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Public Assessment Report

Decentralised Procedure

Paracetamol 500 mg capsules, soft

Procedure No: UK/H/5685/001/DC

UK Licence No: PL 14338/0008

Patheon Softgels B.V. (Trading as Banner Pharmacaps Europe)

Paracetamol 500 mg, capsules soft UK/H/5685/001/DC

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Lay Summary Paracetamol 500 mg, capsules soft

(paracetamol) This is a summary of the public assessment report (PAR) for Paracetamol 500 mg, capsules soft (PL 14338/0008; UK/H/5685/001/DC). Paracetamol 500 mg, capsules soft will be referred to as Paracetamol 500 mg capsules throughout this report, for ease of reading. It explains how the application for Paracetamol 500 mg capsules was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Paracetamol 500 mg capsules. For practical information about using Paracetamol 500 mg capsules, patients should read the package leaflet or contact their doctor or pharmacist. What are Paracetamol 500 mg capsules and what are they used for? Paracetamol 500 mg capsules are a generic medicine. This means that they are similar to a ‘reference medicine’, already authorised in the European Union (EU), specifically France, called Panadol 500 mg comprimé pelliculé sécable (Marketing Authorisation number: 34009 340 330 7 0). Paracetamol 500 mg capsules are used for the relief of headache, tension headache, migraine, backache, rheumatic and muscular pain, toothache and period pain. Paracetamol 500 mg capsules also relieve a sore throat, and the fever, aches and pains of colds and flu, and are recommended for the relief of pain due to mild arthritis. How do Paracetamol 500 mg capsules work? Paracetamol 500 mg capsules contain the active substance paracetamol. Paracetamol is an analgesic and antipyretic, which relieves aches and pains, 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 capsules used? Paracetamol 500 mg capsules should be taken by mouth. The recommended dose in children aged 12 to 15 years is one Paracetamol 500 mg capsule every 4 to 6 hours, as needed. The patient should not take more than 6 capsules in 24 hours. The recommended dose in adults and children 16 years and over is two Paracetamol 500 mg capsules every 4 hours, as needed. The patient should not take more than 8 capsules in 24 hours. 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 capsules can be obtained without a prescription. What benefits of Paracetamol 500 mg capsules have been shown in studies? Because Paracetamol 500 mg capsules are a generic medicine, studies in patients have been limited to determine that they are bioequivalent to the reference medicine, Panadol 500 mg comprimé pelliculé sécable. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are the possible side effects from Paracetamol 500 mg capsules? Because Paracetamol 500 mg capsules are a generic medicine and are bioequivalent to the


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reference medicine, their benefits and possible side effects are taken as being the same as the reference medicine. For information about side effects that may occur when using Paracetamol 500 mg capsules, please refer to the package leaflet or the Summary of Product Characteristics (SmPC) available on the Medicines and Healthcare products Regulatory Agency website. Why are Paracetamol 500 mg capsules approved? It was concluded that, in accordance with EU requirements, Paracetamol 500 mg capsules have been shown to have comparable quality and to be bioequivalent to Panadol 500 mg comprimé pelliculé sécable. The MHRA decided that, as for Panadol 500 mg comprimé pelliculé sécable, the benefits of Paracetamol 500 mg capsules outweigh the identified risks and it was recommended that they be approved for use. What measures are being taken to ensure the safe and effective use of Paracetamol 500 mg capsules? A Risk Management Plan (RMP) has been developed to ensure that Paracetamol 500 mg capsules are used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics (SmPC) and the package leaflet for Paracetamol 500 mg capsules, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore, new safety signals reported by patients and healthcare professionals will be monitored and reviewed continuously as well. Other information about Paracetamol 500 mg capsules France and the UK agreed to grant a Marketing Authorisation to Patheon softgells B.V., trading as Banner Pharmacaps Europe, for Paracetamol 500 mg capsules on 05 August 2015. The Marketing Authorisation in the UK was granted on 27 August 2015. The full PAR for Paracetamol 500 mg capsules follows this summary. For more information about taking Paracetamol 500 mg capsules, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in October 2015.


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Table of Contents

I Introduction Page 5 II Quality aspects Page 7 III Non-clinical aspects Page 9 IV Clinical aspects Page 9 V User consultation Page 14 VI Overall conclusion, benefit/risk assessment and

recommendation Page 14

Table of content of the PAR update for MRP and DCP

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I Introduction Based on the review of the data on quality, safety and efficacy, the Member States have granted a Marketing Authorisation (MA) for the medicinal product Paracetamol 500 mg capsules. Paracetamol 500 mg capsules are a Pharmacy medicine (legal status P), indicated for the treatment of most painful and febrile conditions, for example, headache including migraine and tension headaches, toothache, backache, rheumatic and muscle pains, dysmenorrhoea, sore throat, and for relieving the fever, aches and pains of colds and flu. Paracetamol 500 mg capsules are also recommended for the symptomatic relief of pain due to non-serious arthritis. The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and France as a Concerned Member State (CMS). The application for Paracetamol 500 mg capsules was made under Article 10(1) of Directive 2001/83/EC, as amended, as a generic medicinal product (UK/H/5685/001/DC). 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 500 mg comprimé pelliculé sécable (MA number: 34009 340 330 7 0). This product was authorised to Glaxosmithkline santé grand public in France on 09 February 1996. The UK reference product is Panadol original tablets, which was authorised to SmithKline Beecham (SWG) Limited, in the UK, on 29 May 1984 (PL 00071/5074R). The active substance in Paracetamol 500 mg capsules is paracetamol. Paracetamol is one of the most commonly used drugs for the temporary relief 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 this application is based on being a generic medicinal product of a reference product that has been licensed for over 10 years. Since Paracetamol 500 mg capsules are intended to be used in place of other similar products, this will not lead to an increased exposure to the environment. An Environmental Risk Assessment (ERA) is, therefore, not deemed necessary. With the exception of a bioequivalence study, no new clinical data were provided with this application. One bioequivalence study was performed, which compared the pharmacokinetics of the applicant’s Paracetamol 500 mg capsules with those of the reference product, Panadol 500 mg comprimé pelliculé sécable, 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). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture, assembly and batch release of this product.


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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. A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been provided with this application and these are satisfactory. The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 05 August 2015. After a subsequent National phase, a licence was granted in the UK on 27 August 2015.


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II Quality aspects II.1 Introduction The application is submitted according to Article 10(1) of Directive 2001/83/EC, as amended. The applicant has specified Panadol 500 mg comprimé pelliculé sécable (MA number: 34009 340 330 7 0) as the reference medicinal product. Paracetamol 500 mg capsules are formulated as white, oblong soft gelatin capsules with a logo printed in black ink. Each Paracetamol 500 mg capsule contains 500 mg of paracetamol. The excipients present in the main formulation are: macrogol, purified water, propylene glycol, povidone and colloidal anhydrous silica. The excipients present in the capsule shell are: gelatin, partially dehydrated liquid sorbitol, purified water, glycerol and titanium dioxide (E171). The excipients present in the capsule printing ink are: black iron oxide, propylene glycol and hypromellose. Paracetamol 500 mg capsules are presented in polyvinylidene chloride (PVdC)/polyvinyl chloride (PVC)/aluminium/polyethylene terephthalate (PET) blisters, which are further packed into cardboard cartons of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 or 32 capsules. Not all pack sizes may be marketed. II.2 Drug Substance Paracetamol INN: Paracetamol Chemical Name: N-(4-hydroxyphenyl) acetamide. Structure:

Molecular formula: C8H9NO2 Molecular weight: 151.2 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 a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.

http://www.pharmacopoeia.co.uk/bp2015updated/ixbin/bp.cgi?a=imagezoom&file=bp2015_v2_11_medicinal_and_pharmaceutical_substances_04/large/paracetamol_cf0049-b.png�


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II.3 Medicinal Product Pharmaceutical development The objective of pharmaceutical development was to produce a liquid filled capsule formulation which would be comparable to the reference product Panadol 500 mg comprimé pelliculé sécable. The development of the drug product has been described and is satisfactory. A bioequivalence study has been provided to support the application. This is discussed in Section IV.2 Pharmacokinetics. Comparative dissolution between batches of Paracetamol 500 mg capsules and batches of the reference medicinal product, Panadol 500 mg comprimé pelliculé sécable were undertaken. The results were comparable. All the excipients used in the manufacture of the proposed formulation, with the exception of the printing ink, comply with their respective European Pharmacopoeia monographs. The printing ink complies with a satisfactory in-house specification. None of the excipients are sourced from animal or human origin, except for gelatin. The suppliers of gelatin have provided certificates of suitability from the European Directorate for the Quality of Medicines and Healthcare (EDQM) to show that it is manufactured in line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE). No genetically modified organisms (GMO) have been used in the preparation of this product. Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the finished product, together with an appropriate account of the manufacturing process. A satisfactory process validation protocol has been provided. A commitment has been provided to validate the first three production-scale batches. Product Specifications The finished product specification is satisfactory. Satisfactory batch analysis data showing satisfactory compliance with the specification 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 three batches of the finished product, packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 18 months when stored below 25°C and in the original packaging in order to protect from moisture. Suitable post approval stability commitments have been provided. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of a Marketing Authorisation is recommended for this application.


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III Non-clinical aspects No new non-clinical studies have been submitted in support of this application. 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 SmPC are in line with the information in the reference product SmPC, which is acceptable. There are no objections to approval of Paracetamol 500 mg capsules from a non-clinical point of view. Environmental Risk Assessment (ERA) Since Paracetamol 500 mg capsules 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 application has been submitted under Article 10(1) according to Directive 2001/83/EC, as amended. With the exception of bioequivalence data for Paracetamol 500 mg capsules, no new clinical data was submitted with this application and none was required. 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 this application, the Marketing Authorisation holder has submitted the following bioequivalence study: An open, single-dose, randomised, crossover bioequivalence study of two paracetamol preparations after oral administration of 500 mg in healthy volunteer s 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 (Paracetamol 500 mg capsules) or reference (Panadol 500 mg comprimé pelliculé sécable) treatment (a single oral dose of one capsule) after an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters pre-dose and up to 12 hours post-dose. The two treatment periods were separated by a 5-day washout period.


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The main pharmacokinetic results are presented below: Parameter Geometric

Mean Ratio T/R

Lower Confidence

Limit

Upper Confidence

Limit

Level of Confidence

Intra-subject CV (%)

AUC(0-t)

Cmax 0.9893 1.0088

0.9626 0.9261

1.0166 1.0988

0.9000 0.9000

6.4 20.4

The 90% confidence intervals were within the acceptance criteria of 80.00%-125.00%. Based on these results, the proposed product, Paracetamol 500 mg capsules, can be considered bioequivalent with the reference product Panadol 500 mg comprimé pelliculé sécable. 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 No new clinical safety data have been provided and none are required for this application.


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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 capsules. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is listed below:


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V.7 Discussion on the clinical aspects The grant of a Marketing Authorisation is recommended for this application. V User consultation The patient leaflet for Paracetamol 500 mg capsules 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, as amended. The language used for the purpose of user testing the package leaflet was English. 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. VI Overall conclusion, benefit/risk assessment and recommendation The quality of Paracetamol 500 mg capsules is acceptable, and no new non-clinical or clinical safety concerns have been identified. The application contains an adequate review of published clinical data. The test product, Paracetamol 500 mg capsules, can be considered bioequivalent with the reference product, Panadol 500 mg comprimé pelliculé sécable. The benefit/risk assessment is, therefore, considered to be positive. The Summary of Product Characteristics (SmPC), package leaflet 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 SmPC and package leaflet for this product are available on the Medicines and Healthcare products Regulatory Agency website. The currently approved labels are listed below:


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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)

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