CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 UKPAR TABLE OF CONTENTS

Transcription

1 CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 11 Steps taken after authorisation summary Page 12 Summary of Product Characteristics Page 13 Patient Information Leaflet Page 18 Labelling Page

2 CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency granted Bristol Laboratories Limited a Marketing Authorisation (licence) for the medicinal product Co-codamol 30mg/500mg Tablets (PL 17097/0235 on 23 rd May This is a prescription-only medicine (POM). Co-codamol 30mg/500mg Tablets contain two active ingredients-codeine and paracetamol both of which belong to a group of medicines called painkillers (analgesics). Co-codamol Tablets are a compound analgesic and are used to provide relief from severe pain. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Co-codamol 30mg/500mg Tablets outweigh the risks; hence a Marketing Authorisation has been granted

3 CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Preclinical assessment Page 8 Clinical assessment Page 9 Overall conclusions and risk benefit assessment Page

4 INTRODUCTION The UK granted a Marketing Authorisation for the medicinal product Co-codamol 30mg/500mg (PL 17907/0235) to Bristol Laboratories Limited on 23 rd May This product is a prescription-only medicine. This application was submitted as an abridged application according to Article 10(1) of Directive 2001/83/EC. The applications refer to the originator product, Solpadol 30mg/500mg Caplets (PL 11723/0071), authorised to Sanofi Aventis on 12 September The reference product has been authorised in the EEA for over 10 years. Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Paracetamol also exhibits antipyretic activity. Codeine is a centrally acting analgesic which produces its effect by its action at opioid-binding sites (µ-receptors) within the CNS. It is a full agonist. Co-codamol tablets are indicated in the relief of severe pain. The pharmacovigilance system, as described by the MAH, fulfils the requirements and provides adequate evidence that the MAH has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The MAH has provided adequate justification for not submitting a Risk Management Plan (RMP). As the application is for a generic version of an already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profile of the active is well established. No new pre-clinical or clinical studies were performed, which is acceptable given that the proposed product is a generic medicinal product of the reference product that have been licensed for over 10 years. No new or unexpected safety concerns arose during the review of information provided by the Marketing Authorisation Holder (MAH) and it was, therefore, judged that the benefits of taking product Co-codamol 30mg/500mg Tablets outweigh the risks; hence a Marketing Authorisation has been granted

5 PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE (1) Paracetamol INN: Paracetamol Ph Eur 500mg Chemical name: Paracetamol Acetaminophen N-Acetyl-p-aminophenol Paracetamolum 4 -hydroxyacetanilide N-(4-hydroxyphenyl)acetanilide Structure: Molecular mass: Molecular formula: C 8 H 9 N0 2 General Properties Description: White odourless crystalline powder. Paracetamol is the subject of a European Pharmacopoeia monograph (Ph Eur). Manufacture All aspects of the manufacture and control of the active substance paracetamol are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. DRUG SUBSTANCE (2) Codeine INN: Codeine phosphate hemihydrate Molecular mass: Molecular formula: C 18 H 21 NO 3 H 2 O - 5 -

6 General Properties Description: White odourless crystalline powder. Codeine is the subject of a European Pharmacopoeia monograph (Ph Eur). Manufacture 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 (EDQM) Certificate of Suitability. DRUG PRODUCT Description and Composition Co-codamol 30mg/500mg Tablets are presented as a white to off white capsule shaped biconvex uncoated plain tablets. Each tablet contains 30mg of codeine phosphate hemihydrate and 500mg of paracetamol. Other ingredients consist of pharmaceutical excipients, namely pregelatinised maize starch, microcrystalline cellulose, sodium starch glycollate Type A, sodium metabisulfite, and magnesium stearate. Appropriate justification for the inclusion of each excipient has been provided. All excipients used comply with their relevant European Pharmacopoeia (Ph. Eur) monographs. Satisfactory Certificates of Analysis have been provided for all excipients. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in or used in the manufacturing process of the proposed product. None of the excipients are sourced from genetically modified organisms. Pharmaceutical Development Details of the pharmaceutical development of the medicinal product have been supplied and are satisfactory. The objective was to develop robust, stable, generic formulation, bioequivalent to the innovator product Solpadol 30mg/500mg Caplets. Comparative impurity and dissolution profiles were provided for the test and reference products and were found to be similar. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls were considered appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted and are accepted. 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. Satisfactory batch analysis data are provided and comply with the release specification. Certificates of Analysis have been provided for any reference standards used

7 Container Closure System The finished product is presented in blisters composed of opaque polyvinylidene chloride (PVdC), polyvinyl (PVC) and aluminium which are packed with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 8, 10, 16, 20, 30, 32 and 100 tablets. The MA Holder (MAH) has stated that not all pack sizes may be marketed however, the MAH has committed to submitting the proposed packaging/labelling for any pack size before it is marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. In addition compliance with BS 8404 for child resistant containers has been confirmed. Stability Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 3 years has been set which is satisfactory. Storage conditions for the medicinal product in blister packs are as follows: Do not store above 25 o C and Store in the original package. Bioequivalence Study No bioequivalence studies have been submitted with this application; however; a suitable biowaiver, in accordance with CPMP guidelines, has been submitted and is acceptable. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The approved SmPCs, PILs and labelling are pharmaceutically acceptable. Mock-ups of the package leaflet and labelling have been provided. The labelling fulfils the statutory requirements for Braille. Expert Report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. The CV of the expert has been provided. Conclusion It is recommended that a Marketing Authorisation is granted for this application

8 PRECLINICAL ASSESSMENT This application was submitted as an abridged, application, according to Article 10.1 of Directive 2001/83/EC, as amended. The pharmacodynamic, pharmacokinetic and toxicological properties of co-codamol are well-known. Therefore, no further studies are required and the applicant has provided none. The pre-clinical overview was written by a suitably qualified person and is satisfactory. The curriculum vitae of the expert has been provided. A suitable justification has been provided for the non-submission of an environmental risk assessment

9 CLINICAL ASSESSMENT Pharmacokinetics To support this application the applicant has submitted a biowaiver. No further clinical data are required. Since co-codamol has a precedent for having been approved in the UK via well established use, a satisfactory biowaiver, in accordance with the CPMP Bioequivalence guideline, is accepted. The data supporting the biowaiver is satisfactory; no further clinical studies are required. Pharmacodynamics No new data have been submitted and none are required for an application of this type. Clinical efficacy No new data have been submitted and none are required for an application of this type. Clinical safety No new safety data have been submitted or required for this generic application. As cocodamol is a well-known product with an acceptable adverse event profile, this is satisfactory. Expert Report A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified physician. The curriculum vitae of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC and PIL are medically acceptable, and consistent with those for the reference product. The labelling is medically acceptable and in-line with current requirements. MAA form The MAA form is medically satisfactory. Conclusion There are no objections to approval of Co-codamol 30/500 Tablets from a clinical point of view

10 OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Co-codamol 30mg/500mg Tablets are 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 applicant s Co-codamol 30mg/500mg Tablets has been demonstrated to be a generic version of the reference product, Solpadol 30mg/500mg caplets, marketed by Sanofi Aventis (PL 11723/0071) which was approved in the UK on 12 September No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE The SmPCs and PILs are acceptable, and consistent with those for the reference product. The labelling is acceptable and in-line with current requirements. The package leaflet 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 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. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable, and no new preclinical or clinical safety concerns have been identified. The qualitative and quantitative assessment supports the claim that the applicant s Co-codamol 30mg/500mg Tablets and the reference product Solpadol 30mg/500mg Caplets (Sanofi Aventis) are interchangeable. Extensive clinical experience with paracetamol and codeine is considered to have demonstrated the therapeutic value of the active substances. The benefit:risk is, therefore, considered to be positive

11 CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 STEPS TAKEN FOR ASSESMENT 1 The MHRA received the marketing authorisation application on 28 January Following standard checks and communication with the applicant the MHRA considered the application valid on 4 February Following assessment of the applications the MHRA requested further information relating to the quality dossiers on 12 September 2008, 11 August 2010 and 17 February The applicant responded to the MHRA s requests, providing further information on the quality dossier on 21 May 2010, 30 November 2010 and 11 April The application was determined on 23 May

12 CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 STEPS TAKEN AFTER AUTHORISATION - SUMMARY Date submitted Application type Scope Outcome

13 CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 SUMMARY OF PRODUCT CHARACTERISTICS The UK Summary of Product Characteristics (SmPC) for Co-codamol 30mg/500mg Tablets (PL 17907/0235) is as follows: 1 NAME OF THE MEDICINAL PRODUCT Co-codamol 30mg/500mg Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains Codeine Phosphate Hemihydrate 30mg and Paracetamol 500mg. (as the active ingredients). Each Co-codamol 30mg/500mg Tablet contains mg of sodium. For the full list of excipients, see Section PHARMACEUTICAL FORM Tablets White to off white capsule shaped biconvex uncoated plain tablets 4 CLINICAL PARTICULARS 4.1 Therapeutic indications For the relief of severe pain. 4.2 Posology and method of administration Adults: Two tablets not more frequently than every 4 hours, up to a maximum of 8 tablets in any 24 hour period. Elderly: As adults, however a reduced dose may be required. See warnings. Children: Not recommended for children under 12 years of age. Co-codamol tablets are for oral administration. 4.3 Contraindications Hypersensitivity to paracetamol or codeine or sodium metabisulfite which is rare. Hypersensitivity to any of the other constituents. Conditions where morphine and opioids are contraindicated e.g: Acute asthma Respiratory depression Acute alcoholism Head injuries Raised intra-cranial pressure Following biliary tract surgery Monoamine oxidase inhibitor therapy, concurrent or within 14 days. 4.4 Special warnings and precautions for use Each Co-codamol 30mg/500mg Tablet contains mg of sodium. This sodium content should be taken into account when prescribing for patients in whom sodium restriction is indicated. Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastrointestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy and

14 those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated. Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease. Patients should be advised not to exceed the recommended dose and not take other paracetamol containing products concurrently. Keep the product out of the reach and sight of children. The risk-benefit of continued use should be assessed regularly by the prescriber. The leaflet will state in a prominent position in the 'before taking' section: Do not take for longer than directed by your prescriber. Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets. Taking a pain killer for headaches too often or for too long can make them worse. The label will state (To be displayed prominently on outer pack (not boxed) : Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction. 4.5 Interaction with other medicinal products and other forms of interaction Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance. 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 use of paracetamol with increased risk of bleeding; occasional doses have no significant effect. The effects of CNS depressants (including alcohol) may be potentiated by codeine. 4.6 Pregnancy and lactation There is inadequate evidence of the safety of codeine in human pregnancy, but there is epidemiological evidence for the safety of paracetamol. Both substances have been used for many years without apparent ill consequences and animal studies have not shown any hazard. Nonetheless careful consideration should be given before prescribing the products for pregnant patients. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers. Paracetamol is excreted in breast milk but not in a clinically significant amount. 4.7 Effects on ability to drive and use machines Patients should be advised not to drive or operate machinery if affected by dizziness or sedation. 4.8 Undesirable effects Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, lightheadedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine. Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. Regular prolonged use of codeine/dhc is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped. Prolonged use of a painkiller for headaches can make them worse. Very rare occurrence of pancreatitis

15 4.9 Overdose Codeine The effects of Codeine overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely. Management Management should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg. Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken. Paracetamol 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 carbamazepine, 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 deplete 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. Treatment 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 alternative for remote areas, outside hospital. Management of patients who present with severe hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or or a liver unit. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Anilides, Paracetamol combinations

16 ATC Code: NO2B E51 Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in the CNS rather than the periphery appears to be more sensitive to it. This may explain paracetamol's lack of appreciable anti-inflammatory activity. Paracetamol also exhibits antipyretic activity. Codeine is a centrally acting analgesic which produces its effect by its action at opioid-binding sites (m-receptors) within the CNS. It is a full agonist. 5.2 Pharmacokinetic properties Following oral administration of two tablets (ie, a dose of paracetamol 1000mg and codeine 60mg) the mean maximum plasma concentrations of paracetamol and codeine were 15.96mg/ml and 212.4ng/ml respectively. The mean times to maximum plasma concentrations were 0.88 hours for paracetamol and 1.05 hours for codeine. The mean AUC for the 9 hours following administration was 49.05mg.ml -1.h for paracetamol and ng/ml -1.h for codeine. The bioavailabilities of paracetamol and codeine when given as the combination are similar to those when they are given separately. 5.3 Preclinical safety data There are no preclinical data of relevance which are additional to that already included in other sections of the SPC. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Pregelatinised maize starch Microcrystalline cellulose Sodium starch glycollate Type A Sodium metabisulfite Magnesium stearate 6.2 Incompatibilities None known 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 25 o C. Store in the original package. 6.5 Nature and contents of container Opaque PVDC (40gsm) coated PVC and 20µm aluminium laminated to 15µm PVC blisters, which are placed in an outer carton along with leaflet. The pack size in which the product may be packed are 8 s, 10 s, 16 s, 20 s, 30 s 32 s and 100 s tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7 MARKETING AUTHORISATION HOLDER Bristol Laboratories Ltd, Unit 3, canalside, Northbridge Road, Berkhamsted,

17 Herts, HP4 1EG 8 MARKETING AUTHORISATION NUMBER(S) PL 17907/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 23/05/ DATE OF REVISION OF THE TEXT 23/05/

18 PATIENT INFORMATION LEAFLET

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20 CARTON CO-CODAMOL 30MG/500MG TABLETS PL 17907/0235 BLISTER