ukpar paracetamol hot drink 500mg powder for oral sol in … · · 2012-07-27ukpar paracetamol...

UKPAR Paracetamol Hot Drink 500 mg, powder for oral soln in sachet PL 00079/0673

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Paracetamol Hot Drink 500 mg, Powder for Oral Solution in Sachet PL 00079/0673

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after authorisation – summary

Summary of Product Characteristics Page 12

Patient Information Leaflet

Page 16

Labelling Page 20


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Paracetamol Hot Drink 500 mg, powder for oral solution in sachet PL 00079/0673

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Smithkline Beecham (SWG) Limited (trading as GlaxoSmithkline Consumer Healthcare) a Marketing Authorisation for the medicinal product Paracetamol Hot Drink 500 mg, powder for oral solution in sachet (PL 00079/0673) on 16 May 2012. The product is a General Sales List (GSL) medicine, which can be purchased at pharmacies, supermarkets and other retail outlets without the supervision of a pharmacist. Paracetamol Hot Drink 500 mg, powder for oral solution in sachet is used for the relief of cold and flu symptoms including fever, sore throat, headache, aches and muscle pains. Paracetamol Hot Drink 500 mg, powder for oral solution in sachet contains the active ingredient, paracetamol. Paracetamol is a painkiller (analgesic) and it also helps reduce body temperature when there is a fever (antipyretic). No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Paracetamol Hot Drink 500 mg, powder for oral solution in sachet outweigh the risks and a Marketing Authorisation was granted.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

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Clinical assessment

Page 9

Overall conclusions and risk assessment Page 10


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Smithkline Beecham (SWG) Limited (trading as GlaxoSmithkline Consumer Healthcare) a Marketing Authorisation for the medicinal product Paracetamol Hot Drink 500 mg, powder for oral solution in sachet (PL 00079/0673) on 16 May 2012. The product is a General Sales List (GSL) medicine, which can be purchased at pharmacies, supermarkets and other retail outlets without the supervision of a pharmacist. Paracetamol Hot Drink 500 mg, powder for oral solution in sachet is indicated for the short term relief of the symptoms of cold and flu including fever, sore throat, headache, aches and muscle pains. This is a national, abridged application, submitted under Article 8(3) of Directive 2001/83/EC, as amended, as a line-extension to the existing Marketing Authorisation for Panadol Original 500 mg Tablets (Smithkline Beecham (SWG) Limited, PL 00071/5074R), which was granted a licence of right in the UK on 29 May 1984. The active ingredient, paracetamol is an antipyretic and an analgesic. Its mechanism of action is believed to include inhibition of prostaglandin synthesis, primarily within the central nervous system. The lack of peripheral prostaglandin inhibition confers important pharmacological properties such as the maintenance of the protective prostaglandins within the gastrointestinal tract.

No new non-clinical or clinical data have been submitted, which is acceptable given that paracetamol is a widely used, well-known active substance that has been in clinical use for many years. No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Paracetamol Hot Drink 500 mg, powder for oral solution in sachet outweigh the risks, and a Marketing Authorisation was granted.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Paracetamol Chemical Name: N-(4-hydroxyphenyl)acetamide Molecular Formula: C8H9NO2 Structure:

Relative molecular mass: 151.2 Appearance: A white, crystalline powder Solubility Sparingly soluble in water, freely soluble in alcohol and

very slightly soluble in dichloromethane. Paracetamol is the subject of a European Pharmacopoeia monograph. Manufacture All aspects of the manufacture and control of the active substance paracetamol are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients sucrose, aspartame (E951), tartaric acid, trisodium citrate (anhydrous), blackcurrant flavour (contains sulphites), menthol flavour, and red colouring agent containing carmoisine (E122), sunset yellow (E110) and brilliant black (E151). Appropriate justification for the inclusion of each excipient has been provided. The excipients comply with their respective European Pharmacopoeia monographs, with the exception of trisodium citrate (anhydrous), blackcurrant flavour, menthol flavour and red colouring agent. Trisodium citrate (anhydrous) is compliant with its United States Pharmacopoeia specification and blackcurrant flavour, menthol flavour and red colouring agent comply with suitable in-house specifications. In addition, the specifications for blackcurrant flavour, menthol flavour and red colouring agent are in compliance with current EU Directives concerning the use of colouring agents. Satisfactory Certificates of Analysis have been provided for all excipients. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, stable product that, on reconstitution of a sachet’s content, provided a 500 mg dose of paracetamol as a ‘hot drink’.


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Suitable pharmaceutical development data have been provided for this application. Satisfactory dissolution studies have been provided. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. As the manufacturing process is simple and standard, a validation scheme has been provided and this is acceptable. The Marketing Authorisation Holder has committed to performing full process validation on the commercial-scale production batches in accordance with the EU note for Guidance on Process Validation (CPMP/QWP/848/96). Control of Finished Product The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container Closure System The product is packaged in flexible laminate sachets composed of printed paper/polyethylene/aluminium foil/polyethylene. The sachets are supplied in conventional cardboard cartons with Patient Information Leaflets in pack sizes of 5, 6 and 10 sachets. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food.

Stability Finished product stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. Based on the results, a shelf-life of 30 months has been proposed, with the storage conditions ‘Do not store above 30°C. Store in the original packaging’. Bioequivalence/Bioavailability The justification for a biowaiver was considered acceptable, and as a result, bioequivalence studies were not required.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are satisfactory from a pharmaceutical perspective. The Marketing Authorisation Holder has committed to submitting mock-ups to the competent authorities for approval before marketing any pack size. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups (‘user testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet 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 it contains. MAA (Marketing Authorisation Application) form The MAA form is pharmaceutically satisfactory. Expert Report (Quality Overall Summary) The quality overall summary is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended


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NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY As the pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol are well-known, no further non-clinical studies are required and none have been provided. NON-CLINICAL EXPERT REPORT (NON-CLINICAL OVERVIEW) The applicant’s non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. ENVIRONMENTAL RISK ASSESSMENT Suitable justification has been provided for non-submission of an Environmental Risk Assessment. No increase in environmental burden is anticipated by the introduction of this product. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. CONCLUSION The grant of a Marketing Authorisation is recommended.


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CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of paracetamol is well-known. No new pharmacodynamic or pharmacokinetic data are provided or required for this application. BIOWAIVER The applicant submitted a suitable justification for a biowaiver, in-line with the current guidance (NfG on the Investigation of Bioavaliability and Bioequivalence, CPMP/EWP/QWP/1401/98 Rev. 1). EFFICACY The efficacy of paracetamol is well-known. Efficacy is reviewed in the clinical overview. No new efficacy data have been submitted and none are required for this application. SAFETY No new safety data were submitted or required for this application. The applicant has provided an acceptable safety review from the literature. No new safety issues have been raised from this application. PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant 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. Suitable justification has been provided for not submitting a Risk Management Plan for this product. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SmPC, PIL and labelling are clinically acceptable. The SmPC is consistent with that for Panadol Original 500 mg Tablets (Smithkline Beecham (SWG) Limited, UK). The PIL is consistent with the details in the SmPC and in-line with the current guidelines. The labelling is in-line with current guidance. CLINICAL EXPERT REPORT (CLINICAL OVERVIEW) The clinical overview is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. CONCLUSION The grant of a Marketing Authorisation is recommended.


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OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Paracetamol Hot Drink 500 mg, powder for oral solution in sachet 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. As the pharmacokinetics, pharmacodynamics and toxicology of paracetamol are well-known, no additional data were required. EFFICACY No new data were submitted and none are required for this application. The applicant has submitted suitable justifications to fulfil the biowaiver, in-line with current guidelines. Efficacy is reviewed in the clinical overview. SAFETY No new data were submitted and none are required for this type of application. As the safety profile of paracetamol is well-known, no additional data were required. No new or unexpected safety concerns arose during the assessment of this application. PRODUCT LITERATURE The SmPC, PIL and labelling are acceptable. The SmPC is consistent with that for Panadol Original 500 mg Tablets (Smithkline Beecham (SWG) Limited, UK). The PIL is consistent with the details in the SmPC and in-line with the current guidelines. The labelling is in-line with current guidance. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with paracetamol is considered to have demonstrated the therapeutic value of the product. The benefit/risk balance is, therefore, considered to be positive.


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STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation application on 05 October 2010.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 10 November 2010.

3 Following assessment of the application the MHRA requested further information relating to the clinical dossier on 28 March 2011and the quality dossier on 28 March 2011, 05 December 2011, 24 January 2012

4 The applicant responded to the MHRA’s requests, providing further information on the clinical dossier 22 September 2011 and on the quality dossier on 22 September 2011, 30 December 2011 and 29 February 2012 and 30 March 2012.

5 The application was determined and granted on 16 May 2012.


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Summary of Product Characteristics 1 NAME OF THE MEDICINAL PRODUCT

Paracetamol Hot Drink 500 mg, powder for oral solution in sachet.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Active Constituent mg/3.735g Powder Paracetamol 500.0 mg Excipients: Sucrose 2000.0 mg Aspartame (E951) 50.0 mg Trisodium citrate [(anhydrous) (source of sodium)] 440.0 mg Blackcurrant flavour (contains sulphites) 90.0 mg Red colorant (contains carmoisine (E122), sunset yellow (E110) and brilliant black (E151) 5.0 mg For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM Powder for oral solution in sachet. Pale pink coloured, free flowing powder with characteristic blackcurrant menthol odour.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

The short term relief of the symptoms of cold and flu including fever, sore throat, headache, aches and muscle pains.

4.2 Posology and method of administration For oral use. Adults (including the elderly and children aged 16 years and over): One to two sachets to be taken every 4 to 6 hours as required. Dissolve the contents of sachets in a cup or mug of hot water, but not boiling water, and stir well. The dose should not be repeated more frequently than every 4 hours. Do not exceed 8 sachets in 24 hours. Children aged 12-15 years: One to two sachets to be taken every 4 to 6 hours as required. Dissolve the contents of sachets in a cup or mug of hot water, but not boiling water, and stir well. The dose should not be repeated more frequently than every 4 hours. Do not exceed 6 sachets in 24 hours. Children: Not recommended for children under 12 years, except on medical advice.

4.3 Contraindications Hypersensitivity to paracetamol or any of the other constituents.

4.4 Special warnings and precautions for use

Medical consultation is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Each sachet contains 2 g of sucrose – patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Each sachet contains aspartame (E951) which contains a source of phenylalanine. May be harmful to patients with phenylketonuria. Each sachet contains 118 g of sodium. To be taken into consideration by people on a controlled sodium diet.


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Each sachet contains azo dyes, sunset yellow (E110), carmoisine (E122) and brilliant black (E151) which may cause allergic reactions. Blackcurrant flavour contains sulphites which may rarely cause severe hypersensitivity reactions and bronchospasm. Do not exceed the stated dose. Patients should be advised to consult their doctor if their headaches become persistent. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Pack Label: Immediate medical advice should be sought in the event of an overdose, even if you feel well. Do not take any other paracetamol-containing products. Patient Information Leaflet: Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction with other medicinal products and other forms of interaction The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6 Fertility, pregnancy and lactation Epidermiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

4.7 Effects on ability to drive and use machines None.

4.8 Undesirable effects Paracetamol Adverse events reported from extensive post-marketing experience at therapeutic / labeled dose and considered attributable are tabulated below by MedDRA System Organ Class. As these reactions have been reported voluntarily from a population of uncertain size, the frequency of these reactions is unknown but considered likely to be very rare (<1/10,000).

Body System Undesirable effect Blood and Lymphatic system disorders Thrombocytopenia

Immune System disorders Anaphylaxis

Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens Johnson Syndrome

Respiratory, thoracic and mediastinal disorders

Bronchospasm in patients sensitive to aspirin and other NSAIDs

Hepatobiliary disorders Hepatic dysfunction

4.9 Overdose Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below). Risk factors If the patient a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.


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Or b, Regularly consumes ethanol in excess of recommended amounts. Or c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia. Symptoms Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Management Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the National Poisons Information Service (NPIS) or a liver unit.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides ATC code: N02B E01 Paracetamol is an antipyretic and analgesic. Its mechanism of action is believed to include inhibition of prostaglandin synthesis, primarily within the central nervous system. The lack of peripheral prostaglandin inhibition confers important pharmacological properties such as the maintenance of the protective prostaglandins within the gastrointestinal tract. Paracetamol is, therefore, particularly suitable for patients with a history of disease or on concomitant medication where peripheral prostaglandin inhibition would be undesirable (such as, for example, those with a history of GI bleeding or the elderly).

5.2 Pharmacokinetic properties Paracetamol is rapidly and almost completely absorbed from the gastro-intestinal tract. It is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding. Paracetamol is metabolized in the liver and excretion is almost exclusively renal, in the form of conjugated metabolites.

5.3 Preclinical safety data There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.


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6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Sucrose Aspartame (E951) Tartaric acid Trisodium citrate (anhydrous) Blackcurrant flavour Menthol Flavour Red colouring agent containing: Carmoisine (E122) Sunset yellow (E110) Brilliant black (E151) Blackcurrant flavor contains sulphites.

6.2 Incompatibilities None.

6.3 Shelf life 30 months.

6.4 Special precautions for storage Do not store above 30°C. Store in the original packaging.

6.5 Nature and contents of container Flexible laminate composed of printed paper/polyethylene / aluminium foil / polyethylene. The sachets are supplied in conventional cardboard cartons containing either 5, 6 or 10 sachets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements. The powder dissolves in hot water into a dark red solution. Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER SmithKline Beecham (SWG) Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom Trading as GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8 MARKETING AUTHORISATION NUMBER(S) PL 00079/0673

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 16/05/2012

10 DATE OF REVISION OF THE TEXT

16/05/2012


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PATIENT INFORMATION LEAFLET

The text below is that agreed for the leaflet. The Marketing Authorisation Holder has committed to submitting the mock-up leaflet for review to the competent authorities before marketing the product.


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LABELLING The text below is that agreed for the labelling. The Marketing Authorisation Holder has committed to submitting mock-up labelling for review to the competent authorities before marketing the product.


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ukpar paracetamol hot drink 500mg powder for oral sol in … · · 2012-07-27ukpar paracetamol...

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