PANADOL OA 1000MG TABLETS PL 00071/0456 UKPAR TABLE OF CONTENTS

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1 PANADOL OA 1000MG TABLETS PL 00071/0456 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 13 Steps taken after authorisation summary Page 14 Summary of Product Characteristics Page 15 Product Information Leaflet & Labelling Page 19 1

2 PANADOL OA 1000MG TABLETS PL 00071/0456 LAY SUMMARY The MHRA today granted SmithKline Beecham (SWG) Limited a Marketing Authorisation (licence) for the medicinal products Panadol OA 1000mg Tablets (PL 00071/0456). This is a prescription-only medicine (POM) used for the management of mild to moderate pain, including osteoarthritis. They can also be used to reduce fever. Panadol OA 1000mg Tablets contains the active ingredient paracetamol, which belongs to a group of medicines called analgesics and anti-pyretics. These medicines work by relieving pain and fever. No new or unexpected safety concerns arose from these applications and it was therefore judged that the benefits of taking Panadol OA 1000mg Tablets outweigh the risks; hence a Marketing Authorisation has been granted. 2

3 PANADOL OA 1000MG TABLETS PL 00071/0456 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Preclinical assessment Page 8 Clinical assessment (including statistical assessment) Page 9 Overall conclusions and risk benefit assessment Page 12 3

4 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted a marketing authorisation for the medicinal product Panadol OA 1000mg Tablets (PL 00071/0456) on 24 th August The product is a prescription-only medicine. The application is for a line extension as referred to in annex II of EC Directive 1084/2003 and is made under Article 10a of Directive 2001/83/EC, so called bibliographic application. Paracetamol has a long history of medicinal use, with well established safety and efficacy profile. Paracetamol OA 1000mg Tablets are indicated for the treatment of mild to moderate pain including osteoarthritis The product contains the active ingredient paracetamol. Paracetamol has analgesic and antipyretic actions. Paracetamol is readily absorbed from the upper gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to two hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. 4

5 PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE Paracetamol INN: Paracetamol Chemical Name: N-(4-Hydroxyphenyl) acetamide CAS No: Molecular formula: C 8 H 9 NO 2 Molecular weight: Physical form: Paracetamol is a white or almost white, crystalline powder. Solubility: Freely soluble in alcohol, sparingly soluble in water, practically insoluble in acetone. Paracetamol has no chiral centre. An appropriate specification based on the European Pharmacopoeia has been provided. Paracetamol is sourced from four manufacturers each of which holds a Certificate of Suitability for paracetamol. All aspects of the manufacture of the active substance paracetamol from its starting materials are controlled by a Certificate of Suitability. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. The methods of testing and limits for residual solvents are in compliance with current guidelines. Batch analysis data are provided and comply with the proposed specification. Active paracetamol is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory. Satisfactory certificates of analysis have been provided for working standards used by the active substance manufacturer and finished product manufacturer during validation studies. All potential known impurities have been identified and characterised. Appropriate stability data have been generated showing the active substance to be a physically and chemically stable drug and supports an appropriate retest period. 5

6 DRUG PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients, namely maize starch, pregelatinised starch, potassium sorbate, talc, stearic acid and povidone. All the excipients used in the tablet comply with their relevant European Pharmacopoeia monograph. Appropriate justification for the inclusion of each excipient has been provided. The tablet film coating consists of hypromellose and triacetin. The excipients that make up the film coat comply with their relevant European Pharmacopoeia monograph. Satisfactory certificates of analysis have been provided for all excipients. None of the excipients used contain material derived from animal or human origin. There were no novel excipients used and no overages. Product development The objective of the development programme was to develop film coated tablets containing 1000 mg Paracetamol with similar dissolution performance as Panadol 500 mg tablets. The proposed Panadol 1000 mg tablets are based on a formula identical to Panadol 500 mg tablets. Dissolution profiles The in vitro dissolution performance of Panadol 1000 mg tablets and 2 x 500 mg Panadol tablets was compared using tablets from three production batches of Panadol 1000 mg tablets manufactured from the proposed formula. The dissolution profiles were found to be similar. The dissolution performance of tablets from five production scale batches of Panadol 1000 mg tablets was also compared to evaluate batch to batch variability. The reported dissolution data show acceptable consistency. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are satisfactory based on process validation data and controls on the finished product. Process validation has been carried out on three production-scale batches of the finished product and the results appear satisfactory. Finished product specification The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been 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 opaque high density polyethylene (HDPE) bottles with a polypropylene screw closure and induction seal liner. Specifications and Certificates of Analysis for all packaging types used have been provided. These are satisfactory. All primary product packaging complies with EU legislation regarding contact with food. 6

7 Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 5 years has been set, which is satisfactory. Storage conditions are Do not store above 25 degrees. ADMINISTRATIVE Expert Report A pharmaceutical expert report has been written by a suitably qualified person and is satisfactory. Summary of Product Characteristics (SmPC) This is pharmaceutically satisfactory. Labelling This is pharmaceutically satisfactory. 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 Form This is pharmaceutically satisfactory. Conclusion It is recommended that a Marketing Authorisation is granted for this application. 7

8 PRECLINICAL ASSESSMENT This application for Paracetamol OA 1000mg Tablets is submitted as an abridged standard application according to Article 10a of Directive 2001/83/EC, wellestablished use. Paracetamol has a long history of medicinal use, with well established safety and efficacy profile. No new preclinical data have been supplied with this application and none is required for an application of this type. 8

9 CLINICAL ASSESSMENT 1. INTRODUCTION Paracetamol, a para-aminophenol derivative, has analgesic and antipyretic properties and weak anti-inflammatory activity. Paracetamol is given by mouth or as a rectal suppository for mild to moderate pain and for fever. It may also be given by intravenous infusion for the short-term treatment of moderate pain, particularly following surgery, and fever. Paracetamol is often the analgesic or antipyretic of choice, especially in the elderly and in patients in whom salicylates or other NSAIDs are contra-indicated. Such patients include asthmatics, those with a history of peptic ulcer, and children. Small doses are readily absorbed but the absorption of larger doses varies considerably and is influenced by gastric emptying rate, the presence of food, and the time of day. Paracetamol is widely distributed throughout most body fluids and is present in the saliva at concentrations paralleling those in plasma. It crosses the placenta and is found in breast milk. It undergoes first-pass metabolism and is metabolised mainly by conjugation to form glucuronides and ethereal sulfates; 3- hydroxylation also occurs followed by conjugation or O-methylation of the hydroxy group. Oxidation to a reactive metabolite thought to be acetylimino-p-benzoquinone occurs to a small extent after therapeutic doses but becomes more significant after larger doses, and this metabolite appears to be responsible for hepatic necrosis in paracetamol overdosage; it is normally detoxified by glutathione conjugation to form mercapturic acid and cysteine conjugates but, once sources of glutathione are depleted, the free metabolite is available to bind covalently with liver cell protein; this binding occurs about 10 to 12 h after dosing. About 90% of a therapeutic dose is excreted in the urine in 24 h; of the excreted material, 1 to 4% is unchanged, 20 to 30% is conjugated with sulfate, 40 to 60% is conjugated with glucuronic acid, 5 to 10% consists of the 3-hydroxy-3-sulfate, the 3-methoxyglucuronide, and the 3- methoxy-3-sulfate metabolites, and about 5 to 10% consists of the mercapturic acid and cysteine conjugates; 3-methylthio-4-hydroxyacetanilide has also been identified at concentrations of less than 1%. Larger amounts of the mercapturic acid and cysteine conjugates are excreted in overdose. 2 INDICATIONS For the management of mild to moderate pain, including osteoarthritis and for pyrexia. This is consistent with the SmPC text for the licensed indications of the UK product from which a line extension is being sought, therefore satisfactory. 3 DOSE & DOSE SCHEDULE The proposed posology is consistent with that of detailed in section 4.2 of the SmPC of the originator product and are satisfactory. 9

10 4 CLINICAL PHARMACOLOGY No new data submitted. PHARMACODYNAMICS No new data submitted. The pharmacodynamics of paracetamol are well described. It is an antipyretic analgesic. The mechanism of action is probably similar to that of Aspirin and dependent on the inhibition of prostaglandin synthesis. This inhibition appears, however to be on a selective basis. PHARMACOKINETICS No new data submitted. The pharmacokinetics of paracetamol are well described. It well absorbed from the GI tract and exhibits dose proportional kinetics over the therapeutic range. After oral administration peak blood levels occur at about 30 to 60 minutes. It is widely distributed within the body with variable plasma protein binding, and is primarily excreted by the kidneys in the form of conjugated metabolites with a plasma half life of 1 to 4 hours. 5 EFFICACY No new data are submitted and none are required for this type of application. 6 SAFETY No new data are submitted and none are required for this type of application. 7 EXPERT REPORTS A satisfactory expert report is provided by an appropriately qualified individual. The concern about improper use resulting in overdose of paracetamol has been addressed in the clinical overview (module 2). Panadol OA 1000 mg tablets is mainly targeted to the therapy of osteoarthritis (hence the suffix OA ) especially in the elderly. It is envisaged that one tablet dose instead of the usual two tablets will enhance compliance, improve outcome and delay the need for NSAIDS in this patient group. The clinical overview also addresses the associated risk of inadvertent overdose of 2 tablets instead of one and the consequent plasma level vis-à-vis the level known to cause hepatocellular damage; but the risk of overdose of intermediate duration and where it is not apparent to the patient is not addressed. It is however likely that as a POM, instructions from the prescriber and the pharmacist will help reduce risks of overdose. 8 PATIENT INFORMATION LEAFLET (PIL) The PIL is satisfactory. There has been no readability testing performed and this is a requirement. 9 LABELLING The labelling is satisfactory. 10

11 10 APPLICATION FORM (MAA) The MAA is medically satisfactory. 11 SUMMARY OF PRODUCT CHARACTERISTICS (SPC) The SmPC is consistent with that licensed for the UK reference product and is satisfactory. 12 DISCUSSION A marketing authorisation may be granted for this preparation. 11

12 OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Panadol OA 1000mg Tablets is 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. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY The efficacy of paracetamol has been well documented in the past. No new or unexpected safety concerns arise from this application. The SPC, PIL and labelling are satisfactory. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. Extensive clinical experience with paracetamol is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive. 12

13 PANADOL OA 1000MG TABLETS PL 00071/0456 STEPS TAKEN FOR ASSESMENT 1 The MHRA received the marketing authorisation applications on 29 th April Following standard checks and communication with the applicant the MHRA considered the applications valid on 22 nd August Following assessment of the applications the MHRA requested further information relating to the quality dossiers on 25 th May 2006 and 27 th September The applicant responded to the MHRA s requests, providing further information on 30 th August 2007 and 11 th July 2008 for the quality sections. 5 The application was determined on 24 th August

14 PANADOL OA 1000MG TABLETS PL 00071/0456 STEPS TAKEN AFTER AUTHORISATION - SUMMARY Date submitted Application type Scope Outcome 14

15 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Panadol OA 1000 mg Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains paracetamol 1000 mg For full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablet. White, capsule-shaped tablets having flat edges, debossed with PAN 1G on one side with a break-line on both sides. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. 4 CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS For the management of mild to moderate pain, including osteoarthritis and for pyrexia. 4.2 POSOLOGY AND METHOD OF ADMINISTRATION Panadol OA 1000 mg Tablets are for oral administration. Adults (including the elderly): One tablet up to 4 times daily as required. Not to be given to children under 12 years. The minimum dosing interval is 4 hours and the maximum daily dose is 4000 mg (4 tablets). 4.3 CONTRAINDICATIONS Hypersensitivity to paracetamol or any of the other constituents. 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Do not exceed the stated dose. Patients should be advised not to take other paracetamol-containing products concurrently. This product should only be used by the person for whom it is prescribed when clearly necessary. Pack label: Immediate medical advice should be sought in the event of an overdose, even if you feel well. Do not take with 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. 15

16 4.6 PREGNANCY AND LACTATION Epidemiological 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 Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been very rare reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. 4.9 OVERDOSE Paracetamol Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors (see below). Risk Factors: If the patient Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John s Wort or other drugs that induce liver enzymes. Or Or Regularly consumes ethanol in excess of recommended amounts. Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia. Symptoms Symptoms of paracetamol overdose 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 16

17 alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit. 5 PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependent on the inhibition of prostaglandin synthesis. This inhibition appears, however to be on a selective basis. 5.2 PHARMACOKINETIC PROPERTIES Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Concentration in plasma reaches a peak in 30 to 60 minutes. Plasma half-life is 1-4 hours Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; 20 to 30% may be bound at the concentrations encountered during acute intoxication. Following therapeutic doses % of the drug may be recovered in the urine within the first day. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation. 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. 6 PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS Maize starch Pregelatinised starch Potassium sorbate Talc Stearic acid Povidone Film coat: Hypromellose Triacetin. 6.2 INCOMPATIBILITIES Not applicable. 6.3 SHELF LIFE 5 years. 6.4 SPECIAL PRECAUTIONS FOR STORAGE Do not store above 25 C. 6.5 NATURE AND CONTENTS OF CONTAINER Opaque high density, polyethylene (HDPE) bottles with a polypropylene screw closure and induction seal liner, containing 100 tablets. 6.6 SPECIAL PRECAUTIONS FOR DISPOSAL No special requirements. 7 MARKETING AUTHORISATION HOLDER SmithKline Beecham (SWG) Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom 17

18 8 MARKETING AUTHORISATION NUMBER(S) PL 00071/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 24/08/ DATE OF REVISION OF THE TEXT 24/08/

19 PATIENT INFORMATION LEAFLET & LABELLING PANADOL OA 1000MG TABLETS PL 00071/