Public Assessment Report. Decentralised Procedure

Transcription

1 Public Assessment Report Decentralised Procedure Paracetamol 500 mg effervescent tablets Procedure No: UK/H/5662/ /DC UK Licence No: PL 36390/ Cipla (EU) Limited

2 Lay Summary Paracetamol 500 mg effervescent tablets (paracetamol) This is a summary of the public assessment report (PAR) for Paracetamol 500 mg and 1000 mg effervescent tablets (PL 36390/ ; UK/H/5662/ /DC). It explains how Paracetamol 500 mg and 1000 mg effervescent tablets were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Paracetamol 500 mg and 1000 mg effervescent tablets. For practical information about using Paracetamol 500 mg and 1000 mg effervescent tablets, patients should read the package leaflet or contact their doctor or pharmacist. What are Paracetamol 500 mg and 1000 mg effervescent tablets and what are they used for? Paracetamol 500 mg effervescent tablets are a generic medicine. This means that they are similar to a reference medicine, already authorised in the European Union (EU) called Panadol Soluble 500 mg Tablets (PL 00071/0072R). Paracetamol 500 mg effervescent tablets are used to relieve mild to moderate pain and/or fever such as headache, migraine, neuralgia, toothache, period pain, rheumatic aches and pains, sore throat and the symptoms of colds and flu in adults and adolescents aged 12 years and above. are a hybrid medicine. This means that they are similar to a reference medicine, already authorised in the European Union (EU) called Panadol Soluble 500 mg Tablets (PL 00071/0072R) that contain the same active substance but are available as a different strength: there is 1000 mg paracetamol in Paracetamol 1000 mg effervescent tablets but there is only 500 mg paracetamol in Panadol Soluble 500 mg Tablets. are used to relieve mild to moderate pain and/or fever such as headache, migraine, neuralgia, toothache, period pain, rheumatic aches and pains, sore throat and the symptoms of colds and flu in adults and adolescents aged 16 years and above. How do Paracetamol 500 mg and 1000 mg effervescent tablets work? Paracetamol 500 mg and 1000 mg effervescent tablets contain the active substance paracetamol. Paracetamol is an analgesic and antipyretic, which relieves aches and reduces fever by a mechanism of action that is believed to be mediated through blocking a signalling pathway within the central nervous system. How are Paracetamol 500 mg and 1000 mg effervescent tablets used? One Paracetamol 500 mg or 1000 mg effervescent tablet should be placed in a full glass of water. Once completely dissolved, the patient should drink the solution straight away. Paracetamol 500 mg effervescent tablets In adolescents of 12 to 15 years and weighing 41 to 50 kg the usual dose is one Paracetamol 500 mg effervescent tablet, repeated every 4-6 hours if necessary. The patient should not take more than 4 tablets (2000 mg paracetamol) in 24 hours. In adults and adolescents aged 16 years and older, weighing more than 50 kg, the usual dose is one to two Paracetamol 500 mg effervescent tablets, repeated every 6 hours as needed. The patient should not take more than 8 tablets (4000 mg paracetamol) in 24 hours. 2

3 In adults and adolescents aged 16 years and older, weighing less than 50 kg, the usual dose is one Paracetamol 500 mg effervescent tablet, repeated every 6 hours as needed. The maximum daily dose should not exceed 60 mg per kg of bodyweight; i.e. this would be up to a maximum of 4 tablets (2000 mg paracetamol) in 24 hours. In adults and adolescents aged 16 years and older, weighing more than 50 kg, the usual dose is one Paracetamol 1000 mg effervescent tablet, repeated every 6 hours as needed. The patient should not take more than 4 tablets (4000 mg paracetamol) in 24 hours. In patients with kidney or liver problems the dose should be decreased. The 1000 mg tablet should not, however, be divided into two equal doses to achieve a lower dose; Paracetamol tablets of lower strengths are available on the market to achieve a lower dose. Please read Section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration and the duration of treatment. Paracetamol 500 mg and 1000 mg effervescent tablets can be obtained without a prescription. What benefits of Paracetamol 500 mg and 1000 mg effervescent tablets have been shown in studies? Because Paracetamol 500 mg effervescent tablets are a generic medicine, studies in patients have been limited to determine that they are bioequivalent to the reference medicine, Panadol Soluble 500 mg Tablets. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. are in the form of an oral solution at the time of administration and contain the active substance, paracetamol, in the same concentration as a dose of two Paracetamol 500 mg effervescent tablets. It is considered that one Paracetamol 1000 mg effervescent tablet will be bioequivalent to two Paracetamol 500 mg effervescent tablets. What are the possible side effects from Paracetamol 500 mg and 1000 mg effervescent tablets? Like all medicines, these medicines can cause side effects, although not everybody gets them. For information about side effects that may occur when using Paracetamol 500 mg and 1000 mg effervescent tablets, please refer to the package leaflets or the Summaries of Product Characteristics (SmPCs) available on the Medicines and Healthcare products Regulatory Agency website. For a full list of restrictions, see the package leaflets. Why are Paracetamol 500 mg and 1000 mg effervescent tablets approved? The MHRA decided that the benefits of Paracetamol 500 mg and 1000 mg effervescent tablets outweigh the identified risks and it was recommended that they be approved for use. 3

4 What measures are being taken to ensure the safe and effective use of Paracetamol 500 mg and 1000 mg effervescent tablets? A Risk Management Plan (RMP) has been developed to ensure that Paracetamol 500 mg and 1000 mg effervescent tablets are used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics (SmPCs) and the package leaflets for Paracetamol 500 mg and 1000 mg effervescent tablets, 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 and healthcare professionals will be monitored and reviewed continuously as well. Other information about Paracetamol 500 mg and 1000 mg effervescent tablets Austria, Belgium, Bulgaria, Croatia, Cyprus, the Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Romania, Spain (1000 mg strength only), the Slovak Republic, Slovenia, Sweden and the UK agreed to grant Marketing Authorisations to Cipla (EU) Limited for Paracetamol 500 mg and 1000 mg effervescent tablets on 24 June The Marketing Authorisations in the UK were granted on 24 July The full PAR for Paracetamol 500 mg and 1000 mg effervescent tablets follows this summary. For more information about taking Paracetamol 500 mg and 1000 mg effervescent tablets, read the package leaflets or contact your doctor or pharmacist. This summary was last updated in October

5 Table of Contents I Introduction Page 6 II Quality aspects Page 8 III Non-clinical aspects Page 10 IV Clinical aspects Page 10 V User consultation Page 22 VI Overall conclusion, benefit/risk assessment and recommendation Page 23 Table of content of the PAR update for MRP and DCP Page 30 5

6 I Introduction Based on the review of the data on quality, safety and efficacy, the Member States have granted Marketing Authorisations (MAs) for the medicinal products Paracetamol 500 mg and 1000 mg effervescent tablets. Paracetamol 500 mg effervescent tablets are a general sales list medicine (legal status GSL), indicated for the symptomatic treatment of mild to moderate pain and/or fever in adults and adolescents aged 12 years and above. Owing to the GSL legal supply status in the UK, the marketing of Paracetamol 500 mg effervescent tablets is limited to a maximum of 30 tablets. are a pharmacy medicine (legal status P), indicated for the short term symptomatic treatment of mild to moderate pain and/or fever in adults and adolescents aged 16 years and above. These applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Austria, Belgium, Bulgaria, Croatia, Cyprus, the Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Romania, Spain (1000 mg strength only), the Slovak Republic, Slovenia and Sweden as Concerned Member States (CMSs). The application for Paracetamol 500 mg effervescent tablets was made under Article 10(1) of Directive 2001/83/EC, as amended, as a generic medicinal product (). The reference medicinal product, which has been authorised in accordance with Community provisions in force for not less than 10 years in the European Economic Area (EEA), is Panadol Soluble 500 mg Tablets (PL 00071/0072R). This product was authorised to SmithKline Beecham (SWG) Limited in the UK on 12 January The application for was made under Article 10(1) of Directive 2001/83/EC, as amended, as a generic medicinal product in Ireland and Spain on the basis of the existence of reference products from the GSK / Smithkline Beecham family for paracetamol 1000 mg effervescent tablets. In all the other member states, including the UK, the application for was submitted under Article 10(3) of Directive 2001/83/EC, as amended, as it is a new strength. Consequently, in accordance with the Coordination of Mutual Recognition and Decentralised procedures (CDMh) guidance (CMDh/089/2002) the overall legal basis for the 1000 mg strength () is Article 10. The active substance in Paracetamol 500 mg and 1000 mg effervescent tablets is paracetamol. Paracetamol is one of the most commonly used drugs for the safe and effective treatment of pain and fever. Paracetamol works by lowering cyclo-oxygenase products preferentially in the central nervous system, where oxidant stress is strictly limited. However, the precise mechanism of action for paracetamol on cyclo-oxygenase activity is not known. No new non-clinical studies were conducted, which is acceptable given that these applications are based on being generic and hybrid medicinal products of an originator product that has been licensed for over 10 years. Since Paracetamol 500 mg and 1000 mg effervescent tablets are intended to be used in place of other similar products, this will not lead to an increased exposure to the environment. An 6

7 Environmental Risk Assessment (ERA) is, therefore, not deemed necessary. With the exception of a bioequivalence study, no new clinical data were provided with these applications. One bioequivalence study was performed, which compared the pharmacokinetics of the applicant s Paracetamol 500 mg effervescent tablets with those of the reference product, Panadol Soluble 500 mg Tablets, in healthy subjects under fasting conditions. It is stated by the applicant that the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). In accordance with the CHMP Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), bioequivalence studies may be waived if the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution. The applicant has requested a biowaiver for as the active is in solution at the time of administration. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types at all sites responsible for the manufacture, assembly and batch release of these products. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports issued by the inspection services of the MHRA as certification that acceptable standards of GMP are in place at those non-community sites. A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been provided with these applications and these are satisfactory. The RMS and CMSs considered that the applications could be approved at the end of procedure (Day 210) on 24 June After a subsequent National phase, licences were granted in the UK on 24 July

8 II Quality aspects II.1 Introduction The applications are submitted according to Article 10 of Directive 2001/83/EC, as amended. The applicant has specified Panadol Soluble 500 mg Tablets (PL 00071/0072R) as the reference medicinal product. Paracetamol 500 mg effervescent tablets are formulated as white to off-white, circular, flat-faced, bevelled edge tablets, of diameter mm, debossed with a ring on one side and plain on the other. are formulated as white to off-white, circular, flat-faced, bevelled tablets, of diameter mm, plain on both sides. Each Paracetamol 500 mg and 1000 mg effervescent tablet contains 500 mg and 1000 mg of paracetamol, respectively. The excipients present are: anhydrous citric acid (E330), povidone, sodium bicarbonate (E500), sodium saccharin (E954), anhydrous sodium carbonate (E500), simeticone (E900), polysorbate 80 (E443) and aspartame (E951). Paracetamol 500 mg and 1000 mg effervescent tablets are packaged in 4-ply laminate-glassine paper/polythene/aluminium foil/polythene (PPFP) or 4-ply laminate-glassine paper/polythene/ aluminium foil/surlyn (Surlyn) strips, which are further packed into cardboard cartons of 8, 10, 12, 16, 20, 24, 32, 50, 60, 100 units for Paracetamol 500 mg effervescent tablets and 8, 10, 12, 16, 20, 32, 40, 50, 60, 100 units for Paracetamol 1000 mg effervescent tablets. Owing to the GSL legal supply status of Paracetamol 500 mg effervescent tablets in the UK, pack sizes of this product are limited to a maximum of 30 tablets and, therefore, the maximum approved pack size will be 24 tablets. II.2 Drug Substance Paracetamol INN: Chemical Name: Structure: Paracetamol N-(4-hydroxyphenyl) acetamide. Molecular formula: C 8 H 9 NO 2 Molecular weight: g/mol Appearance: white or almost white, crystalline powder Solubility: sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride. Paracetamol is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance, paracetamol, are covered by European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of Suitability. 8

9 II.3 Medicinal Product Pharmaceutical development The objective of pharmaceutical development was to produce an effervescent tablet comparable to the reference product Panadol Soluble 500mg Tablets (PL 00071/0072R). The development of was subsequently based in the Paracetamol 500 mg effervescent tablet. The development of the drug products has been described, the choice of excipients is justified and their functions explained. Comparative disintegration and assay analysis between batches of Paracetamol 500 mg and 1000 mg effervescent tablets and batches of the reference medicinal product, Panadol Soluble 500mg Tablets (PL 00071/0072R) were undertaken. The results were comparable. All the excipients used in the manufacture of the proposed formulation comply with their respective European Pharmacopoeia monographs. Satisfactory certificates of analysis have been provided for all excipients showing compliance with their proposed specifications. None of the excipients are sourced from animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these products. Manufacture of the product Satisfactory batch formulae have been provided for the manufacture of the finished products, together with an appropriate account of the manufacturing process. Satisfactory process validation was performed for the manufacturing process on six production-scale batches of Paracetamol 500 mg effervescent tablets and five production-scale batches of Paracetamol 1000 mg tablets. Product Specifications The finished product specifications are satisfactory. Satisfactory batch analysis data showing satisfactory compliance with the specifications have been presented. Certificates of analysis have been provided for all working standards used. Stability of the product Stability studies were performed in accordance with current guidelines on at least three batches of each strength of finished product, packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 3 years when stored in the original packaging in order to protect from light and moisture. The solutions are stable up to 8 hours, below 25 C, after dissolving the tablet. Suitable post approval stability commitments have been provided. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of Marketing Authorisations is recommended for these applications. 9

10 III Non-clinical aspects No new non-clinical studies have been submitted in support of these applications. The pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol are well-known. As paracetamol is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. A satisfactory non-clinical overview, based on a review of the literature, has been supplied. The non-clinical sections of the SmPCs have been updated in line with the QRD template and reflect the information in the reference product SmPC, which is acceptable. There are no objections to approval of Paracetamol 500 mg and 1000 mg effervescent tablets from a non-clinical point of view. Environmental Risk Assessment (ERA) Since Paracetamol 500 mg and 1000 mg effervescent tablets are intended to be used in place of other similar products, this will not lead to an increased exposure to the environment. An ERA is, therefore, not deemed necessary. IV Clinical aspects IV.1 Introduction The applications have been submitted under Article 10 according to Directive 2001/83/EC, as amended. With the exception of bioequivalence data for Paracetamol 500 mg effervescent tablets, no new clinical data was submitted with these applications and none are required. The applicant sought a biowaver of clinical studies for and this was accepted please see Section and IV.2. The applicant s clinical overview has been written by an appropriately qualified person and provides an adequate summary of published literature on the clinical pharmacology, efficacy and safety of paracetamol. This is considered acceptable. IV.2 Pharmacokinetics In support of these applications, the Marketing Authorisation holder has submitted the following bioequivalence study: Bioequivalence study comparing Paracetamol 500 mg effervescent tablets with Panadol Soluble 500 mg tablets in healthy adult human subjects under fasting conditions. This was an open label, randomised, two-treatment, two-period, two-sequence, single dose, crossover, bioequivalence study in healthy adult male human subjects under fasting conditions. The subjects received the test or reference treatment (a single oral dose of one tablet with 240 ml water at room temperature) after an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters pre-dose and up to 24 hours post-dose. The two treatment periods were separated by a 2-day washout period. 10

11 The main pharmacokinetic results are presented below: TestGeoLSM geometric least square mean for the test product (Paracetamol 500 mg effervescent tablets) RefGeoLSM geometric least square mean for the reference product (Panadol Soluble 500 mg tablets) The 90% confidence intervals were within the acceptance criteria of 80.00% %. Based on these results, the proposed product, Paracetamol 500 mg effervescent tablets, can be considered bioequivalent with the reference product Panadol Soluble 500 mg tablets. The applicant has requested a biowaiver for. According to the EMEA Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**) bioequivalence studies may be waived if the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution. Paracetamol 1000 mg effervescent tablets are in the form of an aqueous oral solution at the time of administration but there is no approved equivalent effervescent product with the same concentration of active substance. The dissolution profile of has been compared with that of Paracetamol 500 mg effervescent tablets and shown to be comparable, with 100% dissolution achieved in a few minutes. Furthermore, the applicant has provided suitable justification that the excipients do not affect the biopharmaceutical properties of the product. The justification for a biowaver is accepted. IV.3 Pharmacodynamics No new pharmacodynamic data are required and none have been submitted. The applicant s review of the literature in the clinical overview is acceptable. IV.4 Clinical efficacy No new clinical efficacy data are required and none have been submitted. The applicant s review of the literature in the clinical overview is acceptable. IV.5 Clinical safety With the exception of the bioequivalence study, no new data have been provided and none are required for these applications. No serious adverse events were reported during the bioequivalence study. Only one adverse event was reported during the study, which was of mild intensity and not drug-related. 11

12 IV.6 Risk Management Plan (RMP) The marketing authorisation holder has submitted an RMP, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Paracetamol 500 mg and 1000 mg effervescent tablets. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: 12

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22 Missing information V.7 Discussion on the clinical aspects The grant of Marketing Authorisations is recommended for these applications. V User consultation The patient leaflet for Paracetamol 500 mg effervescent tablets has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the package leaflet was English. 22

23 The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. A user consultation with target patient groups on the PIL for Paracetamol 1000 mg effervescent tablets has been performed on the basis of a bridging report making reference to Paracetamol 500 mg effervescent tablets. The bridging report submitted by the applicant has been found to be acceptable. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The applications contain an adequate review of published clinical data. The test product, Paracetamol 500 mg effervescent tablets, can be considered bioequivalent with the reference product, Panadol Soluble 500 mg tablets. A justification for a biowaver for has been accepted. The benefit/risk assessment is, therefore, considered to be positive. The Summaries of Product Characteristics (SmPCs), package leaflets and labelling are satisfactory, in line with current guidelines and consistent with the reference product. In accordance with Directive 2012/84/EU, the current approved UK versions of the SmPCs and package leaflets for these products are available on the Medicines and Healthcare products Regulatory Agency website. The currently approved labels are listed below: 23

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30 Table of content of the PAR update for MRP and DCP Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments) Scope Procedure number Product information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) 30