrochloride 12.2mg per sachet.


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Lemsip Max Cold & Flu Day & Night Capsules are hard gelatin capsules containing paracetamol 500mg, caffeine 25mg and phenylephrine hydrochloride 6.1mg per Day capsule in a powder base and paracetamol 500mg and phenylephrine hydrochloride 6.1mg per Night capsule in a powder base. The Day capsule has a yellow body and red cap printed ‘Lemsip’, whilst the Night capsule has a dark blue body and red cap printed with ‘Lemsip’.

The composition is satisfactory and tabulated below.

Ingredient Function Reference to standards

CAPSULE CONTENTS Active substances Paracetamol Analgesic / Antipyretic Ph. Eur Caffeine anhydrous Analgesic / Antipyretic Ph. Eur Phenylephrine hydrochloride

Nasal decongestant Ph. Eur

Excipients Maize starch Binder / Disintegrant Ph. Eur Croscarmellose sodium Binder / Disintegrant Ph. Eur Sodium lauryl sulphate Wetting agent Ph. Eur Magnesium stearate Lubricant Ph. Eur Talc Glidant Ph. Eur Capsule content weight CAPSULE Body Gelatin Capsule shell Ph. Eur Titanium dioxide (E171) Colorant Ph. Eur Quinoline Yellow (E104)

Colorant FRP

Patent Blue V (E131) Colorant EEC Erythrosin (E127) Colorant FRP CAP* Gelatin Capsule shell Ph. Eur Erythrosine (E172) Colorant FRP Titanium dioxide (E171) Colorant Ph. Eur Quinoline Yellow (E104)

Colorant FRP

Patent Blue V (E131) Colorant EEC * Printing ink contains shellac, aluminium hydroxide and tartrazine (E102) The capsules are packed 250 micron opaque uPVC/20 micron aluminium foil, heat-seal coated, with a perforated "push-through" Pill Protect (TM) self-adhesive paper label applied to the foil side, contained in an outer cardboard carton. Pack sizes of 8 and 16 capsules are approved for marketing. Data are provided for the primary packaging to show compliance with the new ‘Guidance on compliance with the Medicines (Child Safety) Regulations 2003’ which came into force 1st October 2003.


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II.2 Drug Substances Three sources of active substance are approved. The active substances, paracetamol, caffeine anhydrous and phenylephrine hydrochloride, from these sources are the subject of Ph Eur Certificates of Suitability (CEP). A copy of each CEP is included in the dossier. In accordance with current requirements, written assurance from the manufacturers that they will inform the applicant about any changes in the manufacturing process or specifications of the drug substances have been given. Satisfactory drug substance specifications are provided from the manufacturers of the drug substances, confirming compliance with the relevant Ph Eur monograph and additional tests included on the CEP. The finished product manufacturer has also provided drug substance specifications. Certificates of Analysis (CoAs) for batches of the drug substances tested on receipt have been provided. Analytical Procedures Analytical procedures are described. Validation of Analytical Procedures Satisfactory validation data are provided for the analytical procedures. Batch Analysis Results of industrial scale batches of all three drug substances are within specification. Reference standards Satisfactory primary and working reference standards are identified. Stability Batches of all three drug substances stored under ICH real time conditions show compliance with set limits during the approved retest periods. II.3 Medicinal Product Pharmaceutical Development The aim of the pharmaceutical development was to produce a maximum strength GSL product containing active substances suitable for the stated indications for the Day and Night capsules. Essentially the Day capsule would in addition to all the indications for the Night capsule, also be able to overcome fatigue and drowsiness. The initial pharmaceutical development of Lemsip Max Cold & Flu Day & Night Capsules was carried out by Wrafton Laboratories Limited who developed the Day capsule, currently marketed as Lemsip Max Cold & Flu Capsules (PL 00063/0104). The Night capsule was developed by Reckitt Benckiser Healthcare (UK) Limited which involved reformulation of the Day capsule to make it appropriate for night time use. The active drug substances paracetamol, caffeine and phenylephrine hydrochloride are available in several products. Subsequently as the three products have been used in combination, compatibility was not performed nor are they considered to be necessary. All excipients meet the requirements of their respective monographs. The compendial methodology is used in testing. Representative Certificates of Analyses have been provided. The gelatin used in the capsule shell is derived from bovine sources and, therefore, appropriate Certificates of Suitability have been provided. None of the other excipients are of animal origin.


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No genetically modified organisms (GMO) have been used in the preparation of medium-chain triglycerides. Microbiological Attributes The product complies on release with the Ph. Eur requirements for microbiological quality of pharmaceutical preparations. Compatibility Not required. MANUFACTURE GMP Statement and Manufacturing Chain The site of batch release is Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS, United Kingdom. The sites of manufacture and assembly are also stated. All sites comply with GMP requirements and copies of the manufacturer’s licences have been provided. Manufacturing Process A satisfactory formula and description of manufacture are provided. There are no re-processing data provided. Critical phases of the manufacturing process have been satisfactorily identified and appropriate in-process controls are in place. The analytical methods and limits are the same as those used in finished product testing and comply with current guidelines and are accepted. The capsules are blister packed with satisfactory in-process controls. In-process batch data for validation batches are satisfactory. The validation results demonstrate homogeneity of blends and consistent manufacture. Results of industrial scale batches of all three drug substances are within specification. The validation protocol provided is considered adequate for the purpose. Analytical Procedures Satisfactory validation data are provided. Batch data Satisfactory data are provided for batches manufactured at the proposed site and are considered representative of the product to be marketed. Dissolution data including standard deviations and profiles are reported. Characterisation of Impurities This is satisfactory. Reference Samples Reference samples are identified. Control of Finished Product A satisfactory finished product specification is provided Stability of the Product Based on stability data at normal, intermediate and accelerated conditions, a product shelf-life of 36 months and the special storage instructions ‘Do not store above 25°C.’ is approved.


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The samples provided for stability studies are representative of the product to be marketed in the proposed pack. The programme is ongoing. The stability programme is satisfactory as the applicant has agreed to place the first three commercial batches on stability. The results of the stability studies support the proposed shelf life. II.4 Discussion on chemical, pharmaceutical and biological aspects It is recommended that a Marketing Authorisation is granted for this application Lemsip Max Day & Night Cold & Flu Relief Capsules (PL 00063/0143). II.5 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC, PIL and labelling are satisfactory and, where appropriate, in line with current guidance. In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL are available on the MHRA website. The current labelling is presented below:


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III NON-CLINICAL ASPECTS III.1 Introduction No new non-clinical data have been supplied with this application and none are required for an application of this type. III.2 Pharmacodynamics The pharmacodynamic properties of paracetamol, caffeine and phenylephrine hydrochloride are well known and are adequately described in the applicant’s non-clinical overview. III.3 Pharmacokinetics The pharmacokinetic properties of paracetamol, caffeine and phenylephrine hydrochloride are well known and are adequately described in the applicant’s non-clinical overview. III.4 Toxicology No new toxicology data were submitted. The non-clinical pharmacology of the active substances remain satisfactory. III.5 Ecotoxicity/Environmental Risk Assessment (ERA) An ERA was not required at the time of initial assessment of this application. III.6 Discussion on the non-clinical aspects It is recommended that a Marketing Authorisation is granted for Lemsip Max Day & Night Cold & Flu Relief Capsules, from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction This is a national application for a Marketing Authorisation for Lemsip Max Day & Night Cold & Flu Relief Capsules. The legal basis of this application is a well-established medicinal use application according to Article 10a of Directive 2001/83/EC as amended. Bibliographic data to support the clinical pharmacology of each of the actives have been submitted and referenced in the clinical overview as required. The current product Lemsip Max Cold & Flu Day & Night Capsules has been developed to deliver the maximum allowed doses of paracetamol and phenylephrine hydrochloride for ‘self-selection’ use and the maximum amount of paracetamol allowed in paracetamol capsules or tablets (non-effervescent) for General Sales List (GSL). The Day capsule is identical to Lemsip Max Cold & Flu Capsules PL 00063/0104 whilst the Night capsule has the replacement of caffeine by the same weight of maize starch. The Night capsules are identical in dose to PL 00063/0104 Lemsip Max Cold & Flu Lemon PL 00063/0069. Paracetamol has both analgesic and antipyretic activity which is believed to be mediated principally through its inhibition of prostaglandin synthesis within the central nervous system. Caffeine is a central nervous system stimulant. It inhibits the enzyme phosphodiesterase and has an antagonistic effect at central adenosine receptors. Its action on the central nervous system is mainly on the higher centres and it produces a condition of wakefulness and increased mental activity.


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Phenylephrine hydrochloride is a post-junctional alpha1-receptor agonist with low cardioselective beta-receptor affinity and minimal central stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling. The applicant’s clinical overview has been written by an appropriately qualified person and is considered acceptable. IV.2 Pharmacokinetics No new clinical pharmacokinetic data have been submitted and none are required for an application of this type. The pharmacokinetic profiles of paracetamol, caffeine and phenylephrine hydrochloride are well-known. IV.3 Pharmacodynamics The pharmacodynamics profiles of paracetamol, caffeine and phenylephrine hydrochloride are well-known. An adequate summary of the pharmacodynamic profiles of paracetamol, caffeine and phenylephrine hydrochloride has been presented in the clinical overview. IV.4 Clinical Efficacy Efficacy of Lemsip Max Day & Night Cold & Flu Relief Capsules is known through the clinical use of the three actives over many years and extensive publications. The clinical overview has addressed the various indications for this product. The applicant has provided sufficient bibliographic data to support the conclusions. No new data has been submitted and none is required. IV.5 Clinical Safety The clinical safety of the product is well established. No new data has been submitted and none is required. IV.6 Risk Management Plan (RMP) The requirement to submit an RMP with an initial marketing authorisation application came into effect on 21 July 2012. This application was submitted and approved prior to this date. Safety information has been included in the Summary of Product Characteristics and the package leaflet Lemsip Cold & Flu Relief Capsules, including the appropriate precautions to be followed by healthcare professionals and patients. IV.7 Discussion of the clinical aspects It is recommended that a Marketing Authorisation is granted for this application.

V. OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT AND RECOMMENDATION QUALITY The important quality characteristics of Lemsip Max Day & Night Cold & Flu Relief Capsules are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON_CLINICAL No new non-clinical data were submitted and none are required for an application of this type. EFFICACY No new clinical data were submitted and none were required for this type of application.


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The clinical overview has addressed the various indications for this product. The applicant has provided sufficient bibliographic data to support the conclusions SAFETY No new or unexpected safety concerns arose from this application.

BENEFIT/RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The benefit/risk assessment is, therefore, considered to be positive. RECOMMENDATION The grant of a Marketing Authorisation is recommended.


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PL 00063/0143

The following table lists a non-safety update to the Marketing Authorisation for this product that has been approved by the MHRA since the product was first licensed. The table includes an update that has been added as an annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to this Marketing Authorisation.

STEPS TAKEN AFTER AUTHORISATION-SUMMARY

Date submitted Application

type Scope Outcome

22 January 2015 Type II To update sections 5.1 and 5.2 of the Summary of Product Characteristics (SmPC) to align with the Company Core Data Sheet (CCDS), following submission of the latest Periodic Safety Update Report (PSUR) for paracetamol, caffeine and phenylephrine.

Approved on 04 September 2015


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Annex 1

Our Reference: PL 00063/0143 - 0049 Product: Lemsip Max Cold And Flu Day and Night Relief Capsules Marketing Authorisation Holder: Reckitt Benckiser Healthcare (UK) Limited Active Ingredient(s): Paracetamol, caffeine and phenylephrine hydrochloride Type of Procedure: National Submission Type: Variation Submission Category: Type II Submission Complexity: Standard EU Procedure Number (if applicable): Not applicable Reason: To update sections 5.1 and 5.2 of the Summary of Product Characteristics (SmPC), to align with the Company Core Data Sheet (CCDS), following submission of the latest Periodic Safety Update Report (PSUR) for paracetamol, caffeine and phenylephrine. Linked / Related Variation(s) or Case(s): N/A Supporting Evidence Revised SmPC fragments and clinical overview. Evaluation The clinical overview and proposed changes to the SmPC are satisfactory. The clinical overview and updated SmPC fragments have been incorporated into the Marketing Authorisation. Conclusion The proposed changes to the clinical overview and SmPC are acceptable and there are no objections to approval. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website Decision - Approved on 04 September 2015.

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