public assessment report ukpar co-codamol … · co-codamol 15mg/500mg capsules (codeine phosphate...

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Public Assessment Report

UKPAR

Co-codamol 15mg/500mg Capsules

(Codeine phosphate hemihydrate and paracetamol)

UK Licence Number: PL 27827/0037

Galen Limited.

PAR Co-codamol 15mg/500mg Capsules PL 27827/0037

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LAY SUMMARY

Co-codamol 15mg/500mg Capsules

(Codeine phosphate hemihydrate 15 mg, paracetamol 500 mg, capsules)

This is a summary of the Public Assessment Report (PAR) for Co-codamol 15mg/500mg Capsules (PL 27827/0037). It explains how Co-codamol 15mg/500mg Capsules 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 Co-codamol 15mg/500mg Capsules. For practical information about using Co-codamol 15mg/500mg Capsules, patients should read the package leaflet or contact their doctor or pharmacist. What are Co-codamol 15mg/500mg Capsules and what are they used for? Co-codamol 15mg/500mg Capsules are a medicine with ‘well established use’. This means that the medicinal use of the active substances, codeine phosphate hemihydrate and paracetamol, is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety. This medicine is used to relieve moderate pain. How do Co-codamol 15mg/500mg Capsules work? Co-codamol 15mg/500mg Capsules contain the active substances codeine phosphate hemihydrate and paracetamol. Codeine phosphate hemihydrate belongs to a group of medicines called opioid analgesics which act to relieve pain. Paracetamol relieves pain. Codeine can be used in children over 12 years of age for the short-term relief of moderate pain that is not relieved by other painkillers such as paracetamol or ibuprofen alone. How are Co-codamol 15mg/500mg Capsules used? The pharmaceutical form of Co-codamol 15mg/500mg Capsules is a hard capsule and the route of administration is oral (by mouth). The patient should always take this medicine exactly as their doctor or pharmacist has told them. The patient should check with their doctor or pharmacist if they are not sure. The recommended dose for adults and the elderly is one or two capsules taken every four hours. You should not take more than eight capsules in any 24-hour period. Use in children and adolescents The recommended dose for children aged 16 and over is one or two capsules taken every six hours. The patient should not take more than eight capsules in any 24-hour period. The recommended dose for children aged 12 to 15 years is one capsule taken every six hours, up to a maximum of four capsules in any 24-hour period. This medicine should not be taken by children below the age of 12 years, due to the risk of severe breathing problems. Co-codamol 15mg/500mg Capsules should be taken orally (by mouth).


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This medicine should only be taken when necessary. Do not take more than the stated dose and do not take for more than three days. If the pain does not improve after three days, the patient should talk to their doctor for advice. Please read section 3 of the package leaflet for detailed dosing recommendations, the route of administration, and the duration of treatment. This medicine can only be obtained with a prescription. What benefits of Co-codamol 15mg/500mg Capsules have been shown in studies? As codeine phosphate hemihydrate and paracetamol are well-known substances, and their use in the licenced indications is well established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of the use of codeine phosphate hemihydrate and paracetamol in the licensed indications. In addition, the company (Galen Limited) undertook a bioequivalence study to bridge their product to the information found in the bibliographic sources relating to the currently approved codeine phosphate hemihydrate and paracetamol-containing products. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. It was concluded from the study that Co-codamol 15mg/500mg Capsules are bioequivalent with respect to the extent and rate of absorption to another codeine phosphate hemihydrate and paracetamol-containing product already on the market called Kapake/Co-codamol 30mg/500mg Tablets (Galen Limited; PL 27827/0009). What are the possible side effects of Co-codamol 15mg/500mg Capsules? Like all medicines, Co-codamol 15mg/500mg Capsules can cause side effects, although not everybody gets them. For the full list of all side effects reported with Co-codamol 15mg/500mg Capsules, see section 4 of the package leaflet available on the MHRA website. Also, for the full list of restrictions, see the package leaflet. Why were Co-codamol 15mg/500mg Capsules approved? The MHRA concluded that, in accordance with EU requirements, the benefits of Co-codamol 15mg/500mg Capsules outweigh the identified risks and recommended that the product be approved for use. What measures are being taken to ensure the safe and effective use of Co-codamol 15mg/500mg Capsules? A risk management plan (RMP) has been developed to ensure that Co-codamol 15mg/500mg 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 Co-codamol 15mg/500mg 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/healthcare professionals will be monitored/reviewed continuously. Other information about Co-codamol 15mg/500mg Capsules The Marketing Authorisation for Co-codamol 15mg/500mg Capsules was granted in the UK on 06 March 2017.


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The full PAR for Co-codamol 15mg/500mg Capsules follows this summary. For more information about use of Co-codamol 15mg/500mg Capsules, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in March 2017.


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TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 9 IV Clinical aspects Page 9 V User consultation Page 13 VI Overall conclusion, benefit/risk assessment and

recommendation Page 13

Table of content of the PAR update Page 15


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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) granted Galen Limited a Marketing Authorisation for the medicinal product Co-codamol 15mg/500mg Capsules (PL 27827/0037) on 06 March 2017. The product is a prescription only medicine (POM) indicated for the relief of moderate pain. Codeine is indicated in patients older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen (alone). The application was submitted under Article 10a of Directive 2001/83/EC, as amended, claiming to be an application for a product containing active substances of well-established use. This application is a line extension of the existing national marketing authorisation (MA) for Kapake/Co-codamol 30mg/500mg Tablets (PL 27827/0009; Galen Limited), which was first approved in the UK on 03 March 1993. The MA holder of the existing licence is the same as proposed for this application, i.e. Galen Limited. The extension results in a product with:

• a different strength of codeine phosphate hemihydrate (15mg per capsule) in combination with 500mg paracetamol

• and a different immediate release pharmaceutical form (hard gelatin capsule). This is in accordance with the types of MA extension listed in Annex I of Commission Regulation (EC) No 1234/2008, as amended. The legal basis for the line extension application is Article 10a of Directive 2001/83/EC, as amended. This is consistent with the legal basis of the MA for Kapake/Co-codamol 30mg/500mg Tablets and hence in compliance with Article 19 of Regulation (EC) No 1234/2008. Paracetamol has analgesic and antipyretic effects that do not differ significantly from those of aspirin. Its anti-inflammatory action is weak and it has practically no anti-platelet effect. The mechanism of action is unclear, although it is believed to exert its action by inhibition of prostaglandin synthesis. Codeine is a centrally acting weak analgesic. Codeine exerts its effects through µ opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain. Bibliographic data on codeine and paracetamol have been submitted to support this application. No new non clinical studies were conducted for this application, which is acceptable given that this is a bibliographic application for a product containing active ingredients of well-established use. In addition to the submission of published non-clinical and clinical references the applicant has also performed a bioequivalence study (open-label, three-treatment, single-dose, randomised, cross-over study) to bridge their product to the information found in the bibliographic sources relating to a currently approved codeine and paracetamol containing product, Kapake/Co-codamol 30mg/500mg Tablets (Galen Limited; PL 27827/0009). The applicant has stated that the bioequivalence study was conducted in accordance with the Declaration of Helsinki (1964) as modified in Fortaleza (2013), the recommendations on Good Clinical Practice (ICH E6) and the national and local laws of the countries where study sites are located. The MHRA 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 and assembly of this product.


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II QUALITY ASPECTS II.1 Introduction Each hard capsule contains codeine phosphate hemihydrate 15 mg and paracetamol 500 mg. Other ingredients consist of the pharmaceutical excipients:

Magnesium stearate and sodium starch glycolate (type A) Capsule contents:

Cochineal red A (E124), brilliant blue (E133), titanium dioxide (E171) and gelatin. Capsule shell constituents:

Shellac glaze, propylene glycol and black iron oxide (E172). Overprint ink constituents:

The finished product is packed into polyvinyl chloride (PVC)/aluminium blisters and is available in pack sizes of 20, 60 and 100 capsules. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2 Drug Substances (1) Codeine phosphate hemihydrate INN: Codeine phosphate hemihydrate Chemical name: 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate

hemihydrate. Structure:

Molecular formula: C18H24NO7P,½H2O Molecular weight: 406.4 Appearance: White or almost white, crystalline powder or small, colourless crystals. Solubility: Freely soluble in water, slightly soluble or very slightly soluble in ethanol (96 per cent). Codeine phosphate hemihydrate is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance, codeine phosphate hemihydrate, are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. (2) Paracetamol INN: Paracetamol Chemical name: N-(4-Hydroxyphenyl)acetamide.


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Structure:

Molecular formula: C8H9NO2 Molecular weight: 151.2 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. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, hard capsules containing codeine phosphate hemihydrate 15 mg and paracetamol 500 mg per capsule. A satisfactory account of the pharmaceutical development has been provided. All excipients comply with their respective European Pharmacopoeia monographs with the exception of the capsule shell and overprint ink, which are controlled to suitable in-house specifications. Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data have been provided for each excipient. With the exception of gelatin, none of the excipients contain materials of animal or human origin. The suppliers of gelatin have provided Certificates of Suitability from the European Directorate for the Quality of Medicines and Healthcare (EDQM) to show that they are manufactured in line with current European guideline on minimising the 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 Satisfactory batch formulae have been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial scale batch size and has shown satisfactory results. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specification. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of the finished product in the packaging proposed for marketing. The data from these studies support a shelf life of 3 years with the storage recommendations: ‘Do not store above 30°C.’


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Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of this application from a pharmaceutical viewpoint. III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of codeine phosphate hemihydrate and paracetamol are well-known, no new non-clinical studies are required and none have been provided. An overview based on the literature review is, thus, appropriate. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. III.2 Pharmacology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.4 Toxicology Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above. III.5 Ecotoxicity/environmental risk assessment (ERA) Since this medicine is intended for substitution with other Co-codamol products that are currently marketed, no increase in environmental exposure to codeine phosphate hemihydrate and paracetamol is expected when this product is introduced to the market. An environmental risk assessment is therefore not deemed necessary. III.6 Discussion on the non-clinical aspects There are no objections to the approval of this application from a non-clinical viewpoint. IV CLINICAL ASPECTS IV.1 Introduction This is a national application for a MA for Co-codamol 15mg/500mg Capsules. The legal basis of this application is well-established use according to Article 10a of Directive 2001/83/EC as amended, supported by bibliographic literature. This application is a line extension of the existing national MA for Kapake/Co-codamol 30mg/500mg Tablets (PL 27827/0009; Galen Limited), which was first approved in the UK on 03 March 1993. One bioequivalence study was submitted to support this application. The study was designed to demonstrate that the test product, Co-codamol 15mg/500mg Capsules was bioequivalent to the currently approved codeine phosphate hemihydrate and paracetamol containing product, Kapake/Co-codamol 30mg/500mg Tablets (Galen Limited; PL 27827/0009) when the different codeine phosphate hemihydrate content has been taken into consideration. With the exception of the bioequivalence study, no new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature


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has been provided by the applicant, citing the well-established clinical pharmacology, efficacy and safety of codeine phosphate hemihydrate and paracetamol. The Applicant’s clinical overview has been written by an appropriately qualified person and is considered acceptable. IV.2 Pharmacokinetics The applicant submitted the following study:

A randomised, open-label, three-treatment, single dose, crossover study investigating the bioequivalence of Co-codamol 15mg/500mg Capsules (Galen Limited) with Kapake/Co-codamol 30mg/500mg Tablets (Galen Limited) in healthy subjects under fasting conditions.

STUDY

The three treatments to be administered during the study were as follows:

• Test 1: one capsule of test product containing 15mg codeine phosphate hemihydrate and 500mg paracetamol.

• Test 2: two capsules of test product, each containing 15mg codeine phosphate hemihydrate and 500mg paracetamol (i.e. a total dose of 30mg codeine phosphate hemihydrate and 1000mg paracetamol).

• Reference: one tablet of reference product containing 30mg codeine phosphate hemihydrate and 500mg paracetamol.

Subjects were administered a single oral dose of study drug Test 1, Test 2 or Reference with 240 mL of water following an overnight fast. Blood samples were collected for plasma levels before dosing and up to and including 36 hours after each administration. The washout period between the treatment phases was 7 days. The pharmacokinetic results are presented below:


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Study Conclusion The 90% confidence intervals of the test/reference ratio for AUC and Cmax values for paracetamol and codeine lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the applicant’s test product is bioequivalent with respect to the extent and rate of absorption to the reference product Kapake/Co-codamol 30mg/500mg Tablets (Galen Limited). IV.3 Pharmacodynamics No new pharmacodynamic data were submitted and none were required for an application of this type. IV.4 Clinical efficacy No new efficacy data were submitted and none were required for an application of this type. The clinical efficacy of codeine phosphate hemihydrate and paracetamol is well-established. Efficacy is adequately reviewed in the clinical overview. IV.5 Clinical safety No new safety data were submitted and none were required for this application. Safety is adequately reviewed in the clinical overview. The safety profiles of codeine phosphate hemihydrate and paracetamol are well-known. IV.6 Risk Management Plan (RMP) and Pharmacovigilance System The marketing authorisation holder (MAH) has submitted a risk management plan (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 Co-codamol 15mg/500mg Capsules. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below:


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Summary table of safety concerns:

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.


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IV.7 Discussion on the clinical aspects The grant of a marketing authorisation is recommended for this application. V User consultation A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Kapake 30mg/500mg Capsules/Co-Codamol 30mg/500mg Capsules (Galen Limited: PL 27827/0010). The bridging report submitted by the applicant is acceptable. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with codeine phosphate hemihydrate and paracetamol is considered to have demonstrated the therapeutic value of the compounds. The benefit-risk assessment is, therefore, considered to be positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for this medicine is presented below:


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Annex 1

Table of content of the PAR update

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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