PARACETAMOL 500MG TABLETS B.P. (PARACETAMOL) PL 17907/0146 UKPAR TABLE OF CONTENTS

Transcription

1 PARACETAMOL 500MG TABLETS B.P. (PARACETAMOL) PL 17907/0146 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 11 Steps taken after authorisation Page 12 Summary of Product Characteristics Page 13 Product Information Leaflets Page 17 Labelling Page 19 1

2 PARACETAMOL 500MG TABLETS B.P. (PARACETAMOL) PL 17907/0146 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted Bristol Laboratories Limited a Marketing Authorisation (licence) for the medicinal product Paracetamol 500mg Tablets B.P. (PL 17907/0146) on 14 th May This is a medicine available on the General Sales List (GSL), and can be purchased at pharmacies, supermarkets and other retail outlets without the supervision of a pharmacist. Paracetamol 500mg Tablets B.P. contain the active ingredient, paracetamol. Paracetamol belongs to a group of medicines called analgesics and anti-pyretics. These medicines work by relieving pain and fever. It is used to relieve mild to moderate pain, such as headache, migraine, neuralgia, toothache, sore throat, period pain, aches and pains, muscle pains and backache. It can also relieve the symptoms of rheumatic aches and pains, influenza, feverishness and feverish colds. This application is a duplicate of a previously granted application for Paracetamol Tablets BP 500mg (PL 00211/5003R), originally authorised to The Wallis Laboratory Limited on 30 th September The test and reference products are identical. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of using Paracetamol 500mg Tablets B.P. outweigh the risk; hence a Marketing Authorisation has been granted. 2

3 PARACETAMOL 500MG TABLETS B.P. (PARACETAMOL) PL 17907/0146 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Preclinical assessment Page 8 Clinical assessment Page 9 Overall conclusion and risk benefit assessment Page 10 3

4 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Bristol Laboratories Limited a Marketing Authorisation for the medicinal product Paracetamol 500mg Tablets B.P. (PL 17907/0146) on 14 th May The product is available through general supply (GSL). This application was submitted as a simple abridged informed consent application according to article 10c of Directive 2001/83/EC (as amended), cross-referring to Paracetamol Tablets BP 500mg (PL 00211/5003R), originally authorised to The Wallis Laboratory Limited on 30 th September This MA underwent Change of Ownership to PL 29831/0163 (Wockhardt UK Limited) on 18 th August Paracetamol 500mg Tablets B.P. are indicated for the treatment of mild to moderate pain including headache, migraine, dental pain, sore throat, period pains, neuralgia, aches and pains including muscle pains and backache, and for the symptomatic relief of rheumatic aches and pains, influenza, feverishness, feverish colds. 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. 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 PAR was generated for it. 4

5 PHARMACEUTICAL ASSESSMENT LICENCE NUMBER: PL 17907/0146 PROPRIETARY NAME: ACTIVE INGREDIENT/S: COMPANY NAME: E.C. ARTICLE: LEGAL STATUS: Paracetamol 500mg Tablets B.P. Paracetamol Bristol Laboratories Limited Article 10c of Directive 2001/83/EC (as amended) GSL 1. INTRODUCTION This is a simple abridged application, submitted under Article 10c of Directive 2001/83/EC (as amended) for Paracetamol 500mg Tablets B.P. The proposed MA holder is Bristol Laboratories Limited, Unit 3, Canalside, Northbridge Road, Berkhamsted, HP4 1EG. The reference product is Paracetamol Tablets BP 500mg (PL 00211/5003R), originally authorised to The Wallis Laboratory Limited. The test and reference products are identical. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1 Name(s) The approved name of the product is Paracetamol 500mg Tablets B.P. The product name is acceptable. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes Paracetamol 500mg Tablets B.P. are presented as white, flat, circular, bevelled edged tablets with a breakline on one side and debossed P over 500 on the other side. Each tablet contains 500mg paracetamol. The tablets are marketed in PVC (polyvinylchloride) film - aluminium foil blisters, which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 2, 4, 6, 8, 10, 12 and 16. The MAH has stated that not all pack sizes may be marketed. The approved shelf-life (3 years) and storage conditions ( Do not store above 25 o C and Store in the original packaging ) are consistent with the details registered for the cross-reference product. 2.3 Legal status The product is a GSL licensed medicine, available by supply through pharmacies, supermarkets and other retail outlets without the need for supervision by a pharmacist. 2.4 Marketing authorisation holder / Contact Persons / Company The proposed Marketing Authorisation holder is Bristol Laboratories Limited, Unit 3, Canalside, Northbridge Road, Berkhamsted, HP4 1EG. The QP responsible for pharmacovigilance was stated and their CV included. 5

6 2.5 Manufacturers The proposed manufacturing site is consistent with that registered for the crossreference product and evidence of GMP compliance has been provided. 2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the crossreference 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 product. 2.9 Drug substance specification The proposed drug substance specification is consistent with the details registered for the cross-reference product TSE Compliance No materials of animal or human origin are included in the product. The magnesium stearate and stearic acid have been confirmed as being of vegetable origin 3. EXPERT REPORTS Satisfactory expert reports and curriculum vitae of experts were provided. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product name. The appearance of the product (white, flat, circular, bevelled edged tablets with a breakline on one side and debossed P over 500 on the other side) is consistent with 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 patient information leaflet has been prepared in the user tested format and in line with the details registered for the cross-reference product. The approved PIL is satisfactory. 6

7 Labelling Colour mock-ups of the labelling have been provided and are satisfactory. The approved artwork is comparable to the artwork registered for the cross-reference product and complies with statutory requirements. In line with current legislation the applicant has included the name of the product in Braille on the outer packaging. 7. CONCLUSIONS The grounds for this application are considered adequate. A Marketing Authorisation was, therefore, granted. 7

8 PRECLINICAL ASSESSMENT This abridged application was submitted as a simple abridged application according to article 10c of Directive 2001/83/EC (as amended). No new preclinical data have been supplied with this application and none are required for an application of this type. A preclinical expert report has been written by a suitably qualified person and is satisfactory. 8

9 CLINICAL ASSESSMENT This abridged application was submitted as a simple abridged application according to article 10c of Directive 2001/83/EC (as amended). As this is a duplicate application for PL 00211/5003R, no new clinical data have been supplied with the application, and none are required for applications of this type. A clinical expert report has been written by a suitably qualified person and is satisfactory. 9

10 OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The data for this application are consistent with that previously assessed for the crossreference 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 Medicinal products containing paracetamol have been available in the UK for much more than ten years. Their use is well established with recognised efficacy and acceptable safety. This application is identical to the previously granted application for Paracetamol Tablets BP 500mg (PL 00211/5003R, The Wallis Laboratory Limited). No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE The approved SmPC, PIL and labelling are satisfactory and consistent with that for the cross-reference product. 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. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The testing shows that patients/users are able to act upon the information that the leaflet contains. The approved labelling artwork complies with statutory requirements. In line with current legislation, the name of the product in Braille appears on the outer packaging. The Marketing Authorisation Holder (MAH) has stated that not all pack sizes may be marketed. However, they have committed to submitting mock-ups for all packaging for assessment before those pack sizes are commercially marketed. RISK BENEFIT 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 crossreference product. Extensive clinical experience with paracetamol is considered to have demonstrated the therapeutic value of the active substance. The risk: benefit is, therefore, considered to be positive. 10

11 PARACETAMOL 500MG TABLETS B.P. (PARACETAMOL) PL 17907/0146 STEPS TAKEN FOR ASSESSMENT 1 The MHRA received the marketing authorisation application on 26 th October Following standard checks and communication with the applicant the MHRA considered the application valid on 4 th November Following assessment of the application the MHRA requested further information relating to the quality dossier on 25 th October 2005, 21 st September 2006, 19 th November 2007, and 26 th February The applicant responded to the MHRA s request, providing further information for the quality sections on 6 th February 2006, 30 th March 2007, 18 th February 2008, and 1 st December 2008 respectively 5 The application was determined on 14 th May

12 PARACETAMOL 500MG TABLETS B.P. (PARACETAMOL) PL 17907/0146 Not applicable STEPS TAKEN AFTER AUTHORISATION 12

13 SUMMARY OF PRODUCT CHARACTERISTICS The UK Summary of Product Characteristics (SmPC) for Paracetamol 500mg Tablets B.P. is as follows: 1 NAME OF THE MEDICINAL PRODUCT Paracetamol 500 mg Tablets B.P. 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 500mg Paracetamol. For a full list of excipients see section PHARMACEUTICAL FORM Tablet White, flat, circular tablets, bevelled edge, bisected by a breakline on one side and debossed P over 500 on the other side. (Scoreline 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 treatment of mild to moderate pain including headache, migraine, dental pain, sore throat, period pains, neuralgia, aches and pains including muscle pains and backache. Symptomatic relief of rheumatic aches and pains, influenza, feverishness, feverish colds. 4.2 Posology and method of administration Adults and children over 12 years: 1 to 2 tablets (500mg - 1.0g) to be taken orally with water, every 4 hours up to a maximum of 8 tablets in 24 hours. Maximum daily dose: 8 tablets (4.0g) in any 24 hour period in divided doses. Do not give to children under 12 years of age except on the advice of a Doctor. If symptoms persist consult your doctor. Do not take for more than 3 days unless your doctor agrees. DO NOT EXCEED THE STATED DOSE. Keep all medicines out of the sight and reach of children 4.3 Contraindications Hypersensitivity to Paracetamol and/or other constituents 4.4 Special warnings and precautions for use Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease. Paracetamol should be given with care to patients with alcoholic dependence. Paracetamol is well tolerated by the majority of people with asthma. However, a small percentage of aspirin sensitive asthmatics are also sensitive to paracetamol. The likelihood of a reaction to paracetamol increases with a patient s level of sensitivity to aspirin (see also 4.8 Undesirable effects). Do not exceed the recommended dose. Patients should be advised not to take other paracetamol-containing products concurrently. 13

14 The product label will carry the warnings: Do not take with any other paracetamol - containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well. If symptoms persist consult your doctor. Keep out of the sight and reach of children. Do not take for more than three days unless your doctor agrees. 4.5 Interaction with other medicinal products and other forms of interaction Alcohol: Paracetamol should be given with care to patients with alcohol dependence (see section 4.4) Analgesics: Diflunisal increases blood concentrations of paracetamol. Anion exchange resins: Absorption reduced by colestyramine; administration should be separated by at least 1 hour. Antibacterials: Isoniazid may increase the risk of hepatotoxicity with therapeutic doses of paracetamol. Anticoagulants: The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect. Antiepileptics: Carbamazepine, phenobarbital, phenytoin and primidone can reduce the effects of paracetamol and increase the risk of hepatotoxicity. Paracetamol may increase lamotrigine metabolism. Motility stimulants: The speed of absorption of paracetamol may be increased by metoclopramide or domperidone. Oral contraceptives: Paracetamol is cleared from the body more quickly in women taking oral contraceptives and the analgesic effects may be reduced. Uricosurics: Probenecid can reduce the loss of paracetamol from the body. 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. Haematological: There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. Immune system: Hypersensitivity including skin rash may occur. A small percentage of aspirin-sensitive asthmatics are also sensitive to paracetamol. In such cases, the deterioration in respiratory function induced by paracetamol is milder and shorter than with aspirin (see also 4.4 Special warnings and precautions for use). Renal and urinary disorders- Nephropathy has been associated with chronic high dose use. 14

15 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 carbmazepine, phenobarbital, phenytoin, primidone, rifampicin, St John s Wort or other drugs that induce liver enzymes. Or b. Regularly consumes ethanol in excess of recommended amounts Or c. Is likely to be glutathione depleted 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 dosing schedule. If vomiting is not a problem, oral methionine may be 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 NPIS or a liver unit. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC code: N02B E01 Pharmacotherapeutic group: Analgesic and antipyretic Paracetamol has analgesic and antipyretic actions. 5.2 Pharmacokinetic properties 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. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about one hour to four hours. At usual therapeutic concentrations plasma- protein binding is negligible. 15

16 5.3 Preclinical safety data There are no pre-clinical data of any relevance to the prescriber that are additional to those already included in other sections. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Potato Starch Pregelatinised Starch Talc purified Povidone Stearic Acid Sodium Starch Glycollate Nipasept (contains methyl, ethyl and propyl hydroxybenzoates: E218, E214 and E216). Magnesium Stearate 6.2 Incompatibilities None known. 6.3 Shelf Life 3 years 6.4 Special precautions for storage Do not store above 25 C. Store in the original packaging. 6.5 Nature and contents of container Blister packs: 2, 4, 6, 8, 10, 12, 16, Blister strips consist of a 35gsm paper/9µ soft tempered aluminium foil lid and 250µ PVC film base in cartons. Not all pack sizes may be marketed 6.6 Special precautions for disposal No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. 7 MARKETING AUTHORISATION HOLDER Bristol Laboratories Limited Unit 3, Canalside, Northbridge Road, Berkhamsted HP4 1EG 8 MARKETING AUTHORISATION NUMBER(S) PL 17907/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 14/05/ DATE OF REVISION OF THE TEXT 14/05/

17 PRODUCT INFORMATION LEAFLET 17

18 18

19 LABELLING Carton with Braille 10 tablets Braille 19

20 Blister pack 10 tablets 20

21 Carton with Braille 16 tablets Braille 21

22 Blister pack 8 tablets 22